Protein misfolding has been shown to be the direct cause of a number of highly devastating diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob syndrome, affecting the aging population globally. The deposition in tissues of amyloid fibrils is a characteristic of all these diseases, and the mechanisms by which these protein aggregates form continue to be intensively investigated. In only a fraction of cases is an underlying mutation responsible, and accordingly, what initiates amyloid formation in vivo is the major question that is addressed. In this study, we show that membranes containing phosphatidylserine (PS), a negatively charged phospholipid, induce a rapid formation of fibers by a variety of proteins, viz., lysozyme, insulin, glyceraldehyde-3-phosphate dehydrogenase, myoglobin, transthyretin, cytochrome c, histone H1, and alpha-lactalbumin. Congo red staining of these fibers yields the characteristic light green birefringence of amyloid, and fluorescent lipid tracers further reveal them to include phospholipids. Our results suggest that PS as well as other acidic phospholipids could provide the physiological low-pH environment on cellular membranes, enhancing protein fibril formation in vivo. Interestingly, all the proteins mentioned above either are cytotoxic or induce apoptosis. PS-protein interaction could be involved in the mechanism of cytotoxicity of the aggregated protein fibrils, perturbing membrane functions. Importantly, our results suggest that this process induced by acidic phospholipids may provide an unprecedented and generic connection between three current major areas of research: (i) mechanism(s) triggering amyloid formation, (ii) cytotoxicity of amyloidal protein aggregates, and (iii) mechanism(s) of action of cytotoxic proteins.

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Cone-beam CT technology with new design and flexible gantry movements allows both supine and weight-bearing imaging of the lower extremities, with a reasonable radiation dose and excellent image quality. Weight-bearing CT of joints can provide important new clinical information in musculoskeletal radiology.

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We have compared three different methods of treating symptomatic non-traumatic tears of the supraspinatus tendon in patients above 55 years of age. A total of 180 shoulders (173 patients) with supraspinatus tendon tears were randomly allocated into one of three groups (each of 60 shoulders); physiotherapy (group 1), acromioplasty and physiotherapy (group 2) and rotator cuff repair, acromioplasty and physiotherapy (group 3). The Constant score was assessed and followed up by an independent observer pre-operatively and at three, six and twelve months after the intervention. Of these, 167 shoulders were available for assessment at one year (follow-up rate of 92.8%). There were 55 shoulders in group 1 (24 in males and 31 in females, mean age 65 years (55 to 79)), 57 in group 2 (29 male and 28 female, mean age 65 years (55 to 79)) and 55 shoulders in group 3 (26 male and 29 female, mean age 65 years (55 to 81)). There were no between-group differences in the Constant score at final follow-up: 74.1 (sd 14.2), 77.2 (sd 13.0) and 77.9 (sd 12.1) in groups 1, 2 and 3, respectively (p = 0.34). The mean change in the Constant score was 17.0, 17.5, and 19.8, respectively (p = 0.34). These results suggest that at one-year follow-up, operative treatment is no better than conservative treatment with regard to non-traumatic supraspinatus tears, and that conservative treatment should be considered as the primary method of treatment for this condition.

Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

Fluorescent derivatives of phosphatidyl inositol (PtdIns)-(4,5)-P 2 were synthesized and used to test the effects of the PtdIns-(4,5)-P 2 -regulated proteins gelsolin, tau, cofilin, and profilin on labeled PtdIns-(4,5)-P 2 that was either in micellar form or mixed with phosphatidylcholine (PtdCho) in bilayer vesicles. Gelsolin increased the fluorescence of 7-nitrobenz-2-oxa-1,3-diazole (NBD)-or pyrene-labeled PtdIns-(4,5)-P 2 and NBD-PtdIns-(3,4,5)-P 3 . Cofilin and profilin produced no detectable change at equimolar ratios to PtdIns-(4,5)-P 2 , while tau decreased NBD-PtdIns-(4,5)-P 2 fluorescence. Fluorescence enhancement by gelsolin of NBD-PtdIns-(4,5)-P 2 in mixed lipid vesicles depended on the mole fraction of PtdIns-(4,5)-P 2 in the bilayer. Specific enhancement of 3% NBD-PtdIns-(4,5)-P 2 : 97% PtdCho was much lower than that of 10% PtdIns-(4,5)-P 2 : 90% PtdCho, but the enhancement of 3% NBD-PtdIns-(4,5)-P 2 could be increased by addition of 7% unlabeled PtdIns-(4,5)-P 2 . The gelsolin-dependent increase in NBD-PtdIns-(4,5)-P 2 fluorescence was reversed by addition of Ca 2+ or G-actin. Significant, but weaker, fluorescence enhancement was observed with the gelsolin N-terminal domain (residues 1±160) and a peptide comprised of gelsolin residues 150±169. Fluorescence energy transfer from gelsolin to pyrene-PtdIns-(4,5)-P 2 was much stronger with intact gelsolin than the N-terminal region of gelsolin containing the PtdIns-(4,5)-P 2 binding sites, suggesting that PtdIns-(4,5)-P 2 may bind near a site formed by the juxtaposition of the N-and C-terminal domains of gelsolin.Keywords: phosphatidylinositol bisphosphate; gelsolin; tau; profilin; cofilin.The regulation of cytosolic or cytoskeletal protein function by membrane-bound inositol phospholipids has been documented in several cases, and experimental manipulation of cellular phosphoinositide levels has a profound and specific effect on the actin cytoskeleton [1,2]. The reversible effects of inositol lipids on actin regulatory proteins such as gelsolin, profilin, cofilin, and a-actinin provide a set of reactions to cellular stimuli by which cytoskeletal reorganization may occur (reviewed in [3,4]).For practical reasons, most experiments with gelsolin and other proteins in vitro have employed micelles of purified phosphatidylinositol (PtdIns)-(4,5)-P 2 as this is the most abundant polyphosphoinositide. Such highly phosphorylated lipids generally form nonbilayer phases in aqueous solution [5,6], simplifying their preparation and use in vitro. In cells, however, inositol lipids are presumed to be primarily in bilayer membranes, and different forms of inositol lipids have different effects on actin binding proteins. Therefore, a growing number of studies have also examined protein±lipid interactions using other phosphoinositide species [e.g. PtdIns-(3)-P, PtdIns-(3,4)-P 2 , PtdIns-(3,4,5)-P 3 ] in either micellar form or mixed with other phospholipids into bilayer vesicles. In the case of both gelsolin and profilin such studies have shown a stronger effect of lip...

Background and purposeThe clinical findings of adverse reaction to metal debris (ARMD) following large-diameter-head metal-on-metal total hip arthroplasty (LDH MoM THA) may include periarticular fluid collections, soft tissue masses, and gluteal muscle necrosis. The ReCap-M2a-Magnum LDH MoM THA was the most commonly used hip device at our institution from 2005 to 2012. We assessed the prevalence of and risk factors for ARMD with this device.Methods74 patients (80 hips) had a ReCap-M2a-Magnum LDH MoM THA during the period August 2005 to December 2006. These patients were studied with hip MRI, serum chromium and cobalt ion measurements, the Oxford hip score questionnaire, and by clinical examination. The prevalence of ARMD was recorded and risk factors for ARMD were assessed using logistic regression models. The mean follow-up time was 6.0 (5.5–6.7) years.ResultsA revision operation due to ARMD was needed by 3 of 74 patients (3 of 80 hips). 8 additional patients (8 hips) had definite ARMD, but revision was not performed. 29 patients (32 hips) were considered to have a probable or possible ARMD. Altogether, 43 of 80 hips had a definite, probable, or possible ARMD and 34 patients (37 hips) were considered not to have ARMD. In 46 of 78 hips, MRI revealed a soft tissue mass or a collection of fluid (of any size). The symptoms clicking in the hip, local hip swelling, and a feeling of subluxation were associated with ARMD.InterpretationARMD is common after ReCap-M2a-Magnum total hip arthroplasty, and we discourage the use of this device. Asymptomatic patients with a small fluid collection on MRI may not need instant revision surgery but must be followed up closely.