Comparison of two computer-automated procedures for tinnitus pitch matching.

Clinical assessment of the perceptual characteristics of tinnitus usually includes an attempt to match the pitch of tinnitus to a pure tone. A standardized clinical protocol for tinnitus pitch matching does not yet exist, and there is a history of unsuccessful attempts to obtain such measures reliably. The present study was designed to evaluate new protocols for identifying the perceived pitch of tinnitus, with the objectives of reducing testing time and improving test-retest reliability. Two protocols ("Octave" and "Binary") were developed, each of which was patterned after the testing procedure previously developed at the Oregon Tinnitus Clinic and used to assess thousands of tinnitus patients. Both protocols use computer-automation to conduct testing; the protocols differ according to their specific testing algorithms. Twenty subjects with nonfluctuating tinnitus were each tested over two sessions. Results of testing revealed that both protocols could obtain pitch matches within 20 to 25 min. Reliability of responses was good for some subjects but not others, and the Binary protocol generally provided more reliable results.     

Inflammatory and degenerative phases resulting from anterior cruciate rupture in a non‐invasive murine model of post‐traumatic osteoarthritis

Joint injury is the predominant risk factor for post‐traumatic osteoarthritis development (PTOA). Several non‐invasive mouse models mimicking human PTOA investigate molecular mechanisms of disease development; none have characterized the inflammatory response to this acute traumatic injury. Our aim was to characterize the early inflammatory phase and later degenerative component in our in vivo non‐invasive murine model of PTOA induced by anterior cruciate ligament (ACL) rupture. Right knees of 12‐week‐old C57Bl6 mice were placed in flexion at a 30° offset position and subjected to a single compressive load (12N, 1.4 mm/s) to induce ACL rupture with no obvious damage to surrounding tissues. Tissue was harvested 4 h post‐injury and on days 3, 14, and 21; contralateral left knees served as controls. Histological, immunohistochemical, and gene analyzes were performed to evaluate inflammatory and degenerative changes. Immunohistochemistry revealed time‐dependent expression of mature (F4/80 positive) and inflammatory (CD11b positive) macrophage populations within the sub‐synovial infiltrate, developing osteophytes, and inflammation surrounding the ACL in response to injury. Up‐regulation of genes encoding acute pro‐inflammatory markers, inducible nitric oxide synthase, interleukin‐6 and interleukin‐17, and the matrix degrading enzymes, ADAMTS‐4 and MMP3 was detected in femoral cartilage, concomitant with extensive cartilage damage and bone remodelling over 21‐days post‐injury. Our non‐invasive model describes pathologically distinct phases of the disease, increasing our understanding of inflammatory episodes, the tissues/cells producing inflammatory mediators and the early molecular changes in the joint, thereby defining the early phenotype of PTOA. This knowledge will guide appropriate interventions to delay or arrest disease progression following joint injury. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:2118–2127, 2018.     

In vitro activities of 2,4-diaminoquinazoline and 2,4-diaminopteridine derivatives against Plasmodium falciparum

The activities of 28 6-substituted 2,4-diaminoquinazolines, 2,4-diamino-5,6,7,8-tetrahydroquinazolines, and 2,4-diaminopteridines against Plasmodium falciparum were tested. The 50% inhibitory concentrations (IC(50)s) of six compounds were <50 nM, and the most potent compound was 2,4-diamino-5-chloro-6-[N-(2,5-dimethoxybenzyl)amino]quinazoline (compound 1), with an IC(50) of 9 nM. The activity of compound 1 was potentiated by the dihydropteroate synthase inhibitor dapsone, an indication that these compounds are inhibitors of dihydrofolate reductase. Further studies are warranted to assess the therapeutic potential of this combination in vivo.     

Phenotypic resistance of Staphylococcus aureus, selected Enterobacteriaceae, and Pseudomonas aeruginosa after single and multiple in vitro exposures to ciprofloxacin, levofloxacin, and trovafloxacin

The phenotypic resistance of selected organisms to ciprofloxacin, levofloxacin, and trovafloxacin was defined as a MIC of > or =4 microg/ml. The dynamics of resistance were studied after single and sequential drug exposures: clinical isolates of methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa were utilized. After a single 48-h exposure of a large inoculum to four times the initial MIC for the organism, the frequency of selection of resistant mutants of MSSA was greater for trovafloxacin than levofloxacin (P = 0.008); for E. cloacae, the frequency was highest for ciprofloxacin and lowest for levofloxacin and trovafloxacin; for S. marcescens, the frequency was highest for trovafloxacin and lowest for ciprofloxacin (P = 0.003). The results of serial passage experiments were analyzed both by the Kaplan-Meier product-limited method as well as by analysis of variance of mean inhibitory values. By both methods, MSSA and MRSA expressed mutants resistant to ciprofloxacin after fewer passages than were required for either levofloxacin or trovafloxacin. For the aerobic gram-negative bacilli, two general patterns emerged. Mutants resistant to trovafloxacin appeared sooner and reached higher mean MICs than did mutants resistant to levofloxacin or ciprofloxacin. Mutants resistant to ciprofloxacin appeared later and reached mean MICs lower than the MICs of the other two drugs studied. Even though individual strain variation occurred, the mean MICs were reproduced when the serial passage experiment was repeated using an identical panel of E. coli isolates. In summary, the dynamic selection of fluoroquinolone-resistant bacteria can be demonstrated in experiments that employ serial passage of bacteria in vitro.     

The ethics of mandatory elder abuse reporting statutes

The ethics of mandatory elder abuse reporting statutes are analyzed in terms of beneficence, autonomy, and nonmaleficence. The statutes, based on the ethical principle of beneficence, are now the law in 37 states. However, evidence to support that the statutes actually fulfill rules derived from beneficence is weak. As a result, the strength of rules derived from autonomy and nonmaleficence, already strong within nursing, is increased, and potential conflicts between the rules to remove harm but to obtain consent, to prevent harm but to maintain confidentiality, and to provide benefits but to inflict no harm are created.     

The statins: new properties]

The comparison of major statin trials with trials using either cholestyramine or ileal bypass has suggested that the reduction in coronary heart disease events for those patients receiving statin therapy largely result from their low density lipoprotein (LDL)-cholesterol lowering action. LDL-cholesterol lowering has several physiological consequences, including plaque stabilisation with a decrease in the inflammatory process, slowing of plaque progression, and improvement of endothelial function, as evidenced by the measurement of endothelial-dependent vasorelaxation in response to hyperhaemia or acetylcholine infusion. Statins lower C-reactive protein without any consistent effect on the other inflammation acute phase proteins. The cause and consequences of this effect are still debated. In order to explain why some statins can prevent coronary events within a few months, a direct effect of this therapy on thrombosis has also been advocated; however, the evaluation of statin antithrombotic effects in humans has produced conflicting results. By inhibiting L-mevalonic acid synthesis, statins also prevent the farnelysation of small-GTP binding proteins such as Rho and Ras. In vitro, and in animal models, the inhibition of Rho with statins results in a decrease in endothelial nitric oxide production, an inhibition of leucocyte adhesion on endothelium, decrease in PPAR alpha activation and high density lipoprotein (HDL) production by the hepatocyte, decrease in Ca2+ stores in vascular smooth cells, and a stimulation of vascular smooth muscle cell apoptosis. However, most of these effects were obtained with high statin concentrations. Further evidence is needed before a full assessment of the clinical importance of isoprenylation blockage with therapeutic concentrations of statins in humans can be made.     

The iliolumbar ligament: its influence on stability of the sacroiliac joint

STUDY DESIGN: In human specimens the influence of the iliolumbar ligament on sacroiliac joint stability was tested during incremental moments applied to the sacroiliac joints. OBJECTIVES: To assess whether the iliolumbar ligament is able to restrict sacroiliac joint mobility in embalmed cadavers. BACKGROUND: Firstly, the sacroiliac joint can play an important role in non-specific low back pain; hence, its mobility and stability are of special interest. Secondly, the iliolumbar ligament is considered to be an important source of chronic low back pain. Data on a functional relation between the iliolumbar ligament and sacroiliac joint mobility are lacking. METHODS: In 12 human specimens an incremental moment was applied to the sacroiliac joint to induce rotation in the sagittal plane. After the assessment of the relationship between rotation angle and moment in the intact situation, specific parts of the iliolumbar ligaments were transected. After each partial transection the measurements were repeated. RESULTS: Sacroiliac joint mobility in the sagittal plane was significantly increased after a total cut of both iliolumbar ligaments. This increase was in particular due to the transection of a specific part of the iliolumbar ligament, the ventral band. CONCLUSIONS: The main conclusions are: (a) the iliolumbar ligaments restrict sacroiliac joint sagittal mobility; (b) the ventral band of the iliolumbar ligament contributes most to this restriction. RELEVANCE: In embalmed human cadavers, the mobility of the sacroiliac joint increases after sequential cutting of specific parts of the iliolumbar ligaments. It can be expected that severance of this ligament during surgery will lead to increase of mobility and hence loss of stability of the sacroiliac joint. As a consequence adjacent structures will be affected. This may well be a cause of pain in patients with failed back surgery.     

Allosteric properties of G protein-coupled receptor oligomers

Allosteric regulation of ligand binding is a well-established mechanism regulating the function of G protein-coupled receptors (GPCR). Allosteric modulators have been considered so far as molecules binding to an allosteric site, distinct from that of the reference ligand (orthosteric site), and able to modulate the binding affinity at the orthosteric site and/or the signaling properties resulting from orthosteric site occupancy. Given that most GPCR are known to form dimers or higher order oligomers, we explored whether allosteric interactions could also occur between protomers within oligomeric arrays, thereby influencing binding and signaling receptor properties. Two main conclusions emerged from such studies. First, allosteric modulators can affect one receptor by binding to another receptor within a dimeric or oligomeric complex. Second, allosteric modulators might act on a given receptor by targeting the "orthosteric site" in another receptor of the complex. Allosteric regulation within di(oligo)mers thus implies that the pharmacological properties of a given receptor subtype can be influenced by the array of dimerization partners coexpressed in each particular cell type. Ligands could thus act as agonists or antagonists on 1 receptor, while modulating allosterically the function of a variety of other receptors to which they do not bind directly. Allosteric regulation across GPCR oligomeric interfaces is expected to greatly influence the practice of pharmacology. It will likely affect the design of drug discovery programs, which rely mostly on the overexpression of the receptor of interest in a cell line, thereby focusing on homo-oligomers and ignoring the potential effects of other partners.