Patient Concerns and Beliefs Related to Audible Popping Sound and the Effectiveness of Manipulation: Findings From an Online Survey.

OBJECTIVE: The purpose of this study was to assess whether beliefs about the origin of the popping sound and the effects of thrust manipulation (TM) were in agreement with current scientific evidence and whether a practitioner's explanation could influence patient beliefs of theoretical mechanisms. METHODS: A cross-sectional online survey was conducted in Italy from January 7, 2019 to April 20, 2019. The questionnaire was sent to 900 Italian adults through online recruitment, including people with and without a history of manipulation, such as given by physiotherapists, chiropractors, osteopaths, and manual medicine physicians to manage musculoskeletal disorders. The questionnaire consisted of 11 multiple-choice questions and could be completed within 15 weeks. The Likert scale was used to investigate participants' attitudes. Sex and previous experience of TM variables were evaluated using a Student's t-test; a 1-way F analysis of variance test was performed to evaluate age, educational qualification, and the professional who performed the TM. RESULTS: We retrieved 478 questionnaires, including 175 participants with no TM history and 303 with TM history. There were 31% of participants (n = 94) with a history of TM who reported they did not receive explanations regarding manipulation. The participants' beliefs mostly disagreed with the current hypotheses provided by the scientific literature on the theoretical mechanisms of popping sound (tribonucleation and cavitation). There were 9.9% (n = 30) of participants who answered "realignment of bone positional fault" to explain the mechanism behind TM. There was a high degree of agreement with the belief that the popping sound should be present for a successful TM (respectively, 2.8 standard deviation [SD; 1.2] and 2.6 SD [1.2] for TM+ and TM- participants). No statistically significant differences were found between participants with and without a history of TM. CONCLUSION: The participants in this study reported a belief that popping was related to effectiveness of TM. A high percentage of this sample had beliefs about TM mechanisms for the audible popping sound that were inconsistent with current literature. Beliefs were similar between groups, suggesting that instructions given by TM practitioners did not seem to be an influence on these patients' beliefs.

A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency.

Triose phosphate isomerase deficiency (TPI Df) is an untreatable, childhood-onset glycolytic enzymopathy. Patients typically present with frequent infections, anemia, and muscle weakness that quickly progresses with severe neuromusclar dysfunction requiring aided mobility and often respiratory support. Life expectancy after diagnosis is typically ~5 years. There are several described pathogenic mutations that encode functional proteins; however, these proteins, which include the protein resulting from the "common" TPIE105D mutation, are unstable due to active degradation by protein quality control (PQC) pathways. Previous work has shown that elevating mutant TPI levels by genetic or pharmacological intervention can ameliorate symptoms of TPI Df in fruit flies. To identify compounds that increase levels of mutant TPI, we have developed a human embryonic kidney (HEK) stable knock-in model expressing the common TPI Df protein fused with green fluorescent protein (HEK TPIE105D-GFP). To directly address the need for lead TPI Df therapeutics, these cells were developed into an optical drug discovery platform that was implemented for high-throughput screening (HTS) and validated in 3-day variability tests, meeting HTS standards. We initially used this assay to screen the 446-member National Institutes of Health (NIH) Clinical Collection and validated two of the hits in dose-response, by limited structure-activity relationship studies with a small number of analogs, and in an orthogonal, non-optical assay in patient fibroblasts. The data form the basis for a large-scale phenotypic screening effort to discover compounds that stabilize TPI as treatments for this devastating childhood disease.

Rivaroxaban Versus Warfarin in African American Patients with Nonvalvular Atrial Fibrillation.

INTRODUCTION: Black patients are under-represented in randomized trials evaluating oral anticoagulants in non-valvular atrial fibrillation (NVAF). We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in African Americans with NVAF. METHODS: We performed an analysis using Optum® De-Identified Electronic Health Record (EHR) data from 1/1/2012-9/30/2018. We included adult African American patients with a diagnosis of NVAF who were anticoagulant-naïve during the 12-months prior to initiation of rivaroxaban or warfarin. Patients receiving rivaroxaban were 1:1 propensity score matched to warfarin patients. Our primary effectiveness and safety outcomes were the 2-year incidence rates (%/year) of stroke or systemic embolism (SSE) and major bleeding using an intention-to-treat approach. Cohorts were compared using doubly-robust Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We matched 4102 rivaroxaban and 4102 warfarin users with a median (interquartile range) available follow-up of 2.0 (0.9, 2.0) years. Median CHA2DS2-VASc and HASBLED scores were 3 (2, 4) and 2 (1, 3). Rivaroxaban use was associated with a lower risk of SSE (1.99 versus 2.48, HR = 0.77, 95%CI = 0.60-0.99), ischemic stroke (1.84 versus 2.37, HR = 0.76, 95%CI = 0.59-0.98) and major bleeding (4.22 versus 4.98, HR = 0.84, 95%CI = 0.70-0.99). No differences in intracranial hemorrhage or gastrointestinal bleeding were observed. Neither sensitivity analyses utilizing an on-treatment methodology nor inverse probability-of-treatment weighting showed significant differences in SSE or major bleeding between rivaroxaban and warfarin users. CONCLUSIONS: Rivaroxaban appeared at least as effective and safe as warfarin when used to manage African American patients with NVAF in routine practice.

Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy.

Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. We have found that reduction of glycolysis does not confer seizure protection, but that dietary supplementation with ketone bodies or the anaplerotic lipid triheptanoin, which directly replenishes the citric acid cycle, can mimic the success of the ketogenic diet even in the presence of standard carbohydrate levels. We have also shown that the proper functioning of the citric acid cycle is crucial to the success of the KD in the context of ME. Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder with severe neurological consequences. Overall, these studies reveal widespread success of the KD in Drosophila, further cementing its status as an excellent model for studies of KD treatment and mechanism, and reveal key insights into the therapeutic potential of dietary therapy against neuronal hyperexcitability in epilepsy and metabolic disease.

Trypanocidal activity of ß-lactone-γ-lactam proteasome inhibitors.

Four ß-lactone- γ-lactam proteasome inhibitors of natural origin were tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. All four compounds displayed activities in the nanomolar range. The most trypanocidal compounds with 50% growth inhibition (GI(50)) values of around 3 nM were the bromine and iodine analogues of salinosporamide A, a potent proteasome inhibitor produced by the marine actinomycete Salinispora tropica. In general, trypanosomes were more susceptible to the compounds than were human HL-60 cells. The data support the potential of ß-lactone- γ-lactam proteasome inhibitors for rational anti-trypanosomal drug development.

Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model.

Our previous study showed that the novel proteasome inhibitor NPI-0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM-xenografts demonstrated that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase-1 clinical trial of NPI-0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI-0052 using human MM xenograft murine model. Our results showed that NPI-0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin-like (CT-L, beta5), trypsin-like (T-L, beta2), and caspase-like (C-L, beta1) activities in extra-vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound (3H-NPI-0052) in mice demonstrated that NPI-0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S-bearing mice with NPI-0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.

Inhibition of Yin Yang 1-dependent repressor activity of DR5 transcription and expression by the novel proteasome inhibitor NPI-0052 contributes to its TRAIL-enhanced apoptosis in cancer cells.

TRAIL promotes apoptotic tumor cell death; however, TRAIL-resistant tumors need to be sensitized to reverse resistance. Proteasome inhibitors potentiate TRAIL apoptosis in vitro and in vivo and correlate with up-regulation of death receptor 5 (DR5) via an unknown mechanism. We hypothesized that the proteasome inhibitor NPI-0052 inhibits the transcription repressor Yin Yang 1 (YY1) which regulates TRAIL resistance and negatively regulates DR5 transcription. Treatment of PC-3 and Ramos cells with NPI-0052 (

Synthesis of a novel family of diterpenes and their evaluation as anti-inflammatory agents.

The synthesis and biological evaluation of a new family of diterpenes, represented by structures 2 and 3, is presented. These compounds constitute isomeric analogues of acanthoic acid (1) and were examined as potent anti-inflammatory agents. Among them, methyl ester 12 exhibited a low non-specific cytotoxicity, inhibited TNF-alpha synthesis and displayed good specificity in suppressing cytokine expression.