Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators.

Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate.

Auditory driving of the autonomic nervous system: Listening to theta-frequency binaural beats post-exercise increases parasympathetic activation and sympathetic withdrawal.

Binaural beats are an auditory illusion perceived when two or more pure tones of similar frequencies are presented dichotically through stereo headphones. Although this phenomenon is thought to facilitate state changes (e.g., relaxation), few empirical studies have reported on whether binaural beats produce changes in autonomic arousal. Therefore, the present study investigated the effects of binaural beating on autonomic dynamics [heart rate variability (HRV)] during post-exercise relaxation. Subjects (n = 21; 18-29 years old) participated in a double-blind, placebo-controlled study during which binaural beats and placebo were administered over two randomized and counterbalanced sessions (within-subjects repeated-measures design). At the onset of each visit, subjects exercised for 20-min; post-exercise, subjects listened to either binaural beats ('wide-band' theta-frequency binaural beats) or placebo (carrier tones) for 20-min while relaxing alone in a quiet, low-light environment. Dependent variables consisted of high-frequency (HF, reflecting parasympathetic activity), low-frequency (LF, reflecting sympathetic and parasympathetic activity), and LF/HF normalized powers, as well as self-reported relaxation. As compared to the placebo visit, the binaural-beat visit resulted in greater self-reported relaxation, increased parasympathetic activation and increased sympathetic withdrawal. By the end of the 20-min relaxation period there were no observable differences in HRV between binaural-beat and placebo visits, although binaural-beat associated HRV significantly predicted subsequent reported relaxation. Findings suggest that listening to binaural beats may exert an acute influence on both LF and HF components of HRV and may increase subjective feelings of relaxation.

Performance evaluation of the MBio Diagnostics point-of-care CD4 counter.

The measurement of the absolute CD4 T-cell count is critical in the initial evaluation and staging of HIV-infected persons, yet access to this technology remains limited in many low resource settings where disease burden is highest. Here we evaluate the performance of a prototype point-of-care device (POC) to quantify CD4 T cells from MBio Diagnostics, Inc. Whole blood samples, both venous and capillary (finger stick), were collected from known HIV-infected participants at the University of California, San Diego Antiviral Research Center, and tested using the MBio system and conventional flow cytometry. A total of 94 venipuncture and 52 capillary samples were processed and statistical analyses included comparison to flow cytometry results. For the venipuncture samples, Bland-Altman analysis resulted in a mean bias of -10 cells/µL (-23 to +3 cells/µL, 95% CI), and limits of agreement (LOA) of -132 and +112 cells/µL. For the capillary samples, Bland-Altman resulted in a mean bias of -4 cells/µL (-31 to +23 cells/µL, 95% CL), and LOA of -195 and +186 cells/µL. For the San Diego study cohort, the prototype MBio system showed negligible quantitative bias relative to flow cytometry. Higher variability was observed in the capillary samples relative to venipuncture, but system precision for both capillary and venipuncture samples was good. There was also close agreement between results from the same participant when tested with two different systems, different operators and different locations. This preliminary evaluation suggests that the MBio CD4 device holds promise as a POC system for quantitation of CD4 T cells in limited-resource settings.

Optimization of a natural product-based class of γ-secretase modulators.

A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Aß42 levels.

Initial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene Glycoside.

The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.

Rapid multiplexed immunoassay for simultaneous serodiagnosis of HIV-1 and coinfections.

Diagnosis of opportunistic infections in HIV-infected individuals remains a major public health challenge, particularly in resource-limited settings. Here, we describe a rapid diagnostic system that delivers a panel of serologic immunoassay results using a single drop of blood, serum, or plasma. The system consists of disposable cartridges and a simple reader instrument, based on an innovative implementation of planar waveguide imaging technology. The cartridge incorporates a microarray of recombinant antigens and antibody controls in a fluidic channel, providing multiple parallel fluorescence immunoassay results for a single sample. This study demonstrates system performance by delivering antibody (Ab) reactivity results simultaneously for multiple antigens of HIV-1, Treponema pallidum (syphilis), and hepatitis C virus (HCV) in a collection of clinical serum, plasma, and whole-blood samples. By plotting antibody reactivity (fluorescence intensity) for known positive and negative samples, empirical reactivity cutoff values were defined. The HIV-1 assay shows 100% agreement with known seroreactivity for a collection of 82 HIV Ab-positive and 142 HIV Ab-negative samples, including multiple samples with HCV and syphilis coinfection. The treponema-specific syphilis assay correctly identifies 67 of 68 T. pallidum Ab-positive and 100 of 102 T. pallidum Ab-negative samples, and the HCV assay correctly identifies 59 of 60 HCV Ab-positive and 120 of 121 HCV Ab-negative samples. Multiplexed assay performance for whole-blood samples is also demonstrated. The ability to diagnose HIV and opportunistic infections simultaneously at the point of care should lead to more effective therapy decisions and improved linkage to care.

Dual choice health insurance policy: a proposal and a cost analysis.

The central issue in the current health care reform is cost. No health care reform can be successful without putting a rein on cost while maintaining a high quality of health care service. We believe one approach to solving the cost and quality issue is to allow patients the option to choose resources that are currently underutilized. Traditional health insurance plans offer consumers limited choice in that coverage is often denied when patients choose complementary and alternative medicine (CAM) treatments, even though the economic and social cost of treating certain conditions with alternative medicine may be more favorable than with conventional medicine. This article proposes a Dual Choice health insurance plan that would cover the cost of alternative medicines for certain medical conditions in the first stage. Should the alternative treatment turn out to be less effective, patients have the option to switch to conventional treatment in the second stage. Not only does this policy provide patients with more choices than in traditional plans, it will also likely provide significant cost savings while taking into account uncertainty regarding the effectiveness of CAM. By virtue of the wider choice offered to patients and lower cost, which is illustrated by a 2x2 effectiveness matrix, the authors think that insurance companies will be successful offering such an innovative insurance plan and will even out-compete companies offering only traditional plans. Furthermore, there will be substantial benefits that go beyond the cost savings. With both cost savings and patient welfare being central in the health care reform being proposed by the Obama administration, the dual choice plan offers considerable benefits.

Hypopituitarism after multiple concussions: a retrospective case study in an adolescent male.

OBJECTIVE: To describe the development of hypopituitarism in an adolescent athlete after multiple concussions and to raise awareness among sports medicine clinicians concerning the growing concern of hypopituitarism in concussion injury surveillance and management. BACKGROUND: A 14-year-old, previously healthy male athlete suffered 4 head traumas over a 4-month period. The first 3 traumas were considered by the athlete to be minor and were not reported to medical personnel. The fourth trauma was a medically diagnosed concussion suffered during soccer play. Over the next year, the patient noted a decline in strength and conditioning and a failure to grow. DIFFERENTIAL DIAGNOSIS: After physical examination and a full battery of endocrine tests, the patient, then 16.5 years old, was diagnosed with hypopituitarism. Follow-up interviews provided evidence that at least 2 of the 3 head injuries suffered before the last concussion could also be considered concussions, which may have contributed to the severity of the last head injury. TREATMENT: The patient is currently being treated with physiologic replacement hormones (growth hormone, cortisol, and thyroxine), with resumption of linear growth and strength. He is progressing well. UNIQUENESS: In the past few years in the medical literature, increased attention has been drawn to the occult occurrence of hypopituitarism after traumatic brain injury in adults. Initial reports indicate that children are also at risk. To our knowledge, this is the first reported case of hypopituitarism after mild traumatic brain injury in the sports medicine literature. CONCLUSIONS: Symptoms of hypopituitarism are often masked by trauma and postconcussion symptoms and may not appear until months or years after the trauma incident, which can lead to significant delay in proper diagnosis and treatment. We urge greater vigilance by, and training of, sports medicine clinicians toward the goal of recognizing the possibility of pituitary disorders after sports concussion.

Professional practice in exercise science : the need for greater disciplinary balance.

This article describes the current outlook for professional practice for graduates majoring in exercise science. A review of professional and experimental literature reveals that graduates of undergraduate programmes in exercise science are not as prepared as they should be in order to provide professional and comprehensive advice on exercise and human performance, because of the focused academic and professional requirements of exercise physiology. In contrast to the direction of training in other allied health professions, this trend of narrowing of the exercise science curriculum to focus on exercise physiology, at the expense of other subdisciplines in kinesiology, has contributed to a decreasing scope of practice and lack of uniqueness, and has reduced the effectiveness of exercise science graduates. This review focuses on an accumulating body of evidence indicating that improving the training in biomechanics and motor behaviour could increase the professional expertise of exercise science graduates. Small improvements in the exercise science curriculum in biomechanics and motor behaviour are proposed that would move toward greater balance and integration of the academic disciplines in kinesiology and better professional practice in exercise science. The drift away from a balance and integration of academic preparation in exercise science represents a threat to the acceptance of exercise science graduates as exercise professionals that needs to be corrected for the field to advance.

Knowledge and imagery of contractile mechanisms do not improve muscle strength.

Improving performance in strength tasks requires modifications charateristic of motor skill learning, such as more efficacious motor-unit firing behavior. Because domain-specific knowledge is integral to learning and performing motor kills, the present purpose was to examine selected factors of strength-specific knowledge and effects they might have on acquiring strength. Following baseline testing for maximal strength on a knee-extension task, participants were matched by sex and strength and placed into control (n=8) and treatment (n=8) groups. Quadriceps muscle electromyographic data were also collected. The treatment group underwent two educational sessions detailing muscle physiology, neural control of muscle force, and imagery training using this knowledge. The control group underwent two educational sessions about health and fitness. Following the educational sessions the participants were retested for strength. Analysis indicated that the education and imagery treatment had no effect on strength, nor did electromyographic measures indicate that the treatment group benefitted from intervention. It was concluded that the knowledge was simply not relevant to knee extension-force production or that use of the knowledge involved a disadvantageous internal focus of attention away from relevant task demands.

Comments on "the Feldenkrais Method: a dynamic approach to changing motor behavior".

The Feldenkrais Method has recently been discussed to fit within a dynamic systems model of human movement. One basis for this discussion is that small changes in one system--for example, enhanced body awareness--has far reaching implications across the whole of human performance. An alternative view on the Feldenkrais Method is argued here. It is argued that the clinical data do not support the Feldenkrais Method as being an effective way to improve motor performance. Further, it is argued that positive outcomes in pain and other wellness measures following Feldenkrais interventions can be ascribed to self-regulation. As part of this discussion, the role of body awareness, attentional focus, and kinesthesia in motor leaning and control are explored.

Sampling rate effects on surface EMG timing and amplitude measures.

OBJECTIVE: To determine if oversampling the surface electromyographic signal provides any benefit in analyzing common electromyographic timing and amplitude measures used in kinesiological studies. DESIGN: A within subjects (n=8) repeated measures design was used to examine surface electromyographic signals captured under four contraction modes and acquired with five different analog-to-digital sampling rates. BACKGROUND: There is a growing trend to sample surface electromyography at rates higher than the Nyquist rate. Though there is limited evidence to support oversampling, the necessity or benefit of doing so remains unclear. METHODS: Surface electromyography was recorded from the triceps brachii during maximal, submaximal, and fatiguing isometric contractions, as well as dynamic contractions. The analog signals were bandpassed between 20 Hz and 2 kHz, and oversampled at 6 kHz. The signals were then digitally resampled at 3 kHz, 1 kHz, 500 Hz, and 250 Hz without benefit of an anti-aliasing filter. Amplitude and timing variables measured from both the rectified and smoothed signal were compared across sampling rates. RESULTS: Oversampling produced no significant changes in timing and amplitude measures of the rectified or smoothed electromyographic signal. For the smoothed signal, minor undersampling at half the Nyquist rate was sufficient to accurately capture most timing and signal strength measures. CONCLUSIONS: Oversampling is unnecessary to gather typical amplitude and timing measures from the surface electromyographic signal. Electromyography sampled below half the Nyquist rate is likely to result in a poor temporal and amplitude representation of the signal. RELEVANCE: Computer memory and processing resources for analyzing amplitude and timing information need not be expended in oversampling surface electromyography, and results of previous studies need not be outright dismissed because of minor undersampling violations or the lack of an anti-aliasing filter.

Psychophysics in functional strength and power training: review and implementation framework.

Functional training is considered to be training that attempts to mimic the specific physiological demands of real-life activities. Most approaches to functional training, though, omit important factors that contribute to physiological and neuromotor adaptations. Cognitive factors related to sports influence physiological performance, and subsequently, physiological and neuromotor adaptations. We present a rationale and a theoretical framework by which to create effective functional training methods that incorporate cognitive factors. This framework draws upon recent developments and strong empirical evidence in the areas of dynamic systems theory, perceptual skills training, and motor learning/control. Emphasized within rigorous physical training are practice-related techniques and motor-learning strategies. In particular, mental effort, attention, and intention manipulated in a discovery-learning paradigm provide a framework for functional strength and power training. This framework is suggested to help maximize sport-specific physiological adaptations, and subsequently, sports performance.