College of Osteopathic Medicine of the Pacific

About: College of Osteopathic Medicine of the Pacific is a based out in . It is known for research contribution in the topics: Population & Medicine. The organization has 4363 authors who have published 5040 publications receiving 120192 citations.

Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1

Abstract: Wasabi, horseradish and mustard owe their pungency to isothiocyanate compounds Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mechanical stimuli Despite their widespread use in both the kitchen and the laboratory, the molecular mechanism through which isothiocyanates mediate their effects remains unknown Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold These findings identify a cellular and molecular target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors

Alzheimer's disease drug-development pipeline: few candidates, frequent failures

Abstract: Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD. We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline. During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure). The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.

Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.

Abstract: Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition FSGS is characterized by increased urinary protein excretion and decreasing kidney function Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4 Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage

Muscular adaptations in response to three different resistance-training regimens: specificity of repetition maximum training zones.

Abstract: Thirty-two untrained men [mean (SD) age 22.5 (5.8) years, height 178.3 (7.2) cm, body mass 77.8 (11.9) kg] participated in an 8-week progressive resistance-training program to investigate the "strength–endurance continuum". Subjects were divided into four groups: a low repetition group (Low Rep, n=9) performing 3–5 repetitions maximum (RM) for four sets of each exercise with 3 min rest between sets and exercises, an intermediate repetition group (Int Rep, n=11) performing 9–11 RM for three sets with 2 min rest, a high repetition group (High Rep, n=7) performing 20–28 RM for two sets with 1 min rest, and a non-exercising control group (Con, n=5). Three exercises (leg press, squat, and knee extension) were performed 2 days/week for the first 4 weeks and 3 days/week for the final 4 weeks. Maximal strength [one repetition maximum, 1RM), local muscular endurance (maximal number of repetitions performed with 60% of 1RM), and various cardiorespiratory parameters (e.g., maximum oxygen consumption, pulmonary ventilation, maximal aerobic power, time to exhaustion) were assessed at the beginning and end of the study. In addition, pre- and post-training muscle biopsy samples were analyzed for fiber-type composition, cross-sectional area, myosin heavy chain (MHC) content, and capillarization. Maximal strength improved significantly more for the Low Rep group compared to the other training groups, and the maximal number of repetitions at 60% 1RM improved the most for the High Rep group. In addition, maximal aerobic power and time to exhaustion significantly increased at the end of the study for only the High Rep group. All three major fiber types (types I, IIA, and IIB) hypertrophied for the Low Rep and Int Rep groups, whereas no significant increases were demonstrated for either the High Rep or Con groups. However, the percentage of type IIB fibers decreased, with a concomitant increase in IIAB fibers for all three resistance-trained groups. These fiber-type conversions were supported by a significant decrease in MHCIIb accompanied by a significant increase in MHCIIa. No significant changes in fiber-type composition were found in the control samples. Although all three training regimens resulted in similar fiber-type transformations (IIB to IIA), the low to intermediate repetition resistance-training programs induced a greater hypertrophic effect compared to the high repetition regimen. The High Rep group, however, appeared better adapted for submaximal, prolonged contractions, with significant increases after training in aerobic power and time to exhaustion. Thus, low and intermediate RM training appears to induce similar muscular adaptations, at least after short-term training in previously untrained subjects. Overall, however, these data demonstrate that both physical performance and the associated physiological adaptations are linked to the intensity and number of repetitions performed, and thus lend support to the "strength–endurance continuum".