Gender and estradiol as major factors in the expression and dimerization of nNOSα in rats with experimental diabetic gastroparesis.

BACKGROUND: The molecular mechanisms of cellular changes responsible for diabetic gastroparesis, primarily seen in middle-aged women, still remain incompletely defined. We hypothesized that a decrease in the expression, dimerization, and post-translational modification of neuronal nitric oxide synthase alpha (nNOSα) is estrogen mediated and responsible for the gender-specific prevalence of this malady. METHODS: We induced diabetes by injecting male and female rats with streptozotocin. Male diabetic rats without gastroparesis were then injected with estrogen for 3 weeks and evaluated for gastroparesis development. Gastric tissues were analyzed for the elucidation of biochemical events associated with diabetes and gastroparetic dysfunction. RESULTS: Although male diabetic, gastroparetic (either streptozotocin- or estrogen-induced) rats exhibited similarity in disease pathology to that of females, the molecular mechanisms of development were different. Our results indicate that slow gastric emptying in both male diabetic, gastroparetic rat groups was not associated with the level of expression of nNOSα in gastric tissues. However, nNOSα dimerization, which reflects nNOSα activation, did decline slightly in the antrum of diabetic males with estrogen-induced gastroparesis, suggesting a possible estrogen role. Females with diabetic gastroparesis, in contrast, demonstrated significantly impaired levels and dimerization of nNOSα in the antrum and pylorus. Although the precise mechanism remains unknown, nNOSα dimerization impairment in female antrum is apparently associated with reduced phosphorylation of Ser(1416) in the activation loop of nNOSα. CONCLUSION: Taken together, these results demonstrate that gender and estrogens may be leading factors, through molecular changes involved in nitric oxide synthesis down-regulation, within the antrum and pylorus of female diabetic, gastroparetic rats.

Effects of supplemental oxygen and hyperbaric oxygen on tendon healing in a rat model.

Systemic supplemental oxygen therapy (SOT) and hyperbaric oxygen therapy (HBOT) have been shown to positively impact wound healing. The purpose of this study was to evaluate the effects of SOT and HBOT on tendon healing in a rat tendon model. The right patellar tendon of 90 male Sprague-Dawley rats was completely sectioned. Animals were randomized to receive HBOT, SOT, or room air therapy. Animals were sacrificed at 3- and 6-weeks postoperatively. The ultimate tensile strength in axial extension was compared between groups. Statistical significance was calculated using the Student's t-test. The SOT group exhibited the highest tensile strength at both time-points, although HBOT was the only treatment that exhibited a statistically significant increase in tensile strength between time-periods (p = 0.006). There was no statistical difference in ultimate tensile strength when the three groups were compared at the 3- or 6-week time-points. Results presented here cannot support the premise that intermittent HBOT or SOT significantly increases the healing of tendon repairs.

Safety and colonization of two novel VirG(IcsA)-based live Shigella sonnei vaccine strains in rhesus macaques (Macaca mulatta).

Shigella are gram-negative bacterium that cause bacillary dysentery (shigellosis). Symptoms include diarrhea and discharge of bloody mucoid stools, accompanied by severe abdominal pain, nausea, vomiting, malaise, and fever. Persons traveling to regions with poor sanitation and crowded conditions become particularly susceptible to shigellosis. Currently a vaccine for Shigella has not been licensed in the United States, and the organism quickly becomes resistant to medications. During the past 10 y, several live attenuated oral Shigella vaccines, including the strain WRSS1, have been tested in humans with considerable success. These Phase I vaccines lack the gene for the protein VirG also known as IcsA, which enables the organism to disseminate in the host target tissue. However, 5% to 20% of the vaccinated volunteers developed mild fever and brief diarrhea, and the removal of additional virulence-associated genes from the vaccine strain may reduce or eliminate these side effects. We administered 2 Shigella sonnei vaccines, WRSs2 and WRSs3, along with WRSS1 to compare their rates of colonization and clinical safety in groups of 5 rhesus macaques. The primate model provides the most physiologically relevant animal system to test the validity and efficacy of vaccine candidates. In this pilot study using a gastrointestinal model of infection, the vaccine candidates WRSs2 and WRSs3, which have additional deletions in the enterotoxin and LPS modification genes, provided better safety and comparable immunogenicity to those of WRSS1.