Neuroendocrine,epigenetic, and intergenerational effects of general anesthetics

The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.     

ONRAB® oral rabies vaccine is shed from,but does not persist in,captive mammals

ONRAB® is a human adenovirus rabies glycoprotein recombinant vaccine developed to control rabies in wildlife. To support licensing and widespread use of the vaccine, safety studies are needed to assess its potential residual impact on wildlife populations. We examined the persistence of the ONRAB® vaccine virus in captive rabies vector and non-target mammals. This research complements work on important rabies vector species (raccoon, striped skunk, and red fox) but also adds to previous findings with the addition of some non-target species (Virginia opossum, Norway rats, and cotton rats) and a prolonged period of post vaccination monitoring (41 days). Animals were directly inoculated orally with the vaccine and vaccine shedding was monitored using quantitative real-time PCR applied to oral and rectal swabs. ONRAB® DNA was detected in both oral and rectal swabs from 6 h to 3 days post-inoculation in most animals, followed by a resurgence of shedding between days 17 and 34 in some species. Overall, the duration over which ONRAB® DNA was detectable was shorter for non-target mammals, and by day 41, no animal had detectable DNA in either oral or rectal swabs. All target species, as well as cotton rats and laboratory-bred Norway rats, developed robust humoral immune responses as measured by competitive ELISA, with all individuals being seropositive at day 31. Similarly, opossums showed good response (89% seropositive; 8/9), whereas only one of nine wild caught Norway rats was seropositive at day 31. These results support findings of other safety studies suggesting that ONRAB® does not persist in vector and non-target mammals exposed to the vaccine. As such, we interpret these data to reflect a low risk of adverse effects to wild populations following distribution of ONRAB® to control sylvatic rabies.     

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

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Multidimensional Ultrasound Doppler Signal Analysis for Fetal Activity Monitoring

Fetal activity parameters such as movements, heart rate and the related parameters are essential indicators of fetal wellbeing, and no device provides simultaneous access to and sufficient estimation of all of these parameters to evaluate fetal health. This work was aimed at collecting these parameters to automatically separate healthy from compromised fetuses. To achieve this goal, we first developed a multi-sensor–multi-gate Doppler system. Then we recorded multidimensional Doppler signals and estimated the fetal activity parameters via dedicated signal processing techniques. Finally, we combined these parameters into four sets of parameters (or four hyper-parameters) to determine the set of parameters that is able to separate healthy from other fetuses. To validate our system, a data set consisting of two groups of fetal signals (normal and compromised) was established and provided by physicians. From the estimated parameters, an instantaneous Manning-like score, referred to as the ultrasonic score, was calculated and was used together with movements, heart rate and the associated parameters in a classification process employing the support vector machine method. We investigated the influence of the sets of parameters and evaluated the performance of the support vector machine using the computation of sensibility, specificity, percentage of support vectors and total classification error. The sensitivity of the four sets ranged from 79% to 100%. Specificity was 100% for all sets. The total classification error ranged from 0% to 20%. The percentage of support vectors ranged from 33% to 49%. Overall, the best results were obtained with the set of parameters consisting of fetal movement, short-term variability, long-term variability, deceleration and ultrasound score. The sensitivity, specificity, percentage of support vectors and total classification error of this set were respectively 100%, 100%, 35% and 0%. This indicated our ability to separate the data into two sets (normal fetuses and pathologic fetuses), and the results highlight the excellent match with the clinical classification performed by the physicians. This work indicates the feasibility of detecting compromised fetuses and also represents an interesting method of close fetal monitoring during the entire pregnancy.