The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes.

Clinical findings show that the use of valproic acid (VPA) during pregnancy increases the risk of birth defects and autism spectrum disorder in offspring. Although there is a consensus that monitoring of potential long-term outcomes of VPA exposure is needed, especially in undiagnosed individuals, preclinical studies addressing this issue are rare. The present study examined the effects of continuous intrauterine exposure to a wide dose range of VPA (50, 100, 200, and 400 mg/kg/day) on the physical and behavioral response in peripubertal mice as a rodent model of adolescence. Body weight and the hot plate test [on postnatal days (PND) 25 and 32], the elevated plus-maze test (on PND35), and the open field test (on PND40) served to examine physical growth, the supraspinal reflex response to a painful thermal stimulus and conditional learning, anxiety-like/risk-assessment behavior, as well as novelty-induced psychomotor activity, respectively. VPA exposure produced the following responses: (i) a negative effect on body weight, except for the dose of 100 mg/kg/day in both sexes; (ii) an increase in the percentage of animals that responded to the thermal stimulus above the defined cut-off time interval and the response latency in both sexes; (iii) dose-specific changes within sexes in behavior provoked by a novel anxiogenic environment, i.e., in females less anxiety-like/risk-assessment behavior in response to the lowest exposure dose, and in males more pronounced anxiety-like/risk-assessment behavior after exposure to the highest dose and 100 mg/kg/day; (iv) dose-specific changes within sexes in novelty-induced psychomotor activity, i.e., in females a decrease in stereotypy-like activity along with an increase in rearing, and in males a decrease in stereotypy-like activity only. These findings show that continuous intrauterine exposure to VPA produces maladaptive functioning in different behavioral domains in adolescence and that the consequences are delicate to assess as they are dose-related within sexes.

Chronic Polyhydramnios: A Medical Entity Which Could Be a Model of Muscle Development in Decreased Mechanical Loading Condition.

Polyhydramnios is a condition related to an excessive accumulation of amniotic fluid in the third trimester of pregnancy and it can be acute and chronic depending on the duration. Published data suggest that during muscle development, in the stage of late histochemical differentiation decreased mechanical loading cause decreased expression of myosin heavy chain (MHC) type 1 leading to slow-to-fast transition. In the case of chronic polyhydramnios, histochemical muscle differentiation could be affected as a consequence of permanent decreased physical loading. Most affected would be muscles which are the most active i.e., spine extensor muscles and muscles of legs. Long-lasting decreased mechanical loading on muscle should cause decreased expression of MHC type 1 leading to slow-to-fast transition, decreased number of muscle fiber type I especially in extensor muscles of spine and legs. Additionally, because MHC type 1 is present in all skeletal muscles it could lead to various degrees of hypotrophy depending on constituting a percentage of MHC type 1 in affected muscles. These changes in the case of preexisting muscle disorders have the potential to deteriorate the muscle condition additionally. Given these facts, idiopathic chronic polyhydramnios is a rare opportunity to study the influence of reduced physical loading on muscle development in the human fetus. Also, it could be a medical entity to examine the influence of micro- and hypogravity conditions on the development of the fetal muscular system during the last trimester of gestation.

A New Look at an Old Drug: Cumulative Effects of Low Ribavirin Doses in Amphetamine-Sensitized Rats.

BACKGROUND: Psychotic states related to psychostimulant misuse in patients with hepatitis C virus infection may complicate acceptance and reaction to antiviral treatment. This observation equally applies to the widely used ribavirin therapy. OBJECTIVE: We examined psychomotor and body weight gain responses to low ribavirin doses after cessation of intermittent amphetamine treatment in adult rats to assess its role in neurobehavioral outcome during psychostimulant withdrawal. METHOD: The model of amphetamine-induced (1.5 mg/kg/day, i.p., 7 consecutive days) motor sensitization and affected body weight gain was established in adult male Wistar rats. Then, additional cohort of amphetaminesensitized rats was subjected to saline (0.9% NaCl; 1 mL/kg/day; i.p.) or ribavirin (10, 20 and 30 mg/kg/day, i.p.) treatment for 7 consecutive days. Animals' motor activity in a novel environment was monitored after the 1st and the 7th saline/ribavirin injection. Body weight gain was calculated as appropriate. Determination and quantification of ribavirin in the brain tissue were performed also. RESULTS: The 1st application of ribavirin to amphetamine-sensitized rats affected/decreased their novelty-induced motor activity only at a dose of 30 mg/kg. After the 7th application, ribavirin 30 mg/kg/day still decreased, while 10 and 20 mg/kg/day increased novelty-induced motor activity. These behavioral effects coincided with the time required to reach maximum ribavirin concentration in the brain. Body weight gain during withdrawal was not influenced by any of the doses tested. CONCLUSION: Ribavirin displays central effects that in repeated treatment, depending on the applied dose, could significantly influence psychomotor response but not body weight gain during psychostimulant/amphetamine withdrawal.

Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development.

Clinical research has identified developmental delay and physical malformations in children prenatally exposed to the antiepileptic drug (AED) valproic acid (VPA). However, the early signs of neurodevelopmental deficits, their evolution during postnatal development and growth, and the dose effects of VPA are not well understood. The present study aimed to examine the influence of maternal exposure to a wide dose range (50, 100, 200 and 400mg/kg/day) of VPA during breeding and gestation on early physical and neuromotor development in mice offspring. Body weight gain, eye opening, the surface righting reflex (SRR) and tail suspension test (TST) were examined in the offspring at postnatal days 5, 10 and 15. We observed that: (1) all tested doses of VPA reduced the body weight of the offspring and the timing of eye opening; (2) offspring exposed to VPA displayed immature forms of righting and required more time to complete the SRR; (3) latency for the first immobilization in the TST is shorter in offspring exposed to higher doses of VPA; however, mice in all groups exposed to VPA exhibited atypical changes in this parameter during the examined period of maturation; (4) irregularities in swinging and curling activities were observed in animals exposed to higher doses of VPA. This study points to delayed somatic development and postponed maturation of the motor system in all of the offspring prenatally exposed to VPA, with stronger effects observed at higher doses. The results implicate that the strategy of continuous monitoring of general health and achievements in motor milestones during the early postnatal development in prenatally VPA-exposed offspring, irrespectively of the dose applied, could help to recognize early developmental irregularities.

Breech presentation and the cornual-fundal location of the placenta.

AIM: To investigate the association of cornual-fundal location of the placenta and breech presentation at term delivery. METHODS: This study was conducted at the Department of Obstetrics and Gynecology, Novi Sad, in 2011. The inclusion criteria were delivery at ≥37 weeks of gestation, singleton gestation, and cornual-fundal location of the placenta determined by ultrasonography at ≥37 weeks of gestation when 3/4 or more of the placenta was in the cornual-fundal region. RESULTS: Out of 2750 ultrasound examinations performed, 143 showed cornual-fundal location of the placenta (frequency 5.2%). Eighty six cases had cephalic presentation (60.14%) and 57 (39.86%) had breech presentation. Of the remaining cases with non- cornual-fundal location, 2585 had cephalic presentation and 22 (0.84%) had breech presentation. The difference in the frequency of breech presentation between the cornual-fundal and non-cornual-fundal groups was significant (χ(2)=77.78, P<0.001). CONCLUSION: Cornual-fundal location of the placenta may be an important clue in resolving the etiology of a number of cases of breech presentation at term delivery.

Significance of adequate postural control in the appearance of habitual upright bipedal locomotion.

Analysis of qualitative indicators of stability of the body during different types of locomotion in primates suggests that bipedal locomotion is not variation of some other type of locomotion. Transition from quadrupedal to bipedal locomotion is accompanied by a qualitative difference in body stability. Because of assuming an upright bipedal posture, the center of mass is lifted, the surface of the base of support is reduced, and the body structure does not provide passive stability in relation to inertial moments of the body around Y-axis. Additional head movements, trunk rotations, forelimb manipulations with objects and surveying the surroundings are necessary for survival, but they increase the degree of freedom of movement and further complicate the task of maintaining balance in the case of a postural change from erect quadrupedal to erect bipedal. This article presents a hypothesis that the transition from quadrupedal to habitual upright bipedal locomotion was caused by qualitative changes in the nervous system that allowed controlling the more demanding type of locomotion. The ability to control a more demanding posture increases possibilities of interactions between the organism and the complex environment and consequently increases the survival rate, breeding possibilities, and chances for occupying a new environmental niche. Existing data show that ability to execute the more demanding type of locomotion was made possible because of changes in the frontal lobe and pyramidal system. Only after the more demanding posture was enabled by changes in the nervous system, could advantages of bipedal over quadrupedal locomotion be utilized, including better scanning of the environment, carrying food and infants, simultaneous upper extremity movements and observation of the environment, limitless manipulation of objects with upper extremities above the individual, and less space for rotating around the Z-axis. The aforementioned advantages of habitual bipedal over quadrupedal locomotion are present in physically complex environments, such as the forest, which is associated with the appearance of habitual bipedal locomotion.

Spectral and fractal measures of cerebellar and cerebral activity in various types of anesthesia.

The features of rat cerebral and cerebellar electrocortical activity (ECoG) under different types of anaesthesia (nembutal, ketamine or zoletil) were examined by the distribution of spectral entropy across frequency bands of ECoG and by calculation of fractal dimension determined on the basis of Higuchi's algorithm. Spectral entropy, as a measure of activity, in the case of cerebrum had greater values than the spectral entropy of cerebellum in low frequency ranges, regardless of the type of applied anesthetic. Various anesthetics evoked different effects on spectral entropy of electrocortical activity: spectral entropy of delta range greatly dominated under nembutal anesthesia, while ketamine or zoletil appeared to affect the spectral entropy of higher frequency ranges. The pronounced effect of ketamine or zoletil anesthesia on spectral entropy of higher frequency was confirmed by the higher values of Higucihi's fractal dimension (FD) of ECoGs, with a tendency of higher FD values in cerebellar activity than cerebral activity.

Wavelet and fractal analysis of rat brain activity in seizures evoked by camphor essential oil and 1,8-cineole.

We investigated the rat brain activity in acute seizures evoked by camphor essential oil or its main constituent 1,8-cineole by wavelet (primarily) and fractal analysis. Experiments were performed on anesthetized animals before and after intraperitoneal camphor oil or cineole administration. The properties of frequency bands in pre-ictal, ictal and inter-ictal stages have been determined by wavelet analysis. The domination of delta frequency band was confirmed in obtained brain activities, which participate with approximately 45% of mean relative wavelet energy (MRWE) in control signals and arise up to approximately 76% MRWE in energy spectrum during the ictal stage (after drug administration). Other frequency bands decreased during ictal stage and arised in inter-ictal stage. There was a dosedependent response of cineole effect: increase in cineole concentration leaded to the higher values of relative wavelet energy (RWE) of delta frequency band while there were slight changes of the mean fractal dimension (FD) values as a measure of system complexity.