Effect of crossover from placebo to darolutamide on overall survival in men with non-metastatic prostate cancer: sensitivity analyses from the randomised phase 3 ARAMIS study.

Background: In the phase 3 ARAMIS study (NCT02200614), darolutamide significantly improved metastasis-free survival in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Following the primary analysis, the study was unblinded, and placebo recipients were permitted to cross over to open-label darolutamide. Despite crossover, darolutamide significantly improved overall survival (OS).

Effects of perinatal undernutrition on social transmission of food preference in adult male Wistar rats.

Nutrition plays a fundamental role in learning and memory, and early experimental undernutrition interferes with brain memory processes. Social transmission of food preference (STFP) is a natural olfactory paired-associate learning test that has not been used to assess the effects of early undernutrition on memory consolidation. Male Wistar rats were randomly divided into two groups: control and early undernourished.

Late-emerging effects of perinatal undernutrition in neuronal limbic structures underlying the maternal response in the rat.

Maternal care in the rat is an ancient behavioral response to specific multisensory inputs widely integrated in a complex forebrain, limbic and brain stem network to meet the basic needs of the young. Early undernutrition interferes with the morphofunctional organization of the brain, including maternal circuitry. The late-emerging effects of pre- and neonatal undernutrition on nest building and pup retrieval by lactating Wistar rats were correlated with dendritic arbor and perikaryon measurements (Golgi-Cox) in layer II pyramidal neurons of the anterior cingulate cortex, layer III pyramidal neurons of the medial prefrontal cortex and multipolar basolateral amygdala neurons examined on lactation days 4 and 12.

Effects of pre- and neonatal undernutrition on the kyphotic response and c-Fos activity in the caudal periaqueductal gray of primiparous lactating Wistar rats.

In rodents, the most representative component of maternal behavior that meets the purpose of newborn nutrition is the kyphotic posture. During this posture, the mother maintains a unique environment for the protection, thermal regulation and breast-feeding of the progeny. The aim of this study was to investigate possible deficiencies in the kyphotic posture of adult lactating dams with pre- and neonatal undernutrition evoked by their own pups suckling in a home-cage situation.

Maternal alterations induced by exposure to an unfamiliar home cage in early underfed dams.

The expression of different behavioral components in the adult rat depends on a number of early influences, including age, hormones, manipulations of sensory cues, and perinatal undernutrition, all of which impact the development of brain areas underlying adaptive processes, maternal behavior, and the response to novelty. The current study investigates the effects of pre- and neonatal undernutrition on various components of maternal behavior of dams exposed to the challenge of an unfamiliar home cage on days 4, 8, and 12 of lactation. Food restriction was initiated from gestational day (G) G6 to G19 when dams received 50-70% of the normal balanced diet, followed by 100% from G20 to G21.

Effects of perinatal undernutrition on the circumvallate papilla of developing Wistar rats.

During the gestation and the lactating periods the gustatory papillae contain taste buds that respond to different flavors and aversive stimuli. The current study analyzed the effects of pre-and neonatal undernutrition on the circumvallate papillae of rats at 12, 20, and 30days of age. Early undernourishment occurred from gestational days G6 to G19 when dams received low percentages of food followed by a balanced diet from G20-21.

Effects of perinatal undernutrition on the basilar dendritic arbor of the anterior cingulate pyramidal neurons in lactating dams.

In altricial species, early pre- and neonatal undernutrition interferes with the neuronal organization of several brain structures that have critical time windows for synaptic organization, including the prefrontal cortex. In Golgi-Cox stained tissue the basilar dendritic arbor of pyramidal neurons in the anterior cingulate cortex of early underfed adult lactating dams was evaluated. The anterior cingulate of the rat plays a major role in the execution of sexual, maternal and visual attentional control and other cognitive responses.

Effects of perinatal undernutrition on the development of neurons in the rat insular cortex.

The insular cortex (IC) of the rat is a major area for the convergence and integration of olfactory, gustatory, and visual information, and at present it is unclear if perinatal undernutrition interferes with the structure and function of the IC neurons. Golgi-Cox-stained cells of the IC were studied in control and undernourished Wistar rats at 12, 20, and 30 days of age. Pregnant dams were undernourished by the reduction of a balanced diet during a part of the gestational period (G6-G18).

Development of mitral cells and olfactory bulb layers in neonatally undernourished rats.

Cell alterations in the central nervous system are consistent consequences of early undernourishment. Because little is known about the effects of neonatal udernourishment upon the main olfactory bulb (OB) in Golgi-Cox stained material, we evaluated the total OB cross-sectional area, the area of individual OB layers, and the area of type II mitral cells perikarya and their dendritic processes in undernourished Wistar rats of 7, 14, and 21 days of age. Data showed that neonatal undernourishment reduced both the OB and the individual layers areas; minimal perikarya effects and significant reductions in the number and extension of MC dendrites.

Early undernourishment interferes with the maternal aggressive response triggered by an intruder entering the homing cage.

The maternal aggressive response (MAR) against intruders is temporarily expressed during lactation in association with the rearing and protection of offspring to promote their survival and growth in the nest. This normal component of maternal behaviour requires both the hormonal changes occurring at the end of pregnancy and the presence of pups for its establishment. Because early food restriction in the rat results in long-term maternal deficiencies, we analysed in Wistar rats the effects of perinatal undernutrition on the MAR to an intruder at days 1, 4, and 8 postpartum.

Movement activity recovers the loss of spines owing to chronic immobilization.

In chronically movement-restricted Wistar rats, we described a significant decrease of spines along apical shafts of layer V cortical pyramids. Current study indicates that the liberation at 40 days of rats whose movements had been restricted since 20 days of age produces a gradual recovery of the number of spines, reaching the control values at 80 days of age and that this process occurred faster in the motor than in the sensory cortices. Nevertheless, when R(20) rats were liberated at 80 days, the number of spines had not fully recovered when rats were 120 days old.

Early undernutrition decreases the number of neurons in the locus coeruleus of rats.

The effects of perinatal undernutrition on the number of neurons and apoptotic cells of the locus coeruleus (LC) of female and male rats at postpartum days 7, 12, 20, 30 and 60 were studied. Undernutrition reduces the number of neurons in both sexes without affecting cell death, as indicated by the ratio of apoptotic cells to neurons. The data suggest that in the undernourished groups lower rates of neurogenesis and proliferation (neurogenetic/proliferation rates) might avoid these animals achieving the number of LC neurons as in the control subjects.

Contributions of undernutrition and handling to huddling development of rats.

When newborn rats are separated from the mother, they consistently exhibit the huddling response to maintain body temperature and physical contact. Therefore, we investigated if preweaning handling/sensory stimulation may overcome the huddling deficiencies associated to neonatal undernourishment/maternal deprivation of Wistar rats maintained at constant temperature (30 degrees C). The data indicated that initial and final temperatures in the pile of undernourished (U) and undernourished stimulated (Us) pups was reduced compared to their controls (C and Cs, respectively).

Organization of olfactory glomeruli in neonatally undernourished rats.

Newborn rats maintain mother-litter bonds by using olfactory signals. At birth, units in the olfactory glomeruli (OG) are immature and vulnerable to noxious epigenetic factors like undernutrition. Because little is known about the effects of neonatal undernutrition upon the OG morphological organization, different OG parameters were studied in undernourished Wistar rats at 7, 14 and 21 days of age.

Neonatal food restriction and binaural ear occlusion interfere with the maturation of cortical motor pyramids in the rat.

Golgi-Cox-impregnated pyramidal neurons of layer five motor cortical area were investigated in control, binaural ear-occluded control, undernourished and binaural ear-occluded undernourished Wistar rats of 12, 20 and 30 days of age. In neonatally undernourished, binaural ear-occluded-undernourished and partly in ear-occluded-control subjects, there were significant reductions in both the number and extent of the distal part of the dendritic branches of motor pyramids compared to their controls. Moreover, minimal effects on perikarya measurements were observed.

Alterations in the solitary tract nucleus of the rat following perinatal food restriction and subsequent nutritional rehabilitation.

Newborn of altricial species maintain functional gustatory communication with the mother because the neural substrate and the capacity to discriminate and promote gustofacial responses are already operating. Because little is known about the effects of perinatal food restriction upon gustatory neuronal brain stem structures, we characterized neuronal Golgi-Cox alterations of the solitary tract rostral portion (NSTr) where gustatory information is known to convey in neonatal Wistar rats. Pre-and neonatally undernourished rats exhibited a general reduction in the number and extension of distal dendrites particularly in small neurons but little effect upon perikarya measurements of the NSTr neuronal population.

Undernutrition and food rehabilitation effects on the locus coeruleus in the rat.

Perinatal nutrition plays a fundamental role on the morphological organization and function of a number of brain stem structures. Because little is known of the effects of perinatal undernutrition upon sexually dimorphic structures underlying reproductive behavior, the locus coeruleus morphology of 60-day-old male and female Wistar rats was analyzed. Perinatal food deprivation until weaning significantly decreased the volume and neuronal number of locus coerulus in male and female rats, while nutritional rehabilitation ameliorated these alterations in males but not in females.

A paradigm of undernourishing and neonatal rehabilitation in the newborn rat.

Perinatal undernutrition as a deficiency of nutrient availability, affects body and brain developmental processes and promotes recurrent health problems. Thus, altered mother-litter bonds and deficient environmental interactions may interfere with the brain pluripotential capabilities of the newborn. To gather information concerning the mechanisms underlying perinatal undernutrition we designed a paradigm of undernutrition and neonatal rehabilitation in the rat.

Retrieving of pups by neonatally stressed mothers.

In the rat, perinatal food and maternal deprivation provoke long-lasting effects upon the retrieving responses of dams to displaced pups. In the current study, the retrieving latency and the disruption in the body area of pups chosen by the mother to transport them to a new location was investigated on days 4, 8 and 12 postpartum in lactating Wistar rats. Rats, neonatally underfed by daily (12 h) mother-litter separation in an incubator from days 1 to 23 postpartum, exhibited prolonged retrieving latencies and disruption in the body area of young ones chosen by the dam to transport them to the nest.

Neonatal nutritional rehabilitation of morphological features in facial motoneurons altered by prenatally food deprivation in the rat.

Undernutrition alters facial motoneurons development. Here, we evaluated the plastic characteristics of facial motoneurons in response to neonatal rehabilitation. Prenatally undernourished rat pups derived from pregnant rats fed with 50% of the diet from gestational days G6 to G12, and with 60% of food from G13 to G21 and rehabilitated after birth by a pair of control lactating foster dams.