Physician counseling, informed consent and parental decision making for infants with hypoplastic left-heart syndrome.

Until the development in 1980 by William Norwood of a staged palliative surgical procedure for hypoplastic left heart syndrome (HPLHS), there was no treatment for that condition. With medical developments in the 1980s, parents had the option of the Norwood procedure, transplantation or comfort care for a child born with HPLHS. With an improvement in the survival rate for the Norwood procedure from an initial 30% to now better than 80%, some physicians believe that comfort care should no longer be an option. If, however, medically sophisticated parents, who know the neurological and motor skills impairments that accompany HPLHS, object to the surgery, they are allowed to opt for comfort care. This two-pronged approach to medical treatment seems to violate the norms on equity and fairness in the care of the patient. Parents need to be informed about long-term neurological and motor skill development as well as survival rates to give informed consent.

Inhibition of 5α-reductase activity in late pregnancy decreases gestational length and fecundity and impairs object memory and central progestogen milieu of juvenile rat offspring.

Psychological, physical and/or immune stressors during pregnancy are associated with negative birth outcomes, such as preterm birth and developmental abnormalities. In rodents, prenatal stressors can alter the expression of 5α-reductase enzymes in the brain and may influence cognitive function and anxiety-type behaviour in the offspring. Progesterone plays a critical role in maintaining gestation. In the present study, it was hypothesised that 5α-reduced progesterone metabolites influence birth outcomes and/or the cognitive and neuroendocrine function of the offspring. 5α-Reduced steroids were manipulated in pregnant Long-Evans rats via the administration of vehicle, the 5α-reduced, neuroactive metabolite of progesterone, 5α-pregnan-3α-ol-20-one (3α,5α-THP, allopregnanolone; 10 mg/kg/ml, s.c.), or the 5α-reductase inhibitor, finasteride (50 mg/kg/ml, s.c.), daily from gestational days 17-21. Compared to vehicle or 3α,5α-THP treatment, finasteride, significantly reduced the length of gestation and the number of pups per litter found in the dams' nests after parturition. The behaviour of the offspring in hippocampus-dependent tasks (i.e. object recognition, open field) was examined on post-natal days 28-30. Compared to vehicle-exposed controls, prenatal 3α,5α-THP treatment significantly increased motor behaviour in females compared to males, decreased progesterone content in the medial prefrontal cortex (mPFC) and diencephalon, increased 3α,5α-THP and 17ß-oestradiol content in the hippocampus, mPFC and diencephalon, and significantly increased serum corticosterone concentrations in males and females. Prenatal finasteride treatment significantly reduced object recognition, decreased hippocampal 3α,5α-THP content, increased progesterone concentration in the mPFC and diencephalon, and increased serum corticosterone concentration in female (but not male) juvenile offspring, compared to vehicle-exposed controls. Thus, inhibiting the formation of 5α-reduced steroids during late gestation in rats reduces gestational length, the number of viable pups per litter, and impairs cognitive and neuroendocrine function in the juvenile offspring.

Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor.

Progestogens [progesterone (P(4)) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P(4) metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA), 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P(4), in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence). Thus, further understanding of 3α,5α-THP's role and mechanisms to enhance affective and motivated processes is essential.

Progesterone turnover to its 5α-reduced metabolites in the ventral tegmental area of the midbrain is essential for initiating social and affective behavior and progesterone metabolism in female rats.

BACKGROUND: Among women and female rodents, progesterone (P) influences social affiliation and affect. These effects may be partly due to formation of its 5α-reduced, 3α- hydroxylated metabolite, 5α-pregnan-3α-ol-20-one (3α,5α- THP). AIM: To elucidate whether actions of 3α,5α-THP in the midbrain ventral tegmental area (VTA) are both necessary and sufficient to enhance non-sexual and sexual social behaviors, affect, and central 3α,5α-THP metabolism. MATERIALS AND METHODS: P and 3α,5α-THP formation were unperturbed or blocked in VTA via infusions of vehicle, PK11195 (400 ng), and/or indomethacin (10 µg). Rats then received subsequent infusions of vehicle or 3α,5α-THP (100 ng) and were assessed in a battery of tasks that included open field (exploration), elevated plus maze (anxiety behavior), social interaction (social affiliation), and paced mating (sexual behavior) or were not tested. Metabolic turnover of P to its 5α-reduced metabolites was assessed in plasma, midbrain, hippocampus, frontal cortex, diencephalon, and remaining subcortical tissues (control interbrain). RESULTS: Infusions of any combination of inhibitors significantly reduced social and affective behavior in all tasks compared to vehicle, concomitant with reduced turnover of P to its 5α-reduced metabolites, in midbrain only. Subsequent infusions of 3α,5α-THP significantly reinstated/enhanced anti- anxiety behavior, lordosis, and P turnover to its 5α-reduced metabolites in midbrain, as well as hippocampus, cortex, and diencephalon (but not plasma or interbrain). CONCLUSIONS: These data are the first to provide direct evidence that actions of 3α,5α-THP in the VTA are both necessary and sufficient for social and affective behavior, as well as initiation of central 5α-reduction.

Sex-dependent effects of chronic unpredictable stress in the water maze.

Exposure to chronic predictable stress, such as restraint, can affect performance on spatial memory tasks and these effects have been shown to be sex-specific in rats. It is not known whether unpredictable stress has similar sex-specific effects on spatial memory and whether those effects are present after the stress procedure has ended. Therefore, the current study tested male and female rats in the Morris water maze either immediately or 3 weeks following exposure to 10 days of unpredictable stress (CUS). Male and female rats were exposed to 10 days of stressors that varied by type and time of stressor application. Exposure to CUS decreased the distance swam to locate the hidden platform during acquisition training in the water maze for female but not male rats. Overall, male rats performed better than female rats during the acquisition, probe and matching to place trials. These effects were observed when assessing spatial memory performance immediately or 3 weeks following the last stressor. Plasma corticosterone levels followed the behavioral differences during the acquisition trials in that control female rats had increased basal and swim-stimulated corticosterone levels compared to CUS female rats and control male rats. These data demonstrate that unpredictable stress influences performance on the water maze in a sex-specific manner, which parallel plasma corticosterone levels. The improved performance of female rats following CUS exposure was present 3 weeks after the termination of the stress procedures, suggesting that stress may have lasting effects on underlying neural systems.

Gambling pathology is associated with dampened cortisol response among men and women.

Pathological gambling has many similarities to pharmacological addiction. Notably, both pathological gambling and drug addiction are characterized by aberrations in hypothalamic-pituitary-adrenal (HPA) axis responding. As well, there are indications that gender differences may play a role in these processes. Whether gender and/or HPA response are associated with pathological gambling was of interest. Recreational and pathological gamblers (15 men and 6 women per group) had the HPA factor, cortisol, assessed in saliva before and after watching a video of their preferred mode of gambling (slot machines, horse race betting, scratch-off tickets, blackjack, video poker, craps, sports betting, online casino games, or lottery tickets), and a video of neutral stimuli (a rollercoaster ride). Basal levels of salivary cortisol did not significantly differ among recreational and pathological gamblers. However, recreational gamblers demonstrated significantly increased salivary cortisol levels after the gambling and rollercoaster videos, whereas pathological gamblers demonstrated no salivary cortisol increase in response to either video stimulus. There was also a non-significant trend for women to have a greater cortisol response to video stimuli compared to men. These data suggest that pathological gambling is associated with hypoactive HPA response to gambling stimuli, similar to chronic drug exposure, and gender may contribute to this effect.

Male gamblers have significantly greater salivary cortisol before and after betting on a horse race, than do female gamblers.

Prevalence rates of gambling are influenced by gender. Among normative populations, hypothalamic-pituitary-adrenal (HPA) axis response to stress is affected by gender. However, pathological, compared to recreational, gamblers demonstrate perturbations in HPA activation in response to gambling stimuli. We examined whether there were gender differences in HPA response to gambling in a naturalistic setting among horse-race bettors and scratch-off lottery bettors. Salivary cortisol was collected from horse-race gamblers (n=32) and scratch-off lottery ticket players (n=39) before and after (0, 10, or 20 min) betting on a horse race at an off-track betting establishment. Salivary cortisol levels were significantly higher among men than among women, both prior to and following, betting on a horse race. Among women, but not men, there was a decline in salivary cortisol across time in scratch-off bettors, whereas women horse-race bettors maintained consistent low concentrations of salivary cortisol at every time point sampled. Together these data suggest that engaging in gambling may have different effects on stress responses of men, compared to women. Whether these gender differences in HPA activation contribute to gender-related differences in gambling behavior is the subject of ongoing investigation.

Estrogen is necessary for 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) infusion to the ventral tegmental area to facilitate social and sexual, but neither exploratory nor affective behavior of ovariectomized rats.

The progesterone metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP, allopregnanolone), acts in the ventral tegmental area (VTA) to facilitate exploratory, anti-anxiety, and socio-sexual behavior among ovariectomized (OVX), estrogen (E(2))-primed rats and gonadally-intact rats with high (proestrus) or low (diestrus) endogenous E(2) levels. The extent to which E(2) is required for these effects of 3alpha,5alpha-THP is not known. OVX rats were primed with systemic 17beta-estradiol (10 microg) or oil vehicle and were infused 44 h later with 3alpha,5alpha-THP (100 ng) or beta-cyclodextrin vehicle to the VTA, substantia nigra (SN), or central grey (CG). Rats were assessed in a battery of exploratory (open field), anxiety (elevated plus maze), social (partner preference, social interaction), and sexual (paced mating) tasks. E(2)-priming was necessary for 3alpha,5alpha-THP infusions to facilitate social interaction and mating and midbrain 3alpha,5alpha-THP levels were higher among E(2)-compared to vehicle-primed rats. Irrespective of E(2)-priming, rats infused with 3alpha,5alpha-THP to the VTA, but not SN or CG, demonstrated increased exploration in an open field, anti-anxiety behavior on an elevated plus maze, and preference for a male. Thus, actions of 3alpha,5alpha-THP in the VTA to enhance social and sexual behaviors were reliant on E(2) but increases in exploratory and anti-anxiety behavior were not.

Treatment decision-making for patients with the Herlitz subtype of junctional epidermolysis bullosa.

The Herlitz subtype of junctional epidermolysis bullosa (JEB-H) is a lethal genetic disorder characterized by recurrent and persistent erosions of the epithelial surfaces that heal with exuberant granulation tissue. In addition, respiratory distress, refractory anemia and failure to thrive are often seen. Mortality in the first year of life approaches 90%. JEB-H is caused by mutations in the genes that encode the protein laminin 5, a structural molecule involved in the adhesion of epidermis to dermis. There is currently no cure for JEB-H. Medical interventions treat complications but do not ultimately limit mortality. Ethical principles contend that offering comfort and company to the patient and family, not aggressive therapies, should comprise the mainstay of care for affected infants.

Approaches to end-of-life decision-making in the NICU: insights from Dostoevsky's The Grand Inquisitor.

For many parents stopping life-sustaining medical treatment on their dying infant is psychologically impossible. Dostoevsky's insights into human behavior, particularly the fact that individuals do not want the anxiety and guilt associated with responsibility for making difficult decisions, might change the way physicians approach parents for permission to withdraw life-prolonging medical interventions on dying infants.

Resuscitation of the preterm infant against parental wishes.

Over the past 40 years, the norms on who is to make treatment decisions for newborns, and on what standards, have been significantly altered and revised. Today the standard for treatment of newborns is the "best interest" of the child. A recent ruling of the Texas Supreme Court authorizing a doctor to resuscitate a potentially viable very premature newborn over the parents' objection is a challenge to that standard.

Ethical issues in fetal surgery involving a twin pregnancy.

In utero surgery may provide benefit to a compromised fetus. The possibility of fetal surgery in a twin pregnancy extends the risk-benefit calculus beyond that of the fetus and mother to include the companion fetus and raises the issue of when, if ever, may fetus B be placed at substantial risk to benefit fetus A. Insight into the ethical dimensions of this issue is provided by the norms that govern the use of children in nontherapeutic research and the justifications used in twin-to-twin transplant cases.