Impact of hypoxia-ischemia and dopamine treatment on dopamine receptor binding density in the preterm fetal sheep brain.

Dopamine is often used to treat hypotension in preterm infants who are at risk of hypoxic-ischemic (HI) brain injury due to cerebral hypoperfusion and impaired autoregulation. There is evidence that systemically administered dopamine crosses the preterm blood-brain barrier. However, the effects of exogenous dopamine and cerebral HI on dopaminergic signaling in the immature brain are unknown. We determined the effect of HI and dopamine on D1 and D2 receptor binding and expressions of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum of the preterm fetal sheep. Fetal sheep (99 days of gestation, term = 147days) were unoperated controls (n = 6) or exposed to severe HI using umbilical cord occlusion and saline infusion (UCO + saline, n = 8) or to HI with dopamine infusion (UCO + dopamine, 10 µg/kg/min, n = 7) for 74 h. D1 and D2 receptor densities were measured by autoradiography in vitro. DAT, TH, and cell death were measured using immunohistochemistry. HI resulted in cell death in the caudate nucleus and putamen, and dopamine infusion started before HI did not exacerbate or ameliorate these effects. HI led to reduced D1 and D2 receptor densities in the caudate nucleus and reduction in DAT protein expression in the caudate and putamen. Fetal brains exposed to dopamine in addition to HI were not different from those exposed to HI alone in these changes in dopaminergic parameters. We conclude that dopamine infusion does not alter the striatal cell death or the reductions in D1 and D2 receptor densities and DAT protein expression induced by HI in the preterm brain.NEW & NOTEWORTHY This is the first study on the effects of hypoxia-ischemia and dopamine treatment on the dopaminergic pathway in the preterm brain. In the striatum of fetal sheep (equivalent to ∼26-28 wk of human gestation), we demonstrate that hypoxia-ischemia leads to cell death, reduces D1 and D2 receptors, and reduces dopamine transporter. Intravenous dopamine infusion at clinical dosage used in preterm human infants does not alter the striatal cell death, D1 and D2 receptor density levels, and DAT protein expressions after hypoxia-ischemia in the preterm brain.

Determination of dynamic thiol/disulphide homeostasis in children with tetralogy of Fallot and ventricular septal defect.

Oxidative stress may contribute to the pathogenesis of congenital heart defects, but the role of dynamic thiol/disulphide homeostasis has not been evaluated. The objective of this study was to assess whether there are changes in thiol/disulphide homeostasis and nitric oxide levels in children with tetralogy of Fallot (TOF) and ventricular septal defect (VSD). A total of 47 children with congenital heart defects (24 TOF and 23 VSD) and 47 healthy age- and sex-matched controls were included in this study. Serum total thiol and native thiol levels were measured using a novel automatic spectrophotometric method. The amount of dynamic disulphide bonds and related ratios were calculated from these values. Serum nitric oxide levels were detected using a chemiluminescence assay. We found that the average native thiol, total thiol, and disulphide levels were decreased in patients with VSD when compared with healthy individuals (p < 0.001, p < 0.001, and p < 0.01, respectively). While native thiol levels were decreased (p < 0.01), disulphide levels were elevated in the TOF group (p < 0.05). We observed marked augmentation of disulphide/native thiol (p < 0.001) and disulphide/total thiol ratios (p < 0.01) in the TOF group. However, there was a significant decrease in native thiol/total thiol ratio in patients with TOF. No significant changes in these ratios were noted in the VSD group. We detected significant elevations in serum nitric oxide levels in children with TOF and VSD (p < 0.001 for all). These results are the first to demonstrate that thiol/disulphide homeostasis and nitric oxide are associated with TOF and VSD in children.

Genome-wide association study of recurrent early-onset major depressive disorder.

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

Cell migration at the interface of a dual chemical-mechanical gradient.

Cell migration plays a critical role in numerous physiological processes, such as wound healing, response to inflammation, and cancer metastasis. In recent years, accumulating evidence indicates that cell movement is regulated not only by chemical signals but also by mechanical stimuli. In this study, the primary goal is to identify whether a chemical or mechanical stimulus plays the decisive role in directing cell migration. Measuring the motility of cells when they are presented with a combination of chemical and mechanical cues will provide insight into the complex physiological phenomena that guide and direct migration. A novel polyacrylamide hydrogel was designed with an interfacial region where the chemical and mechanical properties varied in opposing directions. One side of the interface was stiff (high Young's modulus) with a low protein concentration, whereas the other side of the interface was compliant (low Young's modulus) with a high protein concentration. The chemical gradient was created by varying the collagen (type I) concentration and the mechanical gradient was introduced by changing the extent of cross-linking in the polymer. The length of the interface with opposing chemical-mechanical profiles was found to be approximately 100 mum. Our results demonstrate that when Balb/c 3T3 fibroblasts were presented with a choice, they either migrated preferentially toward the high-collagen-compliant (low Young's modulus) side of the interfacial region or remained on the high-collagen region, suggesting a more dominant role for chemical stimuli in directing fibroblast locomotion.

Erythropoietin ameliorates damage to the placenta and fetal liver induced by exposure to lipopolysaccharide.

Intrauterine infection and inflammation have been causally linked to preterm birth and fetal brain injury. Using an ovine model of endotoxin-induced brain injury we have recently shown that recombinant human erythropoietin (rhEPO) reduces brain injury and protects against damage to myelination in major myelinated axon tracts. Our present objective was to determine whether rhEPO is also protective of the placenta and the fetal liver, organs which could influence fetal well-being. At 107 +/- 1 days of gestational age (DGA) chronically catheterized fetal sheep were randomly assigned to receive, on 3 consecutive days, either: 1) an i.v. bolus dose of lipopolysaccharide (LPS; approximately 0.9 microg/kg; n = 8); 2) i.v. bolus dose of LPS, followed at 1 h by 5000 IU/kg of rhEPO (LPS + rhEPO, n = 8); 3) rhEPO (n = 3). Seven untreated fetuses served as controls (n = 7). The placenta and fetal liver were examined histologically at 116 +/- 1 DGA; a placental injury index was formulated comprising measures of placental area, apoptosis, tissue injury and the size of the intervillous space. In LPS-exposed fetuses this index was greater than in control or rhEPO alone fetuses (p < 0.02). Treatment of LPS-exposed fetuses with rhEPO resulted in a reduction in the index (p < 0.05) and in the extent of liver necrosis. We conclude that rhEPO offers protection to the placenta and fetal liver in the presence of acute inflammation.

New heads for Freud's hydra: psychoanalysis in Los Angeles.

This paper describes the transplantation of psychoanalysis from Europe to Los Angeles and the similarities and differences in followers, cultural attitudes, institutional organization, and patient symptoms. Psychoanalysis in both places attracted psychiatrists, psychologists, social workers, artists, writers, and movie people, all committed to "modernism" and cultural change. But special American conditions created greater institutional rigidity, medicalization, and a more diffuse patient symptomatology centered on the maternal relationship. Such conditions also fostered bitter disputes over modifications of psychoanalytic theory and practice which have only recently become less acute as the status of psychoanalysis has declined in America.

Negative aging stereotypes and the agentic-communal dichotomy.

Prior research has documented negative aging stereotypes. Our hypothesis is that these only apply when a certain dimension of traits is employed and when older persons occupy certain roles. 42 college students were asked to rate the extent to which each of several "agentic" traits, e.g., active, aggressive, independent, and "communal" traits, e.g., understanding, warm, helpful, characterized a roommate and college professor, both of whom were stated to be either 23 or 65 years of age. For the roommate (but not the professor), the young person was seen as more agentic than the older person. No differences were found on the dimension of communality. It was concluded that young college students may attribute negative behaviors to older persons but this is more likely when the negative behaviors are agentic in nature and the older person occupies certain roles such as "retired person."

Gene-based neurotransmitter modulation in cerebellar granule neurons.

The human glutamic acid decarboxylase (GAD) gene was transferred into rat cerebellar granule neurons. Following adenoviral-mediated gene transfer, nearly 100% of the neurons had transgene expression that persisted for the duration of their survival in culture. GABA levels were elevated both in the growth media and in lysates of GAD-modified granule neurons. In GAD-modified neurons, extracellular GABA levels steadily increased with time, whereas intracellular GABA levels peaked 10 days after gene transfer. GAD-modified neurons released both glutamate and GABA into the surrounding media before and after potassium-induced stimulation, but only the release of glutamate was sensitive to potassium stimulation. These data suggest that glutamatergic neurons, which initially contained no detectable GABA, can be genetically modified to release GABA constitutively.

Prostaglandin-F2 alpha stimulates reproductive behavior of female paradise fish (Macropodus opercularis).

The function of prostaglandin-F2 alpha (PGF2 alpha) in reproductive behavior of adult female paradise fish (Macropodus opercularis) was evaluated. In experiment 1, females were allowed to spawn normally with a male and were left with that male until the following day when testing occurred. Subjects were then randomly assigned to one of three groups: PGF2 alpha (N = 8), vehicle control (N = 3), or a handling control (N = 3); for testing, females were removed, injected, then returned to the same tank. Seven of the eight subjects injected with 500 ng PGF2 alpha initiated complete reproductive behavior following injection. Vehicle and handling control subjects did not show any female reproductive behaviors. Prostaglandin-induced increases in sexual behaviors were seen from 15 to 75 min after the injection and were maximal approximately 45 min postinjection. In experiment 2, mature but unspawned (and presumably sexually naive) females were placed for 1 hr with males which were actively nestbuilding and parenting, following which subjects were either injected with PGF2 alpha (N = 6) or given a vehicle injection (N = 6). Experimental females did not behave differently from control females. Neither groups was observed to approach the male or initiate spawning behaviors following treatment; all subjects in both groups spawned on the following day. In experiment 3, sexually mature females were given extended familiarity with the male and the test tank. Pairs which had not spawned after 6 days (unspawned) were randomly assigned to experimental (N = 6) or control (N = 5) groups. Pairs which had spawned 1 day previously (N = 6) formed a "prespawned" comparison group. Females from the experimental and prespawned groups were injected with PGF2 alpha (500 ng), while the control females received a vehicle injection. Half of the "prespawned" females performed spawning acts while none of the unspawned or control females did so. Detailed behavioral analyses showed little or no effect of PG treatment, despite greater familiarity with the male. In experiment 4, females were placed with males and observed until the early signs of spawning, at which time they were injected with indomethacin (a PG synthesis inhibitor) or vehicle. The behavior of females treated with 35 micrograms (N = 3) or 70 micrograms (N = 6) of indomethacin was unaffected by indomethacin and largely indistinguishable from controls (N = 6). In summary, exogenous prostaglandins reinstate sexual behavior in female paradise fish. However, responsiveness to prostaglandins is influenced by prior sexual experience.(ABSTRACT TRUNCATED AT 400 WORDS)

Freud's Reich, the psychiatric establishment, and the founding of the American Psychoanalytic Association: professional styles in conflict.

Freud's vision of a unified theory of the neuroses has foundered on lack of agreed methods for settling scientific disputes in the field of psychotherapy. Clashes in professional styles and formation of self-validating sub groups have been the dominant trend, exemplified by the founding of psychoanalytic organizations.