Differences in withdrawal symptoms, microglia activity, and cognitive functioning in rats exposed to continuous low-dose heroin in-utero.

INTRODUCTION: Opioid use during pregnancy and subsequent neonatal opioid withdrawal syndrome (NOWS) have been associated with poor developmental outcomes including cognitive functioning. Less is known about the underlying molecular effects of prenatal opioid exposure and subsequent withdrawal; however, given the recent increase in NOWS cases, there is a pressing need to better understand these effects, which may partially explain cognitive deficits that have been observed in both preclinical NOWS models and patients with NOWS. This study evaluated the effects of prenatal heroin exposure and subsequent precipitated withdrawal symptoms on microglial reactivity in the nucleus accumbens (NAc), dorsal hippocampus (HC), and ventral tegmental area (VTA) in rat neonates, as well as cognitive functioning at three developmental time points using the Morris Water Maze (MWM) task. METHODS: Heroin or saline (2 mg/kg) was randomly assigned and administered to six pregnant Sprague Dawley rat dams via osmotic minipump. A total of 63 rat neonates underwent naloxone-precipitated (5 mg/kg, subcutaneous injection) withdrawal testing at postnatal day 10 (PN10). Following withdrawal testing, neonates were randomly assigned to undergo perfusion and subsequent immunohistochemistry experiments to fluoresce Iba-1 for microglia detection, or to undergo the MWM task at three separate developmental time points (PN21-23; PN37; PN60) for cognitive testing. RESULTS: Results suggest that in-utero heroin exposure led to an increase in ultrasonic vocalizations during naloxone-precipitated withdrawal; a sensitive index of withdrawal in rat neonates. Additional results suggest increased microglial reactivity in the HC and VTA, but not the NAc, as well as reduced performance during the MWM in the group exposed to heroin in-utero. DISCUSSION: Together, these data suggest that in-utero opioid exposure is associated with microglial reactivity in brain regions associated with learning and memory, and may be associated with later cognitive deficits. Further research is needed to characterize these findings, which may inform future therapeutic strategies for this vulnerable population.

Relationship between Resident-In-Training Examination in psychiatry and subsequent certification examination performances.

OBJECTIVE: This study analyzed the relationship between performance on The American College of Psychiatrists' Psychiatry Resident-In-Training Examination (PRITE) and the ABPN Part 1 examination. METHODS: Pearson correlation coefficients were used to examine the relationship between performance on the 2002 PRITE and the 2003 Part 1 examination for 297 examinees. RESULTS: The correlation between the PRITE global psychiatry and the Part 1 psychiatry scores was 0.59, and the correlation between the PRITE global neurology and the Part 1 neurology scores was 0.39. CONCLUSION: Although the PRITE and the Part 1 examination have different purposes and are developed independently, the significant correlations between scores on the two tests support the use of PRITE results to guide preparation for the Part 1 examination. Guidelines for PRITE scores associated with poor performance on the Part 1 examination are provided.

S. epidermidis biofilm formation: effects of biomaterial surface chemistry and serum proteins.

Most infections due to implanted cardiovascular biomaterials are initiated by bacterial adhesion of Staphylococcus epidermidis, followed by colonization and biofilm formation on the surface of the implant. This study examined the role of serum proteins and material surface chemistry in the formation of S. epidermidis biofilm on polyurethanes (Elasthane 80A, hydrophobic) modified with polyethylene oxide (Elasthane 80A-6PEO, hydrophilic) and fluorocarbon (Elasthane 80A-6F, hydrophobic). Initial adhesion, aggregation, biofilm thickness, viability, and slime formation of S. epidermidis strain, RP62A in phosphate buffered saline (PBS), tryptic soy broth (TBS), and 20% pooled human serum was quantified. In the presence of adsorbed serum proteins, initial bacterial adhesion was suppressed significantly to <2% relative to adhesion in TSB or PBS. However, adhesion, aggregation, and proliferation increased dramatically in the 12-24 h period on Elasthane 80A and Elasthane 80A-6F, which resulted in an extensive network of biofilm. A contrasting trend was observed on the hydrophilic Elasthane 80A-6PEO surface, with minimal bacterial adhesion, which decreased steadily over 24 h. In the presence of serum proteins, an increasingly thick ( approximately 20 mum) biofilm formed on the hydrophobic surfaces over 48 h whereas the formation of a mature biofilm on the hydrophilic surface was impeded with few viable bacteria present over 48 h. Furthermore, slime was detected during the initial phase of bacterial adhesion at 2 h and increased over time with the formation of biofilm. These results have shown that while initial S. epidermidis adhesion is suppressed in the presence of adsorbed proteins, inter-bacterial adhesion possibly aided by slime production leads to the formation of a robust mature biofilm. Also, biomaterial surface chemistry affected biofilm formation and, most notably, polyethylene oxide significantly inhibited S. epidermidis biofilm formation over 48 h in vitro.

From too little too late to early and often: child psychiatry education during medical school (and before and after).

In this article we propose developmentally informed remedies to the challenges that face research training. The initiatives described in it have been implemented to various degrees at our institution, and several are already being replicated or expanded through strategic partnerships across the country. We are fortunate to work in an environment in which child and adolescent psychiatry is visible and well represented, but we are aware than many of the settings in which education and recruitment needs are most pressing may not have the range of our resources. We view our different programs as seamlessly interconnected with one another but present them as separate entities to facilitate the incorporation of different components into local realities.

Association of a critical CSF tryptophan threshold level with depressive relapse.

This work studies association between relapse during acute tryptophan depletion (ATD) and CSF level of tryptophan (TRP) in remitted depressives treated with sertraline or bupropion. Eight medication-responding depressives ingested an ATD amino acid mixture during 48-h continuous CSF sampling before and after treatment. Mood rating scores were compared with nadir levels of TRP in CSF. CSF TRP nadirs averaged 8.7% of am baselines in remitted patients. Mood relapsed whenever the CSF nadir was below 40 nmol/l TRP in remitted patients, and never when above (Fisher's exact test, P=0.029). Relapsing medication responders also showed very low preantidepressant ATD-induced nadirs. ATD-induced relapses were associated with low CSF TRP levels. Individual susceptibility to depletion may be independent of antidepressant treatment, mood state, or treatment status. Resistance to relapse may invoke an undefined, protective CNS mechanism against extremely low CSF levels of TRP during ATD.

Serial cerebrospinal fluid tryptophan and 5-hydroxy indoleacetic acid concentrations in healthy human subjects.

The role of the serotonergic system in the pathogenesis of behavioral disorders such as depression, alcoholism, obsessive-compulsive disorder, and violence is not completely understood. Measurement of the concentration of neurotransmitters and their metabolites in cerebrospinal fluid (CSF) is considered among the most valid, albeit indirect, methods of assessing central nervous system function in man. However, most studies in humans have measured lumbar CSF concentrations only at single time points, thus not taking into account rhythmic or episodic variations in levels of neurotransmitters, precursors, or metabolites. We have continuously sampled lumbar CSF via subarachnoid catheter in 12 healthy volunteers, aged 20-65 years. One ml (every 10 min) CSF samples were collected at a rate of 0.1ml/min for 24-hour (h), and the levels of tryptophan (TRP) and 5-hydroxy indoleacetic acid (5-HIAA) were measured. Variability across all 12 subjects was significantly greater (P < 0.0001) than the variability seen in repeated analysis of a reference CSF sample for both 5-HIAA (32.0% vs 7.9%) and TRP (25.4% vs 7.0%), confirming the presence of significant biological variability during the 24-hr period examined. This variability could not be explained solely by meal related effects. Cosinor analysis of the 24-hr TRP concentrations from all subjects revealed a significant diurnal pattern in CSF TRP levels, whereas the 5-HIAA data were less consistent. These studies indicate that long-term serial CSF sampling reveals diurnal and biological variability not evident in studies based on single CSF samples.

Gene expression during S. epidermidis biofilm formation on biomaterials.

Biomaterial-centered infections are initiated by adhesion of bacteria to an implant, followed by colonization and mature biofilm formation. Staphylococcus epidermidis is commonly identified as the cause of these device-centered infections. This study used an in vitro model to evaluate temporal changes in the expression of genes-icaADBC, agrBDCA, aap, and atle-that have been identified to play a role in the pathogenesis of S. epidermidis infections. Real-time reverse transcription-polymerase chain reaction was used to determine changes in gene expression from S epidermidis biofilm grown on polyurethanes (Elasthane 80A, hydrophobic) modified with polyethylene oxide (Elasthane 80A-6PEO, hydrophilic) and fluorocarbon (Elasthane 80A-6F, hydrophobic). In vitro expression of the ica locus, which is involved in initial adhesion and intracellular aggregation, increased up to 100-fold from 2 to 48 h, whereas gene expression for autolysin AtlE decreased slightly from 2 to 12 h, followed by a 10-fold increase by 48 h. Upregulation of the aap gene associated with bacterial accumulation and the agr quorum-sensing system was observed during biofilm formation over 48 h. In addition, no correlation was observed between S. epidermidis gene expression and biomaterial surface chemistry. This study used an in vitro model to demonstrate that enhanced expression of the atle, aap, agr, and ica genes plays an important role in initial foreign body colonization and potentially in the establishment of a device-associated infection.

Maintenance of certification in psychiatry.

The American Board of Medical Specialties (ABMS) developed 6 core competencies for physicians of all specialties and a maintenance of certification (MOC) program for board-certified physicians. The MOC program incorporates the 6 competencies into 4 component areas: professional standing, self-assessment and lifelong learning, cognitive expertise, and performance in practice. These 4 components are designed to promote a cycle of lifelong learning, self-assessment and peer review, and incorporation of best practices in order to improve the quality of health care in clinical practice. The American Board of Psychiatry and Neurology is a member board of the ABMS and has adapted the competencies and MOC requirements for psychiatrists and neurologists.

Model curriculum for academic child and adolescent psychiatry training.

OBJECTIVE: The United States is facing a severe shortage of academic child and adolescent psychiatrists. This article reviews a model integrated pathway to improve recruitment. METHODS: The authors review training portals for research in child and adolescent psychiatry. There is a summary of a focus group discussion of the advantages and disadvantages of the Integrated Research Pathway in Child and Adolescent Psychiatry (IRPCAP). RESULTS: The University of Colorado and Yale University have initiated integrated pathways. These pathways integrate research into a 5 or 6-year residency to train the next generation of physician-scientists. CONCLUSION: The innovative Integrated Research Pathway in Child and Adolescent Psychiatry training model has enhanced recruitment of talented physician-scientists. Challenges include long-term financial viability and incorporating all training requirements. Novel pilot models of training are encouraged.

Inhibition of bacterial and leukocyte adhesion under shear stress conditions by material surface chemistry.

Biomaterial-centered infections, initiated by bacterial adhesion, persist due to a compromised host immune response. Altering implant materials with surface modifying endgroups (SMEs) may enhance their biocompatibility by reducing bacterial and inflammatory cell adhesion. A rotating disc model, which generates shear stress within physiological ranges, was used to characterize adhesion of leukocytes and Staphylococcus epidermidis on polycarbonate-urethanes and polyetherurethanes modified with SMEs (polyethylene oxide, fluorocarbon and dimethylsiloxane) under dynamic flow conditions. Bacterial adhesion in the absence of serum was found to be mediated by shear stress and surface chemistry, with reduced adhesion exhibited on materials modified with polydimethylsiloxane and polyethylene oxide SMEs. In contrast, bacterial adhesion was enhanced on materials modified with fluorocarbon SMEs. In the presence of serum, bacterial adhesion was primarily neither material nor shear dependent. However, bacterial adhesion in serum was significantly reduced to < or = 10% compared to adhesion in serum-free media. Leukocyte adhesion in serum exhibited a shear dependency with increased adhesion occurring in regions exposed to lower shear-stress levels of < or = 7 dyne/cm2. Additionally, polydimethylsiloxane and polyethylene oxide SMEs reduced leukocyte adhesion on polyether-urethanes. In conclusion, these results suggest that surface chemistry and shear stress can mediate bacterial and cellular adhesion. Furthermore, materials modified with polyethylene oxide SMEs are capable of inhibiting bacterial adhesion, consequently minimizing the probability of biomaterial-centered infections.

Macrophage behavior on surface-modified polyurethanes.

Adherent macrophages and foreign body giant cells (FBGCs) are known to release degradative molecules that can be detrimental to the long-term biostability of polyurethanes. The modification of polyurethanes using surface modifying endgroups (SMEs) and/or the incorporation of silicone into the polyurethane soft segments may alter macrophage adhesion, fusion and apoptosis resulting in improved long-term biostability. An in vitro study of macrophage adhesion, fusion and apoptosis was performed on polyurethanes modified with fluorocarbon SMEs, polyethylene oxide (PEO) SMEs, or poly(dimethylsiloxane) (PDMS) co-soft segment and SMEs. The fluorocarbon SME and PEO SME modifications were shown to have no effect on macrophage adhesion and activity, while silicone modification had varied effects. Macrophages were capable of adapting to the surface and adhering in a similar manner to the silicone-modified and unmodified polyurethanes. In the absence of IL-4, macrophage fusion was comparable on the modified and unmodified polyurethanes, while macrophage apoptosis was promoted on the silicone modified surfaces. In contrast, when exposed to IL-4, a cytokine known to induce FBGC formation, silicone modification resulted in more macrophage fusion to form foreign body giant cells. In conclusion, fluorocarbon SME and PEO SME modification does not affect macrophage adhesion, fusion and apoptosis, while silicone modification is capable of mediating macrophage fusion and apoptosis. Silicone modification may be utilized to direct the fate of adherent macrophages towards FBGC formation or cell death through apoptosis.