Effect of stress on prefrontal cortex function

Stress is the major epigenetic factor that contributes to the etiology, pathophysiology, and treatment out-come of most psychiatric disorders. Understanding the mechanisms by which stress contributes to these processes can have important implications for improving therapeutic outcome. Considering that a dysfunctional prefrontal cortex has been implicated in many psychiatric disorders, such as schizophrenia and mood disorders, delineating mechanisms by which stress affects prefrontal cortex (PFC) function is critical to our understanding of the role of stress in influencing the disease process. This paper will review recent mechanistic information about the effects of stress on dopamine and glutamate neurotransmission in the PFC.     

The history and future of the fluorescence activated cell sorter and flow cytometry: a view from Stanford

The Fluorescence Activated Cell Sorter (FACS) was invented in the late 1960s by Bonner, Sweet, Hulett, Herzenberg, and others to do flow cytometry and cell sorting of viable cells. Becton Dickinson Immunocytometry Systems introduced the commercial machines in the early 1970s, using the Stanford patent and expertise supplied by the Herzenberg Laboratory and a Becton Dickinson engineering group under Bernie Shoor. Over the years, we have increased the number of measured FACS dimensions (parameters) and the speed of sorting to where we now simultaneously measure 12 fluorescent colors plus 2 scatter parameters. In this history, I illustrate the great utility of this state-of-the-art instrument, which allows us to simultaneously stain, analyze, and then sort cells from small samples of human blood cells from AIDS patients, infants, stem cell transplant patients, and others. I also illustrate analysis and sorting of multiple subpopulations of lymphocytes by use of 8-12 colors. In addition, I review single cell sorting used to clone and analyze hybridomas and discuss other applications of FACS developed over the past 30 years, as well as give our ideas on the future of FACS. These ideas are currently being implemented in new programs using the internet for data storage and analysis as well as developing new fluorochromes, e.g., green fluorescent protein and tandem dyes, with applications in such areas as apoptosis, gene expression, cytokine expression, cell biochemistry, redox regulation, and AIDS. Finally, I describe new FACS methods for measuring activated kinases and phosphatases and redox active enzymes in individual cells simultaneously with cell surface phenotyping. Thus, key functions can be studied in various subsets of cells without the need for prior sorting.     

NMDA antagonist effects on striatal dopamine release: microdialysis studies in awake monkeys.

Brain imaging studies have suggested that the NMDA antagonist ketamine is as potent a releaser of striatal dopamine as amphetamine. This conclusion contradicts microdialysis findings in the rodent that NMDA antagonists, in contrast to amphetamine, have little or no effect on striatal dopamine release. The present study addressed two mechanisms that could account for this discrepancy: 1) whether there is a species difference, i.e., rodents vs. primates, in the responsivity of striatal dopamine to NMDA antagonists, and 2) whether rapid uptake of dopamine prevents reliable measures of synaptic dopamine release by microdialysis in response to NMDA antagonists. MRI-directed in vivo microdialysis was used to compare the effects of psychotomimetic NMDA antagonists phencyclidine (PCP), ketamine, and amphetamine on extracellular striatal dopamine levels in awake rhesus monkeys. The effect of PCP was also investigated in the presence of intrastriatally applied nomifensine, a dopamine uptake blocker. Amphetamine (0.1 or 0.4 mg/kg) produced robust and dose-dependent increases in dopamine release ranging 2-10-fold above baseline. PCP at 0.1 mg/kg had no effect and at 0.3 mg/kg produced a small 50% increase over baseline. Ketamine, at the relatively high dose of 5 mg/kg, produced only a 30% increase in dopamine release. Intrastriatal application of nomifensine did not influence the effect of PCP, suggesting that rapid uptake of dopamine is not preventing the detection of a PCP-induced increase in dopamine release. These findings suggest that in the primate, ketamine and PCP are not effective dopamine releasers, as has been suggested by previous imaging studies.     

Role of microbial toxins in the induction of glucocorticoid receptor beta expression in an explant model of rhinosinusitis

BACKGROUND: Glucocorticoids (GCs) are the most potent agents currently available for relieving the symptoms of chronic rhinosinusitis. The pathogenesis and molecular basis of GC insensitivity in allergic rhinosinusitis are unknown. Studies done on patients with GC-insensitive asthma demonstrated an overexpression of GC receptor beta (GRbeta), an abnormal splice variant and an endogenous inhibitor of the classic GC receptor alpha. The mechanisms that induce the overexpression of GRbeta remain poorly understood. OBJECTIVE: To study the role of Staphylococcus-derived enterotoxin in inducing GRbeta in a human explant model of rhinosinusitis. METHODS: Nasal tissue was obtained from inferior turbinates of nonatopic and ragweed-sensitive patients. Tissue samples from nonatopic patients were incubated in the presence and absence of superantigen (SAg) of staphylococcal enterotoxin. In addition, tissue samples from ragweed-sensitive patients were incubated with and without ragweed allergen in the presence or absence of SAg. The expression of GRbeta was assessed by immunocytochemistry using a specific polyclonal antibody to GRbeta. RESULTS: SAg increased the expression of GRbeta in both atopic and nonatopic tissue. The highest increase in the expression of GRbeta occurred when atopic nasal tissue was incubated with both ragweed and SAg. CONCLUSION: SAg-induced GRbeta is an important modulator of steroid sensitivity in chronic rhinosinusitis.     

Margins of excision for cutaneous melanoma of the eyelid skin: the Collaborative Eyelid Skin Melanoma Group Report

PURPOSE: To evaluate the practice patterns among surgeons who treat melanomas of the eyelid skin with respect to margins of excision and to look for possible correlation between margins of excision and the incidence of local and regional recurrence and distant metastasis. METHODS: A retrospective survey of the members of the American Society of Ophthalmic Plastic and Reconstructive Surgery and the European Society of Ophthalmic Plastic and Reconstructive Surgery yielded 44 cases. The patients' age, sex, date of diagnosis, histologic classification of melanoma, Breslow thickness, Clark level, location of melanoma, size of margins of excision, and findings of local or regional recurrence or distant metastasis were recorded in each case. Patients were stratified on the basis of margins of excision: 5 mm but <10 mm; and >/=10 mm. Patients were also stratified by Breslow thickness. A Cox regression model was used to evaluate the predictive value of each factor for recurrence. Main outcome measures were the incidences of local and regional recurrence and distant metastasis as a function of margins of excision and Breslow thickness. RESULTS: The majority of patients for whom reliable information was available had excision margins of /=10 mm, but this difference was not statistically significant because very few patients had melanomas at least 2 mm thick. Breslow thickness was the only statistically significant predictor of local, regional, and distant metastasis. Margins of excision did not have a statistically significant effect on local, regional, or distant recurrence. CONCLUSIONS: Breslow thickness is an important prognostic indicator for eyelid skin melanomas. A 5-mm margin of excision may be adequate for thin melanomas of the periocular skin, but because of the small number of patients in this series who had >5-mm margins, a definitive comparison of outcome with larger margins of excision cannot be made. For melanomas >/=2 mm, wider margins of excision may be prudent, and careful surveillance for local and regional recurrence is indicated.     

Blockage of the lacrimal drainage apparatus as a side effect of docetaxel therapy

BACKGROUND: The current study was conducted to report the severity and management of canalicular and nasolacrimal duct stenosis as a side effect of docetaxel therapy and to report the outcomes of surgical intervention for this condition. METHODS: The records of 148 patients with epiphora associated with docetaxel therapy who were evaluated at the Ophthalmology Service at The University of Texas M. D. Anderson Cancer Center were reviewed. The frequency of docetaxel administration, the dose intensity, the cumulative dose of docetaxel, and any concomitant chemotherapeutic agents were recorded. Each patient underwent an ophthalmologic examination and in-office probing and irrigation. The patients either were treated with topical steroids or offered a surgical procedure for canalicular stenosis- (silicone intubation, dacryocystorhinostomy [DCR] with the placement of silicone tubes, or DCR with the placement of Pyrex glass tubes), depending on the severity of the canalicular stenosis. RESULTS: Docetaxel was given weekly in 71 patients, every 2 weeks in 5 patients, and every 3 weeks in 72 patients. Thirty patients (59 eyes) who received weekly docetaxel underwent surgery to correct epiphora. Twenty-three patients (39 eyes) were treated with temporary silicone tube placement, 9 patients (13 eyes) were treated with DCR with temporary silicone tube placement, and 4 patients (7 eyes) were treated with DCR with permanent Pyrex glass tube placement. Twenty-nine of the 30 patients who underwent surgery reported improvement or total resolution of epiphora after the procedure. Ten additional patients (20 eyes) who received weekly docetaxel had complete closure of their canaliculi but elected not to undergo surgery. Of special note were two patients who received weekly docetaxel in the neoadjuvant setting and developed complete closure of the canaliculi. Of the patients who received docetaxel every 2 or 3 weeks, only 3 required a surgical intervention to correct epiphora; none required Pyrex glass tube placement. CONCLUSIONS: Canalicular and nasolacrimal duct obstruction is a common side effect of weekly docetaxel therapy and can occur even when this drug is used in the neoadjuvant setting. The results of the current study indicate that early temporary silicone intubation in symptomatic patients receiving weekly docetaxel can prevent further closure of the lacrimal drainage apparatus and obviate more involved surgical interventions and permanent Pyrex glass tube placement. Cancer 2003;98:504-7.     

Pulmonary artery sling associated with tetralogy of fallot

We describe a rare case of pulmonary artery sling occurring simultaneously with tetralogy of Fallot. This report describes the successful concomitant repair of both intracardiac anomalies.