D-cycloserine augmented exposure therapy for obsessive-compulsive disorder.

BACKGROUND: D-cycloserine (DCS), a glutamatergic partial N-methyl-d-aspartate (NMDA) agonist, can facilitate extinction learning related to cued fear in animals and humans. We predicted that DCS would accelerate obsession-related distress reduction in patients with obsessive-compulsive disorder (OCD) undergoing extinction-based exposure therapy. METHODS: We administered DCS (125 mg) or placebo in a double-blind fashion to individuals with OCD approximately 2 hours before each exposure session. RESULTS: D-cycloserine decreased both the number of exposure sessions required to achieve clinical milestones and the rate of therapy dropout. After four exposure sessions, patients in the DCS group reported significantly greater decreases in obsession-related distress compared with the placebo group; however, after additional sessions, the placebo group tended to catch up. CONCLUSIONS: D-cycloserine augmentation has the potential to increase the efficiency, palatability, and overall effectiveness of standard exposure therapy for OCD.     

An Eph-related receptor protein tyrosine kinase gene segmentally expressed in the developing mouse hindbrain.

In search of genes possibly involved in the regulation of hindbrain segmentation, we have isolated mouse cDNA clones corresponding to putative protein kinase genes by polymerase chain reaction amplification of cDNA from 9.5-day-old embryo hindbrains. In situ hybridization analysis revealed that one of these genes, Sek, was expressed in an alternating segment-restricted pattern in the developing hindbrain. Isolation and analysis of Sek cDNAs covering the entire coding sequence indicated that Sek encoded a putative receptor protein tyrosine kinase, belonging to the Eph family. These data are consistent with a role of the Sek gene product in a signal transduction process involved in pattern formation in the hindbrain.     

Ambulatory 24-hour esophageal pH monitoring

If 24-hour esophageal pH monitoring is to be a useful diagnostic tool, it must reliably discriminate gastroesophageal reflux patients despite daily variations in distal esophageal acid exposure. To address this issue, we studied 53 subjects (14 healthy normals, 14 esophagitis patients, and 25 patients with atypical symptoms) with two ambulatory pH tests performed within 10 days of each other. Intrasubject reproducibility of 12 pH parameters to discriminate the presence of abnormal acid reflux was determined. As a group, the parameters of percent time with pH<4 (total, upright, recumbent) were most reproducible (80%). Therefore, a subject was defined as having gastroesophageal reflux disease if at least one of these three values were abnormal. Intrasubject reproducibility for the diagnosis of reflux disease was 89% for the entire sample. Among subsets, the reproducibility was 93% for the normals and esophagitis patients and 84% for the atypical symptom patients. Total percent time with pH<4 was the single most discriminate pH parameter (85%) and nearly equaled that of the three combined parameters (89%). The intrasubject variability of this parameter was determined by the mean ±2sd of the relative differences between the two test results for all 53 subjects. Total percent time with pH<4 may vary between tests by a factor of 3.2-fold or less (218% higher to 69% lower). We conclude: (1) ambulatory 24-hr esophageal monitoring is a reproducible test for the diagnosis of gastroesophageal reflux disease; and (2) the large intrastudy variability in 24-hr total acid exposure may limit this test's usefulness as a measurement of therapeutic improvement.Supported, in part, by Public Health Services Grant AM 34200-01A1 from NIADDIK.     

Development of a reconstructed human skin model for angiogenesis

We have previously shown that reconstructed human skin engineered from autologous keratinocytes, fibroblasts, and sterilized donor allodermis stimulates angiogenesis within 5-7 days when placed on well-vascularized wound beds in nude mice. When this reconstructed skin was used clinically in more demanding wound beds, some grafts were lost, possibly due to delayed vascularization. As this reconstructed skin lacks any endothelial cells, our aim in this study was to develop an angiogenic reconstructed skin model in which to explore strategies to improve angiogenesis both in vitro and in vivo. We report that culture of small-vessel human dermal microvascular endothelial cells (HuDMECs) was achieved using magnetic beads coated with an antibody to platelet cell adhesion molecule as a means of purifying the culture. Keratinocytes, fibroblasts, and HuDMECs could be cultured from the same skin biopsy. Initial studies culturing HuDMECs and other sources of endothelial cells with the tissue-engineered skin showed that these cells were capable of slowly entering the dermis under standard culture conditions in vitro. In conclusion, this provides us with a model in which to explore strategies for improving angiogenesis in vitro and also establishes the culture methodologies for the production of reconstructed skin containing autologous keratinocytes, fibroblasts, and endothelial cells.