Electrical stimulation for gastroparesis. Gastric motility restored.

BACKGROUND: Gastroparesis is a disabling, and sometimes fatal, disease that often does not respond to medical treatment. This single-surgeon prospective study examines the safety and 6-month efficacy of electrical stimulation for the treatment of gastroparesis. METHODS: Sixteen patients with medically refractory gastroparesis underwent laparoscopic implantation of an electrical stimulator device (Enterra Therapy, Medtronic, Minneapolis, MN, USA) consisting of a subcutaneous stimulator and two gastric wall leads. Gastric emptying scans (GES) confirmed the diagnosis of gastroparesis. Patients were evaluated preoperatively using a self-administered GI symptomatology questionnaire and RAND 36 Health Survey. Once patients were >6-months from implantation, a repeat GES was obtained and patients completed a postoperative GI symptomatology questionnaire and RAND 36 Health Survey. Ten of 16 patients in this case series were >6-months from implantation. One was lost to follow-up. An F-test was used to establish equality of standard deviations between the 16 patients evaluated preoperatively and the subset of 10 patients evaluated postoperatively. A Student's t-test was used to evaluate the significance of differences in pre- and postoperative results. RESULTS: Average operating time was 117 min with no intraoperative complications. The majority of patients were discharged on postoperative day 1. There were two complications in the postoperative period. Patients experienced a significant decrease in nausea and vomiting as measured by the GI symptomatology questionnaire. Half of all patients no longer required gastric prokinetic medications and there was a subjective reduction of pyrosis, early satiety, and epigastric pain. A significant increase in quality of life as measured by the RAND 36 Health Survey was seen, and six of eight patients no longer demonstrated gastroparesis on GES. CONCLUSION: Laparoscopic implantation of an electrical stimulation device is a safe and effective treatment by subjective and objective standards for the management of medically refractory gastroparesis.

Characterization of a novel member of the DOK family that binds and modulates Abl signaling.

A novel member of the p62(dok) family of proteins, termed DOKL, is described. DOKL contains features of intracellular signaling molecules, including an N-terminal PH (pleckstrin homology) domain, a central PTB (phosphotyrosine binding) domain, and a C-terminal domain with multiple potential tyrosine phosphorylation sites and proline-rich regions, which might serve as docking sites for SH2- and SH3-containing proteins. The DOKL gene is predominantly expressed in bone marrow, spleen, and lung, although low-level expression of the RNA can also be detected in other tissues. DOKL and p62(dok) bind through their PTB domains to the Abelson tyrosine kinase in a kinase-dependent manner in both yeast and mammalian cells. DOKL is phosphorylated by the Abl tyrosine kinase in vivo. In contrast to p62(dok), DOKL lacks YxxP motifs in the C terminus and does not bind to Ras GTPase-activating protein (RasGAP) upon phosphorylation. Overexpression of DOKL, but not p62(dok), suppresses v-Abl-induced mitogen-activated protein (MAP) kinase activation but has no effect on constitutively activated Ras- and epidermal growth factor-induced MAP kinase activation. The inhibitory effect requires the PTB domain of DOKL. Finally, overexpression of DOKL in NIH 3T3 cells inhibits the transforming activity of v-Abl. These results suggest that DOKL may modulate Abl function.

Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5.

Upon entry into a host cell, retroviruses direct the reverse transcription of the viral RNA genome and the establishment of an integrated proviral DNA. The retroviral integrase protein (IN) is responsible for the insertion of the viral DNA into host chromosomal targets. The two-hybrid system was used to identify a human gene product that binds tightly to the human immunodeficiency virus-type 1 (HIV-1) integrase in vitro and stimulates its DNA-joining activity. The sequence of the gene suggests that the protein is a human homolog of yeast SNF5, a transcriptional activator required for high-level expression of many genes. The gene, termed INI1 (for integrase interactor 1), may encode a nuclear factor that promotes integration and targets incoming viral DNA to active genes.

Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.

Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. The yeast two-hybrid system was used to screen a human complementary DNA (cDNA) library for proteins that associate with YY1, and a c-myc cDNA was isolated. Affinity chromatography confirmed that YY1 associates with c-Myc but not with Max. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.