Differences in the immunogenicity of latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus genomes derived from LMP1-positive and -negative nasopharyngeal carcinoma

We have previously shown that an EBV-encoded latent membrane protein 1 (LMP1) gene derived from a nude mouse-propagated nasopharyngeal carcinoma (NPC) tumor and expressed in nonimmunogenic murine mammary carcinoma S6C cells failed to convey immunogenicity (rejectability) in syngeneic mice, whereas the corresponding B-cell derived LMP1 gene made the mice highly immunogenic. This raised the question of whether LMPL-expressing NPCs have been selected for low immunogenicity at the viral gene expression level. If so, LMP1-negative tumors that carry highly methylated LMP1 regulatory sequences may not have been exposed to a similar immunoselection. In the present study, we have compared LMP1 genes derived from two LMP1-positive NPCs and two LMP1-negative NPCs. All four genes were expressed in S6C cells in parallel with the previously tested isolates from a B-cell (B95-8)-derived and a nude mouse-propagated NPC (Cao)-derived gene. As in the previous study, we have found that the B-cell-derived LMP1 isolate was highly immunogenic. LMP1-positive tumor-derived isolates were poorly immunogenic, whereas the isolates from the LMP1-negative NPC tumor had intermediate immunogenicity. Sequence data revealed that LMP1 genes from LMP1-expressing NPC had 16 amino acid substitutions, whereas LMP1 from non-LMP1-expressing NPC had only 9 amino acid changes in the coding region. Three of the changes were at shared sites, but with different modifications. The fact that the gene from non-LMP1-expressing NPC mutated at a low frequency but was more immunogenic than the LMP1 gene derived from LMP1-expressing NPC, which was highly mutated but less immunogenic, favors the idea that LMP1-positive tumors escape immunosurveillance in immunocompetent hosts by either a selective down-regulation of LMP1 expression, methylation in the LMP1 promoter sequence, or mutation of LMP1 in LMP1-expressing samples.     

Characterization of ultraviolet light-induced relaxation of the isolated duodenum of the rat.

1 Isolated duodenum of the rat, exposed to ultraviolet (u.v.) light in the presence of NO2 ions, responded with reversible relaxation. 2 The photorelaxation response did not seem to involve any known receptor mechanisms and was independent of any ganglionic or neuronal influences. 3 Changes in the ionic environment of the tissue showed that NA+ and Ca2+ were essential for the photorelaxation. K+ depolarized-tissue did not show the photoresponse. 4 The presence of the metabolic inhibitors, iodoacetic acid, 2,4-dinitrophenol, sodium fluoride, sodium azide or potassium cyanide, abolished the photorelaxation response. 5 It is proposed that the photorelaxation of the tissue resulted from the liberation of metabolic energy following NO2 ion-dependent absorption of u.v. light energy, which in turn, interfered with the Na+ ion movement across the cell membrane.     

Lack of significant circadian and post-prandial variation in phosphate levels in subjects receiving chronic hemodialysis therapy

BACKGROUND: The present study was designed to determine the reliability of the current practice of random pre-dialysis phosphate testing in subjects receiving hemodialysis therapy, since phosphate levels exhibit a significant variation in a 24-hour period under usual physiologic conditions. METHODS: Subjects receiving chronic hemodialysis (HD) were invited to participate during an incidental hospitalization. In Study A subjects (n=31) had serum phosphate tested three times on a single non-dialysis day, between 6 to 7 am (A1), between 11 am to 12:30 pm (A2), and 3:45 pm to 4:45 pm (A3). In study B subjects (n=25) had serum phosphate tested just before (B1) and 2 hours after lunch (B2), on a non-dialysis day. For Study A the collection times coincided with the start times of the out-patient dialysis shifts at our institution. All patients continued their usual phosphate binder therapy, if any. For study A the results were analyzed using one-way repeated measures analysis of variance or Friedman repeated measures analysis of variance on ranks, as opposite. Paired t-test was used for Study B. Results are expressed as mean+/- standard deviation. RESULTS: Twenty-three men and eight women (mean age 62.2+/-15.2 years) were enrolled in Study A (24 Caucasian, 7 African-American). Nineteen men and six women (mean age 65.5+/-12.8 years) participated in study B (19 Caucasian, 6 African-American). In Study A, there was no significant difference in the mean serum phosphate levels in the samples collected through the day A1 (4.5+/-1.3 mg/dL), A2 (4.5+/-1.3 mg/dL) and A3 (4.7+/-1.5 mg/dL) (p=0.19 for comparison of the three). The mean amplitude of circadian variation (peak minus trough) was 0.64+/- 0.37 mg/dL. Similarly, there was no significant difference in the mean serum phosphate before (4.4+/-1.4 mg/dL) and two hours after lunch (4.4+/-1.5 mg/dL) (p =0.6). The mean of the difference in serum phosphate (post-prandial minus pre-prandial) was 0.2+/-0.4 mg/dL. CONCLUSION: Our results in hospitalized HD subjects indicate there is no significant difference in phosphate levels at different times of a single day or in relation to meals.     

Does provider adherence to a treatment guideline change clinical outcomes for patients with bipolar disorder? Results from the Texas Medication Algorithm Project

BACKGROUND: Despite increasing adoption of clinical practice guidelines in psychiatry, there is little measurement of provider implementation of these recommendations, and the resulting impact on clinical outcomes. The current study describes one effort to measure these relationships in a cohort of public sector out-patients with bipolar disorder.METHOD:Participants were enrolled in the algorithm intervention of the Texas Medication Algorithm Project (TMAP). Study methods and the adherence scoring algorithm have been described elsewhere. The current paper addresses the relationships between patient characteristics, provider experience with the algorithm, provider adherence, and clinical outcomes. Measurement of provider adherence includes evaluation of visit frequency, medication choice and dosing, and response to patient symptoms. An exploratory composite 'adherence by visit' score was developed for these analyses.RESULTS: A total of 1948 visits from 141 subjects were evaluated, and utilized a two-stage declining effects model. Providers with more experience using the algorithm tended to adhere less to treatment recommendations. Few patient factors significantly impacted provider adherence. Increased adherence to algorithm recommendations was associated with larger decreases in overall psychiatric symptoms and depressive symptoms over time, but did not impact either immediate or long-term reductions in manic symptoms.CONCLUSIONS: Greater provider adherence to treatment guideline recommendations was associated with greater reductions in depressive symptoms and overall psychiatric symptoms over time. Additional research is needed to refine measurement and to further clarify these relationships.     

Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not

CONTEXT: Although various strategies are available to manage nonresponders to an initial treatment for depression, no controlled trials address the utility of switching from an antidepressant medication to psychotherapy or vice versa. OBJECTIVE: To compare the responses of chronically depressed nonresponders to 12 weeks of treatment with either nefazodone or cognitive behavioral analysis system of psychotherapy (CBASP) who were crossed over to the alternate treatment (nefazodone, n = 79; CBASP, n = 61). DESIGN: Crossover trial. SETTING: Twelve academic outpatient psychiatric centers. PATIENTS: There were 140 outpatients with chronic major depressive disorder; 92 (65.7%) were female, 126 (90.0%) were white, and the mean age was 43.1 years. Thirty participants dropped out of the study prematurely, 22 in the nefazodone group and 8 in the CBASP group. INTERVENTIONS: Treatment lasted 12 weeks. The dosage of nefazodone was 100 to 600 mg/d; CBASP was provided twice weekly during weeks 1 through 4 and weekly thereafter. MAIN OUTCOME MEASURES: The 24-item Hamilton Rating Scale for Depression, administered by raters blinded to treatment, the Clinician Global Impressions-Severity scale, and the 30-item Inventory for Depressive Symptomatology-Self-Report. RESULTS: Analysis of the intent-to-treat sample revealed that both the switch from nefazodone to CBASP and the switch from from CBASP to nefazodone resulted in clinically and statistically significant improvements in symptoms. Neither the rates of response nor the rates of remission were significantly different when the groups of completers were compared. However, the switch to CBASP following nefazodone therapy was associated with significantly less attrition due to adverse events, which may explain the higher intent-to-treat response rate among those crossed over to CBASP (57% vs 42%). CONCLUSIONS: Among chronically depressed individuals, CBASP appears to be efficacious for nonresponders to nefazodone, and nefazodone appears to be effective for CBASP nonresponders. A switch from an antidepressant medication to psychotherapy or vice versa appears to be useful for nonresponders to the initial treatment.