Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor

Experimental and MRI evidence suggest that glatiramer acetate's (Copaxone) therapeutic effect in multiple sclerosis (MS) could be mediated by anti-inflammatory GA-reactive Th2 cells that enter the brain, cross-react with myelin antigens, and produce bystander suppression. Furthermore, a neuroprotective effect, possibly mediated by neurotrophic factors such as BDNF, has been suggested based on experimental evidence in animal models, and the observation that inflammatory cells can elaborate BDNF. Therefore, we examined BDNF production in 73 GA, 13 MBP, and 22 TT-reactive short-term T-cell lines from 12 MS patients treated with GA. Ten of 73 GA-TCL (14%), 1 of the MBP-TCL (3%), and 2 of the TT-TCL (9%) produced BDNF levels two standard deviations above the mean levels produced by resting TCL. RT-PCR analysis confirmed BDNF expression in some GA- and MBP-reactive TCL. The mean BDNF level produced by GA-TCL was significantly higher than that for MBP-TCL, or TT-TCL when lines originating from the same patients were compared (P=0.033). All 10 high BDNF-producing GA-reactive TCL were Th2-biased as determined by the IL-5/IFN-gamma levels ratio. A positive correlation was observed between BDNF and IL-5 (Th2 indicator) (P=0.006) but not with IFN-gamma Th1 indicator) levels in GA-TCL derived from MS patients during but not pre-treatment. We conclude that while BDNF production by T cells is not antigen-specific, GA-reactive TCL are more likely to produce BDNF, and to be Th2-biased.     

Long-term population migration: an important aspect to be considered during mass drug administration for elimination of lymphatic filariasis

Annual 2-drug, single-dose mass drug administration (MDA) to 80-90% of the eligible population for 4-6 years are pre-requisites for the successful elimination of lymphatic filariasis (LF) from endemic communities by interruption of transmission and eventual elimination of new infections. In an experimental intervention project on the control of LF in Villupuram district of Tamil Nadu state, India, migration patterns of the villagers were investigated to determine the appropriate timing to implement MDA in order to attain high coverage in a village-level study. Between January and December 1997, 16 observations took place at 3-week intervals, following MDA with two drugs viz., diethylcarbamazine and ivermectin, in July-August 1996. The migrants from the village constituted 17-27% at different points of time and both short-term and long-term migrating patterns were observed. More villagers were available during the agricultural season (September-January), peaking around mid-January [83%; significantly higher (P < 0.05)] than during most of the remaining months, including a substantial portion of the migrant population. There is an urgent need to reschedule the yearly MDA in this area to take place in January and to plan mopping up operations by involving local self-help groups to include migrants (both short-term and long-term) in the LF elimination efforts.     

S-adenosyl-methionine-induced apoptosis in PC12 cells

Our previous studies showed that S-adenosyl-methionine (SAM) induced Parkinson's disease-like changes in rat. It caused death to dopamine neurons in the substantia nigra, which appeared shrunken and fragmented, indicative of apoptosis-like changes (Charlton and Crowell [1995] Mol. Chem. Neuropathol. 26:269-284; Charlton [1997] Life Sci. 61:495-502). In this study, we investigated whether SAM causes apoptosis in both undifferentiated PC12 (PC12) cells and nerve growth factor (NGF)-differentiated PC12 (D-PC12) cells. S-adenosyl-homocysteine (SAH), the nonmethyl analog of SAM, was also tested. SAM and SAH (1.0 nM to 10.0 microM) caused lactate dehydrogenase (LDH) release from the PC12 cells and D-PC12 cells; cells with morphological changes and fluorescent DNA fragmentation staining were detected among both PC12 cell and D-PC12 cell. Compared with the PC12 cell, the D-PC12 cell, a postmitotic cell, was more sensitive to the toxic effects of SAM or SAH and presented much greater LDH release, suggesting a lethal effect; surprisingly, the amounts of apoptotic cells did not differ significantly between the two kinds of cells. In medium deprived of exogenous methionine, a decline in LDH release was observed in PC12 and D-PC12 cells. Also, lower levels of intracellular SAM and SAH were observed in the methionine-deleted media, which were reversed by the addition of either SAM or SAH. An antivitamin B(12) monoclonal antibody was added to methionine-depleted medium, resulting in deficiency of both endogenous and exogenous methionine, which caused further decreases in LDH release and reduction in the levels of intracellular SAM and SAH. The preliminary data showed different sensitivities to SAM or SAH between PC12 cell and D-PC12 cells, which suggests that PC12 cell may be more stable as a metabolic model. Apoptosis of PC12 cells was also assessed by PARP cleavage detection, Western blot analysis of Bax and Bcl-2 proteins, and DNA laddering on agarose gel electrophoresis. The proapoptoic protein Bax was dominantly expressed, whereas Bcl-2 was slightly down-regulated by SAM. SAH weakly induced the expression of Bax and slightly decreased Bcl-2 levels. The effects of SAM and its analog, SAH, were demonstrated conclusively to induce apoptosis in PC12 cells.     

Acute idiopathic scrotal edema in children--revisited

Background: Acute idiopathic scrotal edema (AISE), a self-limiting acute scrotal edema and erythema that resolves without sequela, was first reported by Qvist in 1956. Methods: Thirty eight patients with AISE seen in the authors' department over the last 10 years were reviewed, comprising 44 episodes, most occurring in children under 10 years of age. The average age at presentation was 6.2 years. No past history of allergy was elicited. Results: Unilateral involvement predominated (90.1%). None of the patients was found to have a primary source of scrotal, perineal, or perianal infection. Scrotal discomfort; scrotal, perineal, and inguinal swelling; and erythema were the most common findings. Laboratory and ancillary examination findings were normal, except for the occasional eosinophilia. Characteristic ultrasonographic findings, such as marked thickening of the scrotal wall, with heterogeneous and edematous appearance, increased peritesticular blood flow, mild reactive hydrocele, and enlarged inguinal lymph nodes were found. Treatment was conservative in 92.1% of the patients. Resolution of all episodes occurred within 1 to 4 days. Recurrent episodes were observed in 4 patients (10 episodes), which were clinically more severe than the original episode. Conclusion: Clinical experience, good judgment, and color Doppler ultrasound scan can reliably identify those children with an acute scrotum who require exploration and spare those with AISE, where surgery is not indicated. J Pediatr Surg 37:1200-1202.     

Induction of retinoic acid receptor-beta suppresses cyclooxygenase-2 expression in esophageal cancer cells

Since retinoic acid receptor (RAR)-beta mRNA is frequently lost during esophageal carcinogenesis and esophageal cancer cells that do not express RAR-beta are resistant to retinoic acid (RA), we stably transfected RAR-beta expression vector into an esophageal cancer cell line TE-8 and an antisense RAR-beta into TE-3 cells. Transfection of RAR-beta decreased cell growth and colony formation and induced apoptosis in TE-8 cells. Antisense RAR-beta-transfected TE-3 cells had a shorter doubling time and became resistant to RA. Induction of RAR-beta decreased COX-2 expression in RAR-beta transfected TE-8 cells, whereas antisense RAR-beta transfected TE-3 cells increased COX-2 expression. The inhibitory effect of RAR-beta on COX-2 expression was further enhanced in the presence of RA, which was blocked by an RAR antagonist. The synthetic retinoid N-(4-hydroxyphenyl)retinamide, which does not bind effectively to RAR-beta, had no effect on COX-2 suppression. Furthermore, RA blocked bile acid-induced COX-2 expression and prostaglandin E(2) production only in the RAR-beta positive cells. Our data demonstrated that anticancer effect of RAR-beta may be related to its ability to suppress COX-2 expression and support that the loss of RAR-beta expression may contribute to esophageal carcinogenesis.     

Clearance rates of total prostate specific antigen (PSA) after radical prostatectomy in African-Americans and Caucasians

Racial differences in serum prostate specific antigen (PSA) values in men with and without prostate cancer have been observed but have yet to be explained. We aimed to determine if ethnic variations in the rate of metabolism of PSA could explain the different levels of PSA found in African-American and Caucasian men. In a prospective fashion, patients diagnosed with biopsy-proven clinically localized adenocarcinoma of the prostate and scheduled for radical prostatectomy were selected for the study. Eleven patients (six Caucasian, five African-American) were enrolled in the study. All patients demonstrated normal liver and renal function. Sera for total PSA were obtained at the following time intervals: preoperative (within 3 months of operation), time 0 (at time of prostate removal), 1, 4, 8, 24, 48, 72, 168 and 336 h after removal of the prostate. A log-linear regression model was then used to determine the metabolic clearance rate and half-life of serum total PSA. There were no statistically significant differences between Caucasian and African-American patients with regard to age, PSA prior to surgery, prostate weight, Gleason sum and PSA half-life. The metabolic clearance of total PSA followed first order kinetics. When comparing serum PSA levels expressed as a fraction of the baseline PSA, Caucasian and African-American patients demonstrated similar rates of metabolism. This study found similar rates of elimination of serum total PSA between African-Americans and Caucasians. These findings suggest that the rate of metabolism of PSA is similar for these groups. Further studies are needed to explain racial differences of serum PSA in patients with and without prostate cancer.