High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis

To determine whether counterregulation by interleukin (IL)-10 plays a role in the generation or maintenance of the antigen-specific hyporesponsiveness seen in asymptomatic microfilaremic (MF) patients, parasite antigen (PAg)- and nonparasite antigen (NPAg)-driven IL-10 production by peripheral blood mononuclear cells (PBMC) was studied in 10 MF patients and in ll patients with chronic lymphatic pathology (CP). PBMC from MF patients spontaneously secreted 10-fold more IL-10 than did PBMC from patients with CP. PAg also induced significantly more IL-10 production by PBMC from CP patients. There was a negative correlation between PAg driven IL-10 production by PBMC and PAg-specific T cell proliferation in the MF group. IL-10 secretion by plastic adherent cells from MF persons was higher in response to PAg than NPAg, whereas IL-6 and tumor necrosis factor-alpha secretion were equivalent for PAg and NPAg, suggesting that PAg preferentially induces IL-10 secretion in these cells. Thus, PAg-induced IL-10 likely plays an important role in down-regulating antigen-specific proliferative responses in MF patients.     

A method for radiologic-assisted gastrostomy when percutaneous endoscopic gastrostomy is contraindicated

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) has been established as a faster and safer procedure than open surgical gastrostomy. It cannot be done, however, for many patients with partially obstructing pharyngeal or esophageal carcinoma, previous gastrectomy, upper abdominal surgery, or bowel distension from distal obstruction. PATIENTS AND METHODS: We attempted percutaneous radiologic-assisted gastrostomy (RAG) in 231 patients referred for gastrostomy, 38 of whom had a relative contraindication for PEG. The procedure involves passing, under radiologic guidance, an orogastric inflation tube that contains a snare. We used a 5-inch long, 18-gauge needle to transabdominally insert a wire into the stomach, avoiding loops of bowel visualized by air contrast. Retrieving the transabdominal wire by snare allowed retrograde passage of the gastrostomy tube as done in standard PEG. RESULTS: The procedure was successful in 230 of 231 cases, including 37 of the 38 patients with contraindications. We could not gain gastric access in 1 patient with a 75% gastrectomy. Overall, 6 patients developed complications and 1 died. There was no procedure-related morbidity or mortality in the patients with contraindications to PEG who underwent successful RAG. Subsequent laparotomy indicated tube passage through the liver in 2 of these cases and small bowel mesentery in 1 case without clinical problems. We performed a percutaneous jejunostomy in the efferent limb of the gastrojejunostomy in 1 patient with a previous gastrectomy. CONCLUSION: The snare technique is simpler and faster than the usual radiologic gastropexy technique, and safer than an endoscopic procedure. It has become our procedure of choice for gaining gastric access.     

Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain

A number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.     

Wall effects observed in tissue-equivalent proportional counters from 1.05 GeV/nucleon iron-56 particles

A strong overlap between P-glycoprotein (Pgp) and cytochrome P450 3A (CYP3A) substrates and modulators has been reported. To test the hypothesis that CYP3A and Pgp are coordinately regulated, we examined the effects of known inducers of CYP3A (triacetyloleandomycin, rifampicin, dexamethasone, pregnenolone 16alpha-carbonitrile) on Pgp expression in rat liver. We also investigated the gender-specific expression of Pgp and compared its response to dexamethasone between male and female rats. In male rats, western blot analyses showed that rifampicin and dexamethasone caused 50% and 5-fold increases in Pgp levels, respectively. RNase protection assays using gene-specific probes for the three Pgp isoforms revealed a 3-fold increase in mdr2 mRNA levels after dexamethasone administration and a 2-fold increase following rifampicin treatment. Triacetyloleandomycin and pregnenolone 16alpha-carbonitrile had no effect on Pgp expression and mRNA levels. We also observed that the basal level of Pgp was 40% lower in male rats than in females and that mdr2 mRNA levels in male rats were one-half those in females. As opposed to the results in male rats, dexamethasone reduced Pgp expression by approximately 60% and caused a 30% decrease in mdr2 mRNA levels in female rats. Mdr1a was not affected and mdr1b was not detected in female or male rats. We conclude that, at the dosage regimen used, CYP3A and Pgp responses to CYP3A inducers are regulated independently in rat liver. In addition, this study shows that Pgp expression and regulation are gender specific.     

Prophylactic effect of Korean mistletoe (Viscum album coloratum) extract on tumor metastasis is mediated by enhancement of NK cell activity

We here demonstrated the prophylactic effect of an extract (KM-110) from Viscum album coloratum, a Korean mistletoe, on tumor metastasis produced by highly metastatic tumor cells, colon 26-M3.1 carcinoma, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, using experimental models in mice. Intravenous (i.v.) administration of KM-110 (100 microg/mouse) 2 days before tumor inoculation significantly inhibited lung metastasis of B16-BL6 and colon 26-M3.1 cells, and liver and spleen metastasis of L5178Y-ML25 cells. The prophylactic effect of KM-110 on tumor metastasis was evident with various administration routes, i.e. subcutaneous, oral, intranasal as well as i.v., and was dependent upon the dose of KM-110 administered. Furthermore, mice given KM-110 (100 microg) 2 days before tumor inoculation showed significantly prolonged survival rates compared with the untreated mice. In a time course analysis of NK activity, i.v. administration of KM-110 (100 microg) significantly augmented NK cytotoxicity to Yac-a tumor cells from 1 to 3 days after KM-110 treatment. Furthermore, depletion NK cells by injection of rabbit anti-asialo GM1 serum completely abolished the inhibitory effect of KM-110 on lung metastasis of colon 26-M3.1 cells. These results suggest that KM-110 possesses immunopotentiating activity which enhances the host defense system against tumors, and that its prophylactic effect on tumor metastasis is mediated by NK cell activation.     

Data quality review program: the Society of Thoracic Surgeons Adult Cardiac National Database

In summary, the National Database Committee's Audit and Validation Subcommittee is working to maximize the data completeness and quality of the STS National Database. Toward this end, we welcome your suggestions for improvement.     

On histocompatibility barriers, Th1 to Th2 immune deviation, and the nature of the allograft responses

In the present study, we have sought to determine the basis for the frequent failure of Th1 to Th2 immune deviation to blunt the severity of allograft rejection, as such immune deviation has proven highly effective in the treatment of several T cell-dependent autoimmune states. Our study demonstrates that treating islet allograft recipient mice with anti-IL-12 mAb is highly effective in producing Th1 to Th2 immune deviation in several model systems (i.e., fully MHC, partially MHC, or multiple minor Ag barriers). Nevertheless, anti-IL-12 failed to prolong the engraftment of fully MHC-mismatched islet allografts. However, anti-IL-12-treated recipients carrying MHC-matched but multiple minor Ag-mismatched allografts experienced prolonged engraftment; allograft tolerance was frequently achieved in the DBA/2J (H-2d) to BALB/c (H-2d) strain combination. In another model, in which the host response was dominated by CD4+ T cells responding to donor allopeptides presented upon host APCs in the context of self MHC class II molecules, anti-IL-12 treatment proved to be extremely potent. Thus, Th1 to Th2 immune deviation produces prolonged engraftment as compared with recipients of MHC-mismatched allografts when rejection is dependent upon indirectly presented allogeneic peptides and a reduced mass of responding alloreactive T cells.     

Investigations of the problems of assessing aflatoxin levels in peanuts

In this study, a number of probability distributions that have been used to model the occurrence of aflatoxin in peanuts are compared. Two distributions, the compound gamma and the negative binomial, are shown to have special appeal in that both can be justified by reasoning from the fundamental biological and stochastic processes that generate the aflatoxin. Since method of moments and maximum likelihood give consistent estimates of parameters in both models, practical considerations suggest using the former. One hundred twenty data sets, each consisting of fifty observations, were not sufficient to provide goodness-of-fit tests to establish either as superior to the other as a model. Both models fit the data well, appreciably better than other models examined. An attractive aspect of the compound gamma and the negative binomial distributions is that, as a consequence of their theoretical underpinnings, both involve parameters that have meaningful interpretations. In the compound gamma, the alpha parameter reflects the shape of the kernel-to-kernel aflatoxin content distribution, the lambda parameter reflects the number (or frequency) of contaminated kernels in the sample, and the beta parameter is a scale parameter. In the negative binomial, the two parameters can be used as measures of mean or location and shape.