Interleukins 2 and 12 produce significant recovery of cytotoxic function in dibutyltin-exposed human natural killer cells

Cytotoxic function of human natural killer (NK) cells is modulated by a variety of cytokines. Interleukins (IL) 2, 12, 15, and 18 and Interferon gamma (IFNgamma) are potent stimulators of NK cell cytotoxicity. Butyltins (BTs) are used in a variety of consumer products and industrial applications. Dibutyltin (DBT) is found in plastic products, beverages stored in PVC pipes during manufacturing, and poultry products. BTs appear to increase the risk of cancer and viral infections in exposed individuals. Recently, we have demonstrated that the ability of NK cells to kill tumor cells is greatly diminished after a 1-h exposure to dibutyltin. This inhibition of tumor killing function continues even after removal of the compound. There is no significant recovery of NK cytotoxic function even when the cells are allowed to recover for 6 days. In the current study we examine the effects of NK-stimulatory cytokines on the ability of NK cells to recover from the inhibitory effects of a 1-h DBT treatment. Highly purified NK cells (>95% CD16(+)) or a lymphocyte preparation containing both T lymphocytes and NK cells were treated with 5 microM DBT and then allowed to recover for 24 h, 48 h, 4 days, and 6 days in DBT-free medium containing either no cytokine or a maximally stimulatory dose of several NK-stimulatory cytokines. Tumor killing function was tested using a radioactive chromium release assay. As seen in our previous studies there is no recovery of NK cell cytotoxic function even after a 6-day recovery period when no cytokine is present in the medium. However, there is significant recovery of NK cytotoxic function when IL2, IL12, or the combination of IL2 plus IL12 is present in the medium during the recovery period. The other cytokines tested (IL15, IL18, and IFNgamma) were unable to increase the cytotoxicity of DBT-exposed NK cells.     

Developmental Issues: Physiologic Factors Affecting the Safety and Bioavailability

In this expanded overview, the development of digestive and absorptive function at birth and during the first year of life are reviewed. Concerns regarding these functions in premature will be considered. In addition, nonspecific and specific host immune function in the developing gut are considered in the context of bioavailability of dietary supplements. Having reviewed what is known about these developmental gut functions and their maturation in the first year of life, safety and bioavailability issues and recommendations are considered.     

HIV/AIDS in South Africa: an overview

This paper presents an overview of the development of HIV/AIDS in South Africa, taking into consideration the social context and analyzing the factors most likely to have influenced its spread as well as the societal response to it. The authors argue that macro factors such as social and political structures, in addition to behavioral ones, have combined to shape the course of the epidemic. Since various factors linked to social inequalities have combined to shape the pattern and growth of the HIV/AIDS epidemic in South Africa, it is inappropriate to focus on only one dimension in an attempt to combat the epidemic. Following the psycho-socio- environmental model, all potential contributing elements need to be addressed simultaneously. This calls for a true interdisciplinary and multi-sectorial approach. It also requires great commitment as well as strong political will.     

Emerging and reemerging rickettsiosis in an endemic area of Minas Gerais State,Brazil

This article describes a serological survey for rickettsiosis in the county of Novo Cruzeiro, Minas Gerais State, Brazil, in 1998, testing schoolchildren and dogs. Sera included 331 samples from schoolchildren from an endemic area and 142 samples from schoolchildren from a non-endemic area in the county. All children examined were healthy and had not reported clinical symptoms of Brazilian spotted fever prior to the serological survey. Some 35 children in the endemic area were reactive to Rickettsia rickettsiiby indirect fluorescent antibody (IFA) with a titer of 1:64, corresponding to 10.6%. Sera from 73 dogs were tested, showing seroreactivity (IFA 1:64) to Rickettsia rickettsi, Ehrlichia chaffeensis, and Ehrlichia canisin 3 (4.11%), 11 (15.07%), and 13 (17.81%), respectively. The results in schoolchildren and the presence of canine seroreactivity to Ehrlichiaspecies that are potentially pathogenic to humans suggests the risk of transmission of other Rickettsiaein the study area.     

Fibroid embolization

The most common surgical treatment for fibroids is hysterectomy and approximately 30,000 are carried out annually in the UK for this condition. The operation, however, carries a significant complication rate. Since the first case was carried out in 1989 there has been increasing interest in the interventional radiological procedure called fibroid embolization where angiographic techniques are used to occlude the vascular supply of fibroids. This article is a review of the world experience of fibroid embolization, its development, techniques, indications, results and complications. So far evidence indicates very promising mid-term results but more long-term comprehensive data is needed from large trials.     

Modeling Alzheimer's disease immune therapy mechanisms: interactions of human postmortem microglia with antibody-opsonized amyloid beta peptide

The induction of an antibody response to amyloid beta (Abeta) peptide has become a strategy for the treatment of Alzheimer's disease (AD). This has proven effective in reducing the plaque burden in transgenic mice that develop Abeta plaques similar to human AD patients. The mechanism for enhanced clearance of Abeta is partly due to the interaction of immunoglobulin Fcgamma receptor-expressing microglia and specific antibody-opsonized Abeta deposits. This interaction can stimulate Fcgamma receptor-mediated phagocytosis, but also results in inflammatory activation of these cells. Consequently, interaction of microglia with antibody-antigen complexes could exacerbate the existing inflammation in the brains of AD patients. In this study, we used substrate-bound Abeta and cultured human microglia from AD and non-demented cases to model interaction of microglia and antibody-opsonized plaques in AD brains. Enhanced production of tumor necrosis factor-alpha, macrophage colony stimulating factor, interleukin-10, and superoxide ions was detected. We also demonstrated enhanced uptake of opsonized Abeta by microglia, which was reduced significantly in the presence of excess IgG, indicative of the involvement of Fcgamma receptor-mediated mechanisms. Human microglia were shown in this study to express mRNA for Fcgamma receptors I, IIa, IIb, and III. The expression of Fcgamma receptor II was augmented by proinflammatory stimulation. These results suggest that initial interactions of human microglia with antibody-opsonized amyloid could result in increased inflammation. The consequence of this on inflammatory pathology in AD brains needs to be considered before immunization is used as a strategy for treating AD.     

Activated microglia do not mediate the early deposition of Abeta in carriers of the apolipoprotein Eepsilon4 allele

Activated microglia are a prominent component of the senile plaques in end-stage Alzheimer's disease, but whether microglia contribute to the initiation of the lesions remains unknown. In a previous postmortem study of non-demented elderly cases, we found that amyloidogenesis is advanced by at least 10 years in carriers of the apoEepsilon4 allele. To determine whether microglia are involved in the initial stages of beta-amyloid pathogenesis and whether apoE genotype influences microglial activation, we quantified HLA-DR-immunoreactive microglia in the medial temporal lobe of 229 non-demented humans of various APOE genotypes who had died between 50 and 91 years of age. Our results show that the number of HLA-DR-immunoreactive microglia increases with advancing age in both the gray matter and the white matter. In contrast to amyloid plaques and neurofibrillary tangles, there is no significant correlation between apoE genotype and density of microglia, although apoEepsilon4 homozygotes tended to have more microglia than did other apoE groups. In sections double-immunostained for Abeta and activated microglia, activated microglia were associated with dense-cored plaques but not with diffuse plaques, suggesting that microglial activation is a relatively late event in the genesis of beta-amyloid. Activation of microglia thus appears not to be the initial impetus for Abeta-deposition in the elderly.     

Conantokin-L,a new NMDA receptor antagonist: determinants for anticonvulsant potency

Conantokins are N-methyl-D-aspartate receptor antagonist peptides found in the venoms of marine cone snails. Current intense interest in this peptide family stems from the discovery of their therapeutic potential as anticonvulsants. It was recently reported that conantokin-R is a highly potent anticonvulsant compound, with a protective index of 17.5 when tested in the audiogenic mouse model of epilepsy. Conantokin-L was characterized from Conus lynceus and found to have extensive homology with conantokin-R, except For the C-terminal amino acids. Although conantokin-L appears almost as potent as conantokin-R in standard in vivo assays for conantokins and NMDA receptor binding assays, it is far less potent as an anticonvulsant, with a protective index of 1.2 in the audiogenic mouse model. The results suggest that the C-terminal sequences of conantokin-R and conantokin-L are a major determinant of their anticonvulsant potency.     

Dimensional measures of psychopathology. The probability of being classified with a psychiatric disorder using empirically derived symptom scales

Objectives: We sought to develop a ranking scheme that assigns a probability of having one of four psychiatric disorders to children based on their scores on a symptom scale. We then estimated the impact of each scale symptom on the prevalence of the disorder in the population. Method: Logistic regressions were specified for ADHD, ODD, depressive, and conduct disorders using all the individual symptoms in the pertinent scale as predictors. Individual fitted values from the regression function then served as a probability scale measure. We combined the prevalence and influence of each scale symptom to calculate its overall impact on the prevalence of the disorder. Results: Probability distributions had a wide range of values and discriminated between cases and non-cases. Those having a disorder were consistently associated with higher probabilities in the scale. The estimated probability corresponds to the empiric prevalence of the diagnosis in a group of persons sharing the same estimated probabilities. Symptoms varied on their impact on the prevalence of the disorder. Conclusions: We recommend the estimated probability of the disorder based on the empirically defined scales as dimensional measures that complement prevalence of the disorder. Different symptoms are identified as targets for screening when selection is based on their impact on the prevalence of the disorder than when selection is based on the strength of the association with the disorder. We recommend using a common nosology with different classification schemes; the categorical definition of the disorder, the probability of having the disorder, and the impact of each symptom in the prevalence. Different measures serve different purposes. Accepted: 5 April 2002 Correspondence to Maritza Rubio-Stipec