RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.

Inherited disorders of elastic tissue represent a complex and heterogeneous group of diseases, characterized often by sagging skin and occasionally by life-threatening visceral complications. In the present study, we report on an autosomal-recessive disorder that we have termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis). The disorder was mapped to chromosome 20p11.21-p11.23, and a homozygous frameshift mutation in RIN2 was found to segregate with the disease phenotype in a large consanguineous kindred. The mutation identified results in decreased expression of RIN2, a ubiquitously expressed protein that interacts with Rab5 and is involved in the regulation of endocytic trafficking. RIN2 deficiency was found to be associated with paucity of dermal microfibrils and deficiency of fibulin-5, which may underlie the abnormal skin phenotype displayed by the patients.

Effects of 5-fluorouracil on human mitogen-activated peripheral blood lymphocytes from healthy individuals.

BACKGROUND: The effect of 5-fluorouracil (5-FU) on activated lymphocytes was explored. MATERIALS AND METHODS: The in vitro effects of 5-FU on DNA synthesis in mitogen-activated lymphocytes from healthy volunteers were compared to those of the antimetabolites doxorubicin, cyclophosphamide and 6-mercaptopurine. These effects were assessed by alterations in the phenotypic profile and the percentage of cells in various phases of the cell cycle, as well as by the secretion of T helper (Th)1 and Th2 cytokines (ELISA). RESULTS: Unlike 5-FU, the other antimetabolites failed to augment DNA synthesis in activated lymphocytes. The effect of 5-FU correlated with an increase in the percentage of cells in the S-phase and caused an increased in CD4+ cells, a decrease in CD56+ cells and a shift of the cytokine secretion pattern from Th2 to Th1. CONCLUSION: 5-FU exhibited a unique effect on DNA synthesis in activated lymphocytes which was accompanied by selective effects on various lymphocyte subpopulations.

Chlorpyrifos exacerbating pemphigus vulgaris: a preliminary report and suggested in vitro immunologic evaluation model.

BACKGROUND: There is accumulating evidence on the role of pesticides in the etiology of pemphigus vulgaris (PV). OBJECTIVE: To determine whether chlorpyrifos, an organophosphate pesticide, is involved in the immunopathology of PV. METHODS: Normal human skin biopsy specimens incubated with progressively diluted chlorpyrifos solutions were used as indirect immunofluorescence substrates for sera from two PV patients previously exposed to the agent and from healthy controls. Involvement of T-cell lymphocytes was assessed by release of interferon-g in the presence of chlorpyrifos. RESULTS: In one PV patient, immunofluorescence was strongly positive for the specimen incubated with the pesticide and weakly positive for the specimen incubated with medium alone. Immunofluorescence was negative in the patient under immunosuppression with prednisolone and in all controls. Both patients tested positive on interferon-g assay; controls tested negative. CONCLUSIONS: Findings suggest an immunopathogenic role of chlorpyrifos in PV. Interferon-g cytokine assay with the pesticide combined with immunofluorescence tests may provide an in vitro diagnostic tool in suspected pesticide-induced/exacerbated pemphigus.

The effect of fish oil supplementation on cytokine production in children.

The ex vivo production of inflammatory cytokines during fish oil supplementation (n-3 polyunsaturated fatty acids, n-3 PUFA) is a matter of considerable controversy. Studies on human subjects have generally reported decreased lymphocyte proliferation and decreased production of IL-2, interferon-gamma, IL-1beta, IL-6 and TNF-alpha, but other studies showed no effect or even increased production. There are no published reports on ex vivo cytokine production in children on long-term, n-3 PUFA supplementation. The current double-blind study explored cytokine production by peripheral blood mononuclear cells (PBMCs), with and without lipopolysaccharide (LPS) stimulation in children on 12 weeks' supplementation with 300 mg/day of n-3 PUFA. Twenty-one children (aged 8-12 years) were randomized to receive 1 g canola oil (control) or 300 mg n-3 PUFA + 700 mg canola oil in a chocolate spread. Blood was then drawn and PBMCs were separated and cultured for 24 h in a culture medium with or without 10 microg/mL LPS for 5 x 10(6) PBMCs. The pro-inflammatory cytokines, IL-1beta, TNF-alpha and IL-6, and the anti-inflammatory cytokines, IL-10 and IL-1RA, were evaluated by ELISA. The levels of all the cytokines were higher in non-stimulated and LPS-stimulated cultures, from n-3 PUFA-treated subjects as compared to controls. There was no difference in the IL-1beta/IL-1RA ratio between the two groups, with and without LPS stimulation. Nevertheless, the ratio tended to be lower in the treated subjects on both occasions. In conclusion, our results indicate an increased production of both pro-inflammatory and anti-inflammatory cytokines, with and without LPS stimulation, in children on 12 weeks' n-3 PUFA supplementation.