The tyrosine kinase inhibitor dasatinib reduces lung inflammation and remodelling in experimental allergic asthma.

BACKGROUND AND PURPOSE: Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in understanding of its pathophysiology, asthma remains a major public health problem, and new therapeutic strategies are urgently needed. In this context, we sought to ascertain whether treatment with the TK inhibitor dasatinib might repair inflammatory and remodelling processes, thus improving lung function, in a murine model of asthma. EXPERIMENTAL APPROACH: Animals were sensitized and subsequently challenged, with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, animals were treated with dasatinib, dexamethasone, or saline, every 12 h for 7 consecutive days. Twenty-four hours after the last treatment, the animals were killed, and data were collected. Lung structure and remodelling were evaluated by morphometric analysis, immunohistochemistry, and transmission electron microscopy of lung sections. Inflammation was assessed by cytometric analysis and ELISA, and lung function was evaluated by invasive whole-body plethysmography. KEY RESULTS: In OVA mice, dasatinib, and dexamethasone led to significant reductions in airway hyperresponsiveness. Dasatinib was also able to attenuate alveolar collapse, contraction index, and collagen fibre deposition, as well as increasing elastic fibre content, in OVA mice. Concerning the inflammatory process, dasatinib reduced inflammatory cell influx to the airway and lung-draining mediastinal lymph nodes, without inducing the thymic atrophy promoted by dexamethasone. CONCLUSIONS AND IMPLICATIONS: In this model of allergic asthma, dasatinib effectively blunted the inflammatory and remodelling processes in asthmatic lungs, enhancing airway repair and thus improving lung mechanics.

Frequency and characteristics of circulating CD4(+) CD28(null) T cells in patients with psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory disease that affects the skin. CD4(+) CD28(null) cells are a subset of T lymphocytes associated with systemic inflammation and increased cardiovascular disease risk, and may be involved in the pathogenesis of psoriasis. OBJECTIVES: To study the features of circulating CD4(+) CD28(null) cells in patients with psoriasis, adjusted for the influence of known cardiovascular disease risk factors. METHODS: Forty-two patients with psoriasis and 42 controls entered the study. Peripheral blood mononuclear cells were analysed for the frequency of CD4(+) CD28(null) T lymphocytes and their expression of cytotoxic granules and homing receptors. Immunostaining for cutaneous cytotoxic granules was assessed in skin biopsies from 11 patients. RESULTS: There were no differences in the frequency of CD4(+) CD28(null) T cells between groups in all situations analysed. However, there was an increased number of cells expressing cytotoxic granules and a decreased number expressing CXCR3 in ex vivo samples of patients with psoriasis. A negative correlation was observed between the frequency of ex vivo CD4(+) CD28(null) cells and psoriasis severity. After clinical remission in nine patients, ex vivo CD4(+) CD28(null) lymphocytes expressing cytotoxic granules decreased. Perforin-, granzyme B- and granulysin-containing cells were found in skin lesions. Patients with psoriasis also had increased plasma levels of C-reactive protein. CONCLUSIONS: These data suggest that cytotoxic cells, such as CD4(+) CD28(null) lymphocytes, within an inflammatory environment may play a role in the pathogenesis of psoriasis.

Bartonella henselae survives after the storage period of red blood cell units: is it transmissible by transfusion?

Bartonella henselae is the agent of cat scratch disease and bacillary angiomatosis. Blood donors can be asymptomatic carriers of B. henselae and the risk for transmission by transfusion should be considered. The objective of this study was to demonstrate that B. henselae remains viable in red blood cell (RBC) units at the end of the storage period. Two RBC units were split into two portions. One portion was inoculated with B. henselae and the other was used as a control. All units were stored at 4 degrees C for 35 days. Aliquots were collected on a weekly basis for culture in a dish with chocolate agar, ideal for the cultivation of this agent. Samples were collected on days 1 and 35 and taken for culture in Bact/Alert R blood culture bottles. Aliquots taken simultaneously were fixed in Karnovsky's medium for subsequent electron microscopy evaluation. Samples from infected bags successfully isolated B. henselae by chocolate agar culture, although Bact/Alert R blood culture bottles remained negative. Bartonella spp. structures within erythrocytes were confirmed by electron microscopy. The viability of B. henselae was demonstrated after a storage period of RBC units. These data reinforce the possibility of infection by transfusion of blood units collected from asymptomatic blood donors.

Association of HLA-A, -B, -C genes and TNF microsatellite polymorphism with psoriasis vulgaris: a study of genetic risk in Brazilian patients.

This study investigated the genetic association of HLA class I genes and TNF-alpha microsatellites. HLA-A, -B, -C typing was carried out in 92 psoriasis vulgaris patients and 160 healthy individuals using a PCR-SSP method. 70 patients and 71 controls were typed for five microsatellite polymorphisms, TNFa-e. HLA-B*13 Cw*06, HLA-B*57 Cw*06 and HLA-B*39 Cw*12 haplotypes were found to be increased in patients with psoriasis type I when compared to controls, which could determine the susceptibility to development of psoriasis. TNFa4, TNFb1, TNFe1 and TNFa2 b1 c2 d4 e1 haplotypes showed a decreased frequency (p < 0.05) in psoriasis patients when compared to controls. HLA-B*13 allele and HLA-B*13 Cw*06, TNFa11 b4 c1 d3 e3 haplotypes showed increased frequencies (p < 0.05) in patients with type II psoriasis, which suggests susceptibility to the onset of psoriasis. Our results detected polymorphisms of the HLA class I and microsatellite TNF locus which could be markers of genetic predisposition to the disease.

[Comparison of two strategies for the early detection of congenital hypothyroidism]. / Comparação entre duas estratégias para a detecção precoce do hipotiroidismo congênito.

OBJECTIVE: Compare two different strategies in newborn screening for congenital hypothyroidism, primary TSH in the umbilical cord blood (method 1) and primary T4 in blood collected from the heel in the 2nd day of life (method 2). METHODS: We compared both strategies in 10,000 newborns, measuring TSH by a sensitive immunofluorimetric assay and T4 by a radioimmunoassay. RESULTS: Both strategies detected all cases of hypothyroidism (4 cases, 1/2,500 newborns). The recalling index owing to insufficient amount of blood to perform the assays was zero in method 1 and 8.5% (850 newborns) in method 2. The recalling index for confirmation of the results was 0.06% (6 newborns) in method 1 and 2.25% (225 newborns) in method 2; when method 2 included supplementary TSH, the recalling index was reduced to 1.63% (163 newborns). CONCLUSION: Our data indicate the technical superiority of the umbilical cord blood compared to heel and primary TSH compared to primary T4 in the neonatal thyroid screening for congenital hypothyroidism.

Comparaçäo entre duas estratégias para a detecçäo precoce do hipotireoidismo congênito / Comparison between two strategies for the precocious detection of congenital hypothyroidism

Objetivo. Comparar em recém-nascidos (RN) duas estratégias diferentes para o rastreamento do hipotiroidismo congênito (HC), a dosagem primária de TSH no sangue colhido do cordao umbilical (método 1) e a dosagem primária de T4 no sangue colhido por punçao de calcanhar no 2 dia de internaçao (método 2). Métodos. Os autores compararam as duas estratégias em 10.000 RN. Dosaram o TSH por método imunofluorimétrico sensível em papel de filtro e o T4 por radioimunoensaio em papel de filtro. A coleta de sangue do calcanhar foi realizada no 2 dia de vida. Resultados. Os dois programas diagnosticaram todos os casos de HC nos RN (4 casos, 1/2.500 RN). O índice de rechamada por coleta inadequada foi nulo no método 1 e de 8,5 por cento (850RN) no método 2. O índice de reconvocaçao para confirmaçao de resultados foi de 0,06 por cento (6RN) no método 1 e 2,25 por cento (225 RN) no método 2; quando este método incluía também a dosagem suplementar de TSH, o índice baixou para 1,63 por cento (163 RN). Conclusao. Os dados dos autores evidenciam a superioridade técnica da coleta de sangue a partir do cordao umbilical em relaçao à punçao de calcanhar, assim como da dosagem primária de TSH em relaçao à de T4, uma vez que apresentam índices muito menores de reconvocaçao.