Paradoxical effects of brain death and associated trauma on rat mesenteric microcirculation: an intravital microscopic study

OBJECTIVE: Experimental findings support clinical evidence that brain death impairs the viability of organs for transplantation, triggering hemodynamic, hormonal, and inflammatory responses. However, several of these events could be consequences of brain death-associated trauma. This study investigated microcirculatory alterations and systemic inflammatory markers in brain-dead rats and the influence of the associated trauma. METHOD: Brain death was induced using intracranial balloon inflation; sham-operated rats were trepanned only. After 30 or 180 min, the mesenteric microcirculation was observed using intravital microscopy. The expression of Pselectin and ICAM-1 on the endothelium was evaluated using immunohistochemistry. The serum cytokine, chemokine, and corticosterone levels were quantified using enzyme-linked immunosorbent assays. White blood cell counts were also determined. RESULTS: Brain death resulted in a decrease in the mesenteric perfusion to 30 percent, a 2.6-fold increase in the expression of ICAM-1 and leukocyte migration at the mesentery, a 70 percent reduction in the serum corticosterone level and pronounced leukopenia. Similar increases in the cytokine and chemokine levels were seen in the both the experimental and control animals. CONCLUSION: The data presented in this study suggest that brain death itself induces hypoperfusion in the mesenteric microcirculation that is associated with a pronounced reduction in the endogenous corticosterone level, thereby leading to increased local inflammation and organ dysfunction. These events are paradoxically associated with induced leukopenia after brain damage.

A doença arterial coronariana sob o prisma da genética molecular / A genetic view of the coronary artery disease

A biologia molecular evolui de forma vertiginosa e atualmente é tida como ferramenta indispensável na compreensão de doenças complexas e multifatoriais como a doença arterial coronariana. Tal abordagem gera uma nova forma de avaliação de doenças conhecidas e propicia a criação de novas técnicas, novos métodos diagnósticos e possíveis abordagens terapêuticas, interferindo diariamente no desfecho clínico final do paciente. O número de publicações em genética cardiovascular aumentou cinco vezes nos últimos 20 anos e a descoberta de novos polimorfismos e mutações bem como marcadores de inflamação, coagulação e genes relacionados ao metabolismo lipídico contribuem para se conhecer cada vez mais os aspectos intrínsecos envolvidos na aterosclerose. Este artigo irá abordar os principais avanços nessa área, identificando os polimorfismos mais comuns e sua relevância clínica segundo grandes ensaios e meta-análises,bem como fazer um breve racional acerca do desenho atual dos ensaios clínicos em biologia molecular

P-selectin, carcinoma metastasis and heparin: novel mechanistic connections with therapeutic implications

Metastasis is a multistep cascade initiated when malignant cells penetrate the tissue surrounding the primary tumor and enter the bloodstream. Classic studies indicated that blood platelets form complexes around tumor cells in the circulation and facilitate metastases. In other work, the anticoagulant drug heparin diminished metastasis in murine models, as well is in preliminary human studies. However, attempts to follow up the latter observation using vitamin K antagonists failed, indicating that the primary mechanism of heparin action was unrelated to its anticoagulant properties. Other studies showed that the overexpression of sialylated fucosylated glycans in human carcinomas is associated with a poor prognosis. We have now brought all these observations together into one mechanistic explanation, which has therapeutic implications. Carcinoma cells expressing sialylated fucosylated mucins can interact with platelets, leukocytes and endothelium via the selectin family of cell adhesion molecules. The initial organ colonization of intravenously injected carcinoma cells is attenuated in P-selectin-deficient mice, in mice receiving tumor cells pretreated with O-sialoglycoprotease (to selectively remove mucins from cell surfaces), or in mice receiving a single dose of heparin prior to tumor cell injection. In each case, we found that formation of a platelet coating on cancer cells was impeded, allowing increased access of leukocytes to the tumor cells. Several weeks later, all animals showed a decrease in the extent of established metastasis, indicating a long-lasting effect of the short-term intervention. The absence of obvious synergism amongst the three treatments suggests that they all act via a common pathway. Thus, a major mechanism of heparin action in cancer may be inhibition of P-selectin-mediated platelet coating of tumor cells during the initial phase of the metastatic process. We therefore suggest that heparin use in cancer be re-explored, specifically during the time interval between initial visualization of a primary tumor until just after definitive surgical removal.