Characterization of the kynurenine pathway and quinolinic Acid production in macaque macrophages.

The kynurenine pathway (KP) and one of its end-products, the excitotoxin quinolinic acid (QUIN), are involved in the pathogenesis of several major neuroinflammatory brain diseases. A relevant animal model to study KP metabolism is now needed to assess whether intervention in this pathway may improve the outcome of such diseases. Humans and macaques share a very similar genetic makeup. In this study, we characterized the KP metabolism in macaque primary macrophages of three different species in comparison to human cells. We found that the KP profiles in simian macrophages were very similar to those in humans when challenged with inflammatory cytokines. Further, we found that macaque macrophages are capable of producing a pathophysiological concentration of QUIN. Our data validate the simian model as a relevant model to study the human cellular KP metabolism in the context of inflammation.

The testis and epididymis are productively infected by SIV and SHIV in juvenile macaques during the post-acute stage of infection.

BACKGROUND: Little is known about the progression and pathogenesis of HIV-1 infection within the male genital tract (MGT), particularly during the early stages of infection. RESULTS: To study HIV pathogenesis in the testis and epididymis, 12 juvenile monkeys (Macacca nemestrina, 4-4.5 years old) were infected with Simian Immunodeficiency Virus mac 251 (SIVmac251) (n = 6) or Simian/Human Immunodeficiency Virus (SHIVmn229) (n = 6). Testes and epididymides were collected and examined by light microscopy and electron microscopy, at weeks 11-13 (SHIV) and 23 (SIV) following infection. Differences were found in the maturation status of the MGT of the monkeys, ranging from prepubertal (lacking post-meiotic germ cells) to post-pubertal (having mature sperm in the epididymal duct). Variable levels of viral RNA were identified in the lymph node, epididymis and testis following infection with both SHIVmn229 and SIVmac251. Viral protein was detected via immunofluorescence histochemistry using specific antibodies to SIV (anti-gp41) and HIV-1 (capsid/p24) protein. SIV and SHIV infected macrophages, potentially dendritic cells and T cells in the testicular interstitial tissue were identified by co-localisation studies using antibodies to CD68, DC-SIGN, alphabetaTCR. Infection of spermatogonia, but not more mature spermatogenic cells, was also observed. Leukocytic infiltrates were observed within the epididymal stroma of the infected animals. CONCLUSION: These data show that the testis and epididymis of juvenile macaques are a target for SIV and SHIV during the post-acute stage of infection and represent a potential model for studying HIV-1 pathogenesis and its effect on spermatogenesis and the MGT in general.

Simplified acute physiology score II: a valid role in the assessment of patients with medically refractory upper gastrointestinal bleeding?

BACKGROUND AND AIM: Medically refractory upper gastrointestinal hemorrhage (UGIH) is a complex clinical problem. Selection of patients suitable for surgery is difficult and often involves subjective clinical judgment. The simplified acute physiology score (SAPS) II is a validated predictor of mortality in the intensive care setting. Our aim was to assess the SAPS II score in patients with medically refractory UGIH who were referred for a surgical opinion. Patients were subsequently classed as 'accepted' or 'declined' for surgery and SAPS II scores were compared between these two groups. METHODS: From July 1996 to July 1999, patients referred for surgical intervention with UGIH were included (varices excluded). The SAPS II was calculated at the time of surgical referral. This was converted into a mortality probability using multiple regression analysis. Clinical outcome was defined as either survival to discharge or death while an inpatient. RESULTS: Ninety-nine patients were referred for surgical review. Sixty-five patients were accepted for surgery and 34 were declined. The mean SAPS II score for those who were accepted was 31.7 (mortality probability 0.16, actual mortality 15.4%, 10/65) and 30.2 (mortality probability 0.15, actual mortality 29.4%, 10/34) for those who were declined. CONCLUSION: The SAPS II scores were no different between the two groups. Observed mortality was consistent with mortality predicted in the operated group but twice that predicted in those where surgical intervention was declined. This suggests that clinical selection criteria for patients undergoing surgery for UGIH are inconsistent.