Comparative study of the fate of a pancreatic stump treated by ligature or by pancreatico-jejunal anastomosis (author's transl)]

The authors studied in a series of 23 dogs divided up into two groups the fate of the pancreatic stump treated either by pancreatico-jejunostomy with a Y loop, or by a simple ligature. They note that although the mortality is slightly higher in the anastomoses, histological lesions are constant in both series and are fairly similar. This agrees with the findings in man by Goldsmith and justifies ligature of the remaining pancreatic stump after cephalic duodeno-pancreatectomy.     

Differential effects of ellipticine and aza-analogue derivatives on cell cycle progression and survival of BALB/c 3T3 cells released from serum starvation or thymidine double block

10-[Diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5] pyrrolo[2,3-g]isoquinoline (BD-40) (NSC-327471D) is an aza-ellipticine derivative with a promising antitumor activity (M. Marty, C. Jasmin, P. Pouillard, C. Gisselbrecht, G. Gouvenia, and H. Magdalainat, 17th Annual Meeting of the American Society of Clinical Oncology, C-108, 1981) and less toxicity than ellipticine. We have compared the effects of ellipticine, several of its analogues, and two aza-analogue ellipticine derivatives (BD-40 and BR-1376) on cell cycle progression of BALB/c 3T3 mouse cells under different growth conditions. Both drug series were found to stop cell growth and block cells in G2 phase in exponentially growing cultures and cultures released from a thymidine double block. Long-term viability of these cells was completely suppressed after a short exposure to the drugs. In contrast, while ellipticine and its derivatives caused identical effects in cells recovering from serum starvation, BD-40 and BR-1376 did not block cells in G2 phase and did not prevent the completion of the first division round occurring after serum addition to quiescent cells. This transient refractory state was accompanied by a total conservation of long-term viability of these cells at least for the next 6 h following serum and drug addition. This lack of effect was not related to an impaired drug uptake by cells recovering from serum starvation or by a dramatic change in drug distribution inside the cells. These results indicate that the nitrogen substitution in the ellipticine heterocycle is an important if not unique feature for the particular effect of the aza-analogues of ellipticine. Furthermore, they suggest that, in contrast to ellipticine derivatives, these compounds require an activation step before exhibiting cytotoxicity.     

Macrophage activation switching: an asset for the resolution of inflammation

Macrophages play a central role in inflammation and host defence against microorganisms, but they also participate actively in the resolution of inflammation after alternative activation. However, it is not known whether the resolution of inflammation requires alternative activation of new resting monocytes/macrophages or if proinflammatory activated macrophages have the capacity to switch their activation towards anti-inflammation. In order to answer this question, we first characterized differential human macrophage activation phenotypes. We found that CD163 and CD206 exhibited mutually exclusive induction patterns after stimulation by a panel of anti-inflammatory molecules, whereas CCL18 showed a third, overlapping, pattern. Hence, alternative activation is not a single process, but provides a variety of different cell populations. The capacity of macrophages to switch from one activation state to another was then assessed by determining the reversibility of CD163 and CD206 expression and of CCL18 and CCL3 production. We found that every activation state was rapidly and fully reversible, suggesting that a given cell may participate sequentially in both the induction and the resolution of inflammation. These findings may provide new insight into the inflammatory process as well as new fields of investigation for immunotherapy in the fields of chronic inflammatory diseases and cancer.     

Decreased Specificity of an Assay for Recent Infection in HIV-1-Infected Patients on Highly Active Antiretroviral Treatment: Implications for Incidence Estimates

The aim of this study was to estimate the rate of misclassification in treated HIV patients who initiated treatment at the chronic stage of HIV infection using an enzyme immunoassay (EIA) that discriminates between recent infection (RI; within 6 months) and established infection. The performance of EIA-RI was evaluated in 96 HIV-1 chronically infected patients on highly active antiretroviral therapy (HAART) with an undetectable viral load (VL) for at least 3 years. Demographic data, HIV-1 viral load, CD4(+) T-cell count, viral subtype, and treatment duration were collected. The subset of misclassified patients was further analyzed using samples collected annually. The impact on incidence estimates was evaluated by simulation. The specificity in treated patients was significantly lower (70.8 to 77.1%) than that observed in untreated patients (93.3 to 99.3%, P < 0.001). Patients falsely classified as recently infected had been treated for a longer period and had longer-term viral suppression than those correctly classified. The loss of specificity of the test due to treatment may have a dramatic impact on the accuracy of the incidence estimates, with a major impact when HIV prevalence is high. The cross-sectional studies intended to derive HIV incidence must collect information on treatment or, alternatively, should include detection of antiretroviral drugs in blood specimens to rule out treated patients from the calculations.     

A structural voyage toward an understanding of the MHC-I-restricted immune response: lessons learned and much to be learned

T cells that express clonally distributed αβ T-cell receptors (TCRs) corecognize antigenic peptides (p) bound to major histocompatibility complex class I (MHC-I) and class II molecules (MHC-II). Extensive human leukocyte antigen (HLA) polymorphism enables HLA molecules from different haplotypes to capture an array of self- and microbe-derived peptide antigens that is fundamental to adaptive immunity. T cells developing in the thymus are selected for weak binding to self-peptide-HLA complexes generating a vast repertoire of clonally distinct T cells in the periphery. Indeed, diversity within germline loci and the finally assembled TCR genes, coupled with inherent TCR cross-reactivity, enables CD8⁺ T cells to survey the multitude of pHLA-I landscapes. Precisely how does the TCR ligate to pHLA-I, and how does knowledge of the detailed structural interactions inform immunobiology? A recent number of our structural studies concerning the TCR-pMHC-I axis, alongside others in the field, have provided insight into HLA-I polymorphism, pMHC-I flexibility, TCR bias, TCR polymorphism, maintenance of self-tolerance, T-cell cross-reactivity, and alloreactivity. Collectively, the data also provide an opportunity to address the structural correlates of MHC-I restriction. Here, we provide our perspective concerning these advances in the field. Although much key information has been gleaned, the structural data show that some of the key concepts surrounding the TCR-pMHC-I interaction remain controversial and unresolved.