Decreased apoptosis despite severe CD4 depletion in the thymus of a human immunodeficiency virus-1 infected child.

Thymic epithelial space (TES), where thymopoiesis is located, and thymic perivascular space (PVS), where T lymphocytes are pooled, appear differentially involved in human immunodeficiency virus 1 (HIV-1)-infected children. The decline of CD4+ T cells during HIV-1 infection is probably due to a relative predominance of CD4+ T cell destruction on cell proliferation. Antiretroviral therapy (ART) typically increases circulating CD4+ T cell counts, but it is debated whether ART reduces the destruction of existing CD4+ T cells or enhances the production of new cells. We report on postmortem flow-cytometry, immunohistochemistry, and terminal deoxynucleotide transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) studies performed on thymus of an 11-year-old vertically HIV-1 infected child receiving ART. Thymus tissue sections showed that CD4+ and CD8+ cells were more numerous in PVS than in TES (p=0.0334 for CD4+ cells, p<0.0001 for CD8+ cells). Thymus cell suspension showed that CD4+ CD8+ cells (immature thymocytes) were 15.4% (age-related control: 80.5%). Very few apoptotic CD4+ cells were seen in TES. Very low to absent proliferation activity was demonstrated in both TES and PVS. We suggest that 1) lymphocyte depletion in HIV-1 infection is more pronounced in TES than in PVS, 2) immature thymocytes are not enhanced, and 3) an anti-apoptotic effect in the thymus seems to be a potential ART mechanism to explain the CD4+ pool increase.

[How nationally concordated measures for quality assurance in clinical care of term and preterm infants are put into practice in Baden-Württemberg]. / Zur Umsetzung national vereinbarter Massnahmen zur Qualitätssicherung in der klinischen Versorgung Früh- und Neugeborener in Baden-Württemberg.

BACKGROUND: By the end of the year 2007, pediatric hospitals in Baden-Württemberg had assigned themselves to one of three levels of perinatal care according to a checklist of the German Federal Joint Committee (F-JC) effective since January 1st, 2006. The Medical Service of Statutory Health Insurance had been assigned to prove the plausibility of that self-assessment according to quality criteria for clinical care of term and preterm newborn infants concordated by the F-JC. METHODS: Between November 2007 and October 2008 31 providers were audited. Observations were documented in a checklist, reviewed and evaluated by expert auditors. For that purpose, quality criteria given by the F-JC were grouped into 7 quality categories which were weighted according to their practical relevance. In addition, a graded numeric system of evaluation was used for comparative analysis (absolute and relative benchmarking values). RESULTS: 3 of 23 providers fulfilled the quality criteria of the F-JC for PNC level 1 (highest level of care), 6 of 23 fulfilled them in part, and 14 of 23 did not fulfill them as judged by the auditors. Criteria for PNC level 2 were "fulfilled in part" by 2 of 6 providers and "not fulfilled" by 4. Both providers of perinatal special care ("level 3") fulfilled the quality criteria for "level 3" completely. There was no linear correlation between absolute or relative benchmarking values and assessment by expert auditors. CONCLUSION: If the criteria of the F-JC were interpreted very strictly, it would be difficult to guarantee comprehensive regional delivery of care in the state of Baden-Württemberg at the level formally requested by the F-JC for PNCs.

FTY720: early clinical experience.

FTY720 is the first in a new class of immunomodulators--sphingosine 1-phosphate receptor (S1P-R) agonists. It is highly effective in prolonging allograft survival in preclinical models of transplantation. Furthermore, FTY720 acts synergistically with calcineurin inhibitors and proliferation inhibitors in these models, suggesting that use of FTY720 in combination with classical immunosuppressants may be a promising new option for transplant patients. Phase I studies conducted in stable renal transplant patients maintained on a cyclosporine (CsA)-based regimen have revealed a tolerable profile of FTY720 for transplant pharmacotherapy. The pharmacokinetics of FTY720 is characterized by linear dose-proportional exposure over a wide range of doses, only moderate interpatient variability, and a prolonged elimination half-life (t(1/2) 89 to 157 hours). These factors suggest that FTY720 can be administered according to a simple once-daily schedule, without the need for blood-level monitoring or dose titration. The pharmacodynamics of FTY720 in humans are characterized by a significant reduction in peripheral blood count by up to 85%. In contrast to the nonspecific myelosuppressive effects of other immunosuppressants, this effect of FTY720 is specific for lymphocytes, with no effect observed on monocytes or granulocytes. In combination with CsA, FTY720 was well tolerated following single or multiple dosing, without any evidence of additional toxicities, indicating that FTY720 may be useful in the future design of more effective and less toxic regimens for prevention of graft rejection.

Autoamplification of apoptosis following ligation of CD95-L, TRAIL and TNF-alpha.

CD95-L, TNF-alpha and TRAIL are death-inducing ligands (DILs) which may signal apoptosis via crosslinking of their cognate receptors. The present study shows that treatment of cells with agonistic mAB alpha APO-1 (CD95), recombinant TRAIL or TNF-alpha leads to enhanced mRNA and protein expression of each DIL with concomitant death in target cells. Immunoprecipitation of CD95-L protein from supernatant as well as neutralizing antibodies suggest DIL proteins to be cooperatively acting mediators of these cytotoxic activity. Autoamplification of the death signal was blocked in cells with a defect in apoptosis signaling either due to a dysfunctional FADD molecule or to the failure to activate JNK/SAPKs. Phosphorylation and enhanced binding of cJun and ATF-2 to DIL promoters suggest JNK/SAPKs as activators of these transcription factors following death receptor triggering. In consequence, autocrine production of DILs allows the spread of death signals to sensitive target cells. Oncogene (2000) 19, 4255 - 4262

TRAIL/Apo-2-ligand-induced apoptosis in human T cells.

Members of the tumor necrosis factor (TNF) family such as CD95 (APO-1/Fas) ligand (L) trigger apoptosis in lymphoid cells. Recently, a new member of apoptosis-inducing ligands, TRAIL (TNF-related-apoptosis-inducing-ligand)/Apo-2 ligand, was identified that might act in a similar way. We compared TRAIL and CD95L-induced apoptosis in human lymphoid cells. Expression of TRAIL was found in CD4+ and CD8 T cells following activation, suggesting that TRAIL participates in T cell-mediated induction of apoptosis. Similar to CD95L, TRAIL-induced apoptosis in target cells is mediated by activation of caspases (ICE/Ced-3 proteases). However, different human lymphoid cell lines and peripheral T cells differ in sensitivity towards induction of apoptosis by TRAIL and CD95L. In addition, T cells are highly sensitive towards CD95L-induced apoptosis after prolonged activation in vitro, but remain completely resistant to TRAIL-induced apoptosis. In contrast, T cells from HIV-1-infected patients previously shown to exhibit increased CD95 sensitivity are even more susceptible towards TRAIL-induced cell death. These data suggest that TRAIL might participate in CD95-independent apoptosis of lymphoid cells and might be involved in deregulated apoptosis in diseases such as leukemias and HIV-1 infection.

Age dependency of red blood cell deformability and density: studies in transient erythroblastopenia of childhood.

Several investigators have demonstrated that red blood cell (RBC) deformability decreases progressively with increasing cell density and proposed that reduction in deformability plays a role in the senescence process of normal RBCs. Transient erythroblastopenia of childhood (TEC) results from temporary cessation of erythropoiesis. Since no new RBCs are produced for some time, the circulating RBCs are relatively old. RBS density (phthalate-oil method) and RBC deformability (RBC elongation in a counter-rotating rheoscope) were studied in seven children with TEC and in 10 control children. The mean values of MCHC, RBC density and RBC deformation were not significantly different between TEC and control children. Compared to controls, the frequency distribution of RBC density in TEC was slightly shifted to higher values. The percentage of RBCs with extremely low densities (< 1.090 g/ml) was 0.9 +/- 1.2% in the patients and 5.6 +/- 2.3% in the controls (P < 0.001). The percentage of RBCs with high density (> 1.106 g/ml) was 6.4 +/- 2.1% in the patients and 4.9 +/- 1.8% in the controls (P > 0.10). The reduction of RBCs with low density in TEC suggests that RBCs with low density are relatively young. Since the percentage of RBCs with high density increased only slightly in TEC, we conclude that only a fraction of dense RBCs is old. In TEC, the frequency distribution of RBC elongation was slightly shifted to lower values. 5% of the RBCs studied in the control children had RBC elongation values above 0.39 (TEC 1.2%) and 5% had elongation values below 0.16 (TEC 6.7%). Thus, only a small fraction of highly deformable RBCs was diminished in TEC. These data suggest that a decrease in deformability is not a significant part of the normal ageing process of human RBCs.