Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of T cell dysregulation caused by defective Fas-mediated apoptosis. Patients with ALPS can develop a myriad of clinical manifestations including lymphadenopathy, hepatosplenomegaly, autoimmunity and increased rates of malignancy. ALPS may be more common that originally thought, and testing for ALPS should be considered in patients with unexplained lymphadenopathy, hepatosplenomegaly, and/or autoimmunity. As the pathophysiology of ALPS is better characterized, a number of targeted therapies are in preclinical development and clinical trials with promising early results. This review describes the clinical and laboratory manifestations found in ALPS patients, as well as the molecular basis for the disease and new advances in treatment.     

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling

The efficient engraftment in immune-deficient mice achieved with both acute lymphoblastic leukemia (ALL) cell lines and primary samples has facilitated identification of the antileukemia activity of a wide variety of agents. Despite widespread usage, however, little is known about the early ALL localization and engraftment kinetics in this model, limiting experimental read-outs primarily to survival and endpoint analysis at high disease burden. In this study, we report that bioluminescent imaging can be reproducibly achieved with primary human ALL samples. This approach provides a noninvasive, longitudinal measure of leukemia burden and localization that enhances the sensitivity of treatment response detection and provides greater insight into the mechanism of action of antileukemia agents. In addition, this study reveals significant cell line- and species-related differences in leukemia migration, especially early in expansion, which may confound observations between various leukemia models. Overall, this study demonstrates that the use of bioluminescent primary ALL allows the detection and quantitation of treatment effects at earlier, previously unquantifiable disease burdens and thus provides the means to standardize and expedite the evaluation of anti-ALL activity in preclinical xenograft studies.     

The antimicrobial resistance patterns and associated determinants in Streptococcus suis isolated from humans in southern Vietnam, 1997-2008

Background

Our objective was to determine the frequency and determinants of presentation to care with advanced HIV disease in patients who discover their HIV diagnosis at this stage as well as those with delayed presentation to care after HIV diagnosis in earlier stages.

Methods

We collected data on 1,819 HIV-infected patients in Brussels (Belgium) and Northern France from January 1997 to December 2007. "Advanced HIV disease" was defined as CD4 count <200/mm³ or clinically-defined AIDS at study inclusion and was stratified into two groups: (a) late testing, defined as presentation to care with advanced HIV disease and HIV diagnosis ≤6 months before initiation of HIV care; and (b) delayed presentation to care, defined as presentation to care with advanced HIV disease and HIV diagnosis >6 months before initiation of HIV care. We used multinomial logistic regression to determine the factors associated with delayed presentation to care and late testing.

Results

Of the 570 patients initiating care with advanced HIV disease, 475 (83.3%) were tested late and 95 (16.7%) had delayed presentation to care. Risk factors for delayed presentation to care were: age 30-50 years, injection drug use, and follow-up in Brussels. Risk factors for late testing were: sub-Saharan African origin, male gender, and older age. HIV transmission through heterosexual contact was associated with an increased risk of both delayed presentation to care and late testing. Patients who initiated HIV care in 2003-2007 were less likely to have been tested late or to have a delayed presentation to care than patients who initiated care before 2003.

Conclusion

A considerable proportion of HIV-infected patients present to care with advanced HIV disease. Late testing, rather than a delay in initiating care after earlier HIV testing, is the main determinant of presentation to care with advanced HIV disease. The factors associated with delay presentation to care differ from those associated with late testing. Different strategies should be developed to optimize early access to care in these two groups.     

A case of pulmonary vein obstruction: evaluation using newer echocardiographic imaging techniques

A 59-year-old woman was admitted in our hospital due to persistentcough and dyspnea. Transthoracic 2-dimensional echocardiographydemonstrated a cardiac mass (29x34 mm) that extended from theright upper pulmonary vein into the left atrium causing thepartial obstruction of the right lower vein as indicated bythe increased Doppler velocities. Contrast echocardiographyconfirmed the presence of microcirculation within the mass.During transesophageal (TEE) echocardiographic study, colorDoppler imaging and power Doppler imaging (Angio^® Vivid7, GE Medical System, Horten, Norway) demonstrated the presenceof vascular flow within the mass. A chest magnetic resonancetomography showed a pulmonary mass of 30x25x28 mm infiltratingthe pulmonary veins. After surgery, biopsy confirmed a highgrade mucoepidermoid lung cancer with few large arterioles.The new echocardiographic techniques can reliably differentiatea cardiac tumor from a cardiac thrombus.     

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheral-blood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy.     

Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest

Febrile convulsions are a common form of childhood seizure. It is estimated that between 2 and 5% of children will have a febrile convulsion before the age of 5. It has long been recognized that there is a significant genetic component for susceptibility to this type of seizure. Wallace, Berkovic and co-workers recently reported linkage of a putative autosomal dominant febrile convulsion gene to chromosome 8q13-21. We report here another autosomal dominant febrile convulsion locus on chromosome 19p. Linkage analysis in this large multi- generational family gave a maximum pairwise lod score of 4.52 with marker Mfd120 at locus D19S177. Linkage to the chromosome 8 locus was excluded in this family. Haplotype analysis using both affected and unaffected family members indicates that this febrile convulsion gene, which we call FEB2 , can be localized to an 11.7 cM, 1-2 Mb section of chromosome 19p13.3, between loci D19S591 and D19S395.      

自体血照射回输提高食管癌患者抗辐射的作用

目的探讨自体血液照射回输提高食管癌患者抗辐射能力及对机体正常组织的合理防护．方法食管癌患者６６例随机分为研究组（自体血液照射回输加放疗）和对照组（常规放疗组）．观察两组急性放射性食管炎的发生率及研究组患者血疗前后ＩＬ２，Ｔ淋巴细胞亚群的变化．结果急性放射性食管炎发生率：研究组为１２１％（４／３３），对照组６０６％（２０／３３，Ｐ＜００１）；发生急性放射性食管炎的平均放疗剂量（Ｘ±ＳｃＧＹ）研究组４０５０±８２２，对照组２４６０±６０９（Ｐ＜００１）；研究组血疗前后ＩＬ２，Ｔ淋巴细胞亚群也都有非常显著变化．结论自体血液照射回输可提高食管癌患者抗辐射功能，可能是低剂量辐射刺激诱发机体的适应性和刺激机体的免疫功能，提高了正常组织对放疗的耐受量而不对肿瘤组织起保护作用．     

Inhibitory effect of a fava bean component on the in vitro development of Plasmodium falciparum in normal and glucose-6-phosphate dehydrogenase deficient erythrocytes

We examined the hypothesis that G-6-PD deficiency associated with fava bean ingestion confers resistance to malaria by studying the in vitro interactions between malaria parasites (Plasmodium falciparum), human erythrocytes with varying degrees of G-6-PD deficiency, and isouramil (IU), a fava bean extract that is known to cause oxidant stress and hemolysis of G-6-PD-deficient erythrocytes. Untreated G-6-PD-deficient and normal erythrocytes supported the in vitro growth of P. falciparum equally well. However, after pretreatment with IU, G-6-PD-deficient erythrocytes did not support parasite growth in vitro, whereas growth remained high in normal erythrocytes. Parasite growth was proportional to the G-6-PD activity of the IU-treated erythrocytes. In contrast, when parasitized erythrocytes were exposed to IU, parasites even in normal erythrocytes were destroyed. Ring forms were much less sensitive than late trophozoites and schizonts. The results suggest that there are two modes by which IU affects the development of P. falciparum and demonstrate in vitro that G-6-PD deficiency confers resistance against malaria under conditions of fava-bean-associated oxidant stress.