Belimumab Therapy in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex heterogeneous disease, posing challenges to clinical trials. As in other autoimmune diseases, B-lymphocytes play a central role in lupus pathogenesis. The finding that selection and survival of B cells are controlled by a variety of signals, including those provided by the longevity factor BAFF (B-cell activating factor), also called BLyS (B-lymphocyte stimulator), led to preclinical trials that revealed that BAFF represents a promising therapeutic target for human lupus. Belimumab is a fully human monoclonal antibody directed against BAFF. Lessons learned from early clinical trials led to improved methods and success of phase III trials, with recruitment of patients with both clinically and serologically active disease, development and use of a novel SLE Responder Index, and progressive and special restrictions on immunosuppressive and corticosteroid use. These studies offer an attractive blueprint to conduct future clinical trials in SLE. The overall steroid-sparing ability and benefits of belimumab on musculoskeletal and mucocutaneous organ systems suggest that it has an impact on the clinical management of SLE patients. Future directions include studies to determine the role of belimumab in early SLE, as well as in renal or CNS involvement.     

Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes

Pathogenic autoimmunity requires a combination of inherited and acquired factors. In as much as hormones influence the sexual dimorphism of the immune system, it is possible that they can initiate or accelerate an autoimmune process, and contribute to gender-biased autoimmune disorders. Not only natural hormones, but also endocrine disruptors, such as environmental estrogens, may act in conjunction with other factors to override immune tolerance to self-antigens. In lupus, murine and human studies demonstrate that female sex hormones are implicated in disease pathogenesis. In the B cell compartment, both prolactin and estrogen are immunomodulators that affect maturation, selection and antibody secretion. Their impact may be based on their capacity to allow autoreactive B cells to escape the normal mechanisms of tolerance and to accumulate in sufficient numbers to cause clinically apparent disease. Both hormones lead to the survival and activation of autoreactive B cells, but they skew B cell maturation towards different directions, with prolactin inducing T cell-dependent autoreactive follicular B cells and estrogen eliciting T cell-independent autoreactive marginal zone B cells. Differential modulation of the cytokine milieu by hormones may also affect the development and activation of specific mature B cell subsets. This novel insight suggests that targeted manipulation of these pathways may represent a promising avenue in the treatment of lupus and other gender-biased autoimmune diseases.     

<Emphasis Type="Italic">Fasciola hepatica</Emphasis>: the effect of food quality on the development of redial generations in<Emphasis Type="Italic"> Galba truncatula</Emphasis> infected with allopatric miracidia

Individual bimiracidial infections of French Galba truncatula with an allopatric (Moroccan) isolate of Fasciola hepatica were carried out under laboratory conditions to count free rediae and intraredial daughter rediae in snails just after their death, and to determine whether feeding the snails on lettuce only or lettuce plus Tetraphyll had an effect on the development of redial generations. Controls consisted of snails infected with sympatric (French) miracidia and reared with lettuce only. In the allopatric group, reared with lettuce only as food, a higher mortality rate of snails in the first 4 weeks of the experiment was noted, and most G. truncatula showed 1-sporocyst infections, with the usual development of redial generations. Compared to the sympatric group, the growth of the first mother redia (R1a redia) in each snail of the allopatric group was significantly slower during the first weeks of infection, whereas a significantly increased formation of intraredial daughter rediae in the other mother rediae (R1b rediae) was noted over the same period. In the allopatric group, reared with cos lettuce and commercial fish food, 1-sporocyst infections (45.5% of snails) and 2-sporocyst infections (53.9%), with the usual development of redial generations, were noted. Compared to the sympatric group, a significantly slower development of the first mother redia during the first weeks of the experiment was noted in the 1-sporocyst infections, whereas the values in the 2-sporocyst infections did not significantly differ from those noted in the sympatric group. Similar results were noted for the production of intraredial daughter rediae in the R1b rediae during the first weeks of the experiment. In all infections derived from the growth of a single sporocyst per snail, the differentiation of numerous daughter rediae inside R1b rediae would be induced by the slow growth of the R1a redia (from which the most important group of R2a rediae originated) during the first weeks of infection and might represent a mechanism to replace free rediae absent from the inside of the snail.     

Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis: longitudinal cohort study of initially healthy adolescents

Aggregatibacter actinomycetemcomitans is frequently associated with localized aggressive periodontitis (LAP); however, longitudinal cohort studies relating A. actinomycetemcomitans to initiation of LAP have not been reported. A periodontal assessment was performed on 1,075 primarily African-American and Hispanic schoolchildren, ages 11 to 17 years. Samples were taken from each child for A. actinomycetemcomitans. A cohort of 96 students was established that included a test group of 38 A. actinomycetemcomitans-positive students (36 periodontally healthy and 2 with periodontal pockets) and 58 healthy A. actinomycetemcomitans-negative controls. All clinical and microbiological procedures were repeated at 6-month intervals. Bitewing radiographs were taken annually for definitive diagnosis of LAP. At the initial examination, clinical probing attachment measurements indicated that 1.2% of students had LAP, while 13.7% carried A. actinomycetemcomitans, including 16.7% of African-American and 11% of Hispanic students (P = 0.001, chi-square test). A. actinomycetemcomitans serotypes a, b, and c were equally distributed among African-Americans; Hispanic students harbored predominantly serotype c (P = 0.05, chi-square test). In the longitudinal phase, survival analysis was performed to determine whether A. actinomycetemcomitans-positive as compared to A. actinomycetemcomitans-negative students remained healthy ("survived") or progressed to disease with attachment loss of >2 mm or bone loss (failed to "survive"). Students without A. actinomycetemcomitans at baseline had a significantly greater chance to remain healthy (survive) compared to the A. actinomycetemcomitans-positive test group (P = 0.0001). Eight of 38 A. actinomycetemcomitans-positive and none of 58 A. actinomycetemcomitans-negative students showed bone loss (P = 0.01). A. actinomycetemcomitans serotype did not appear to influence survival. These findings suggest that detection of A. actinomycetemcomitans in periodontally healthy children can serve as a risk marker for initiation of LAP.     

Paternal age and sperm DNA decay: discrepancy between chromomycin and aniline blue staining

The effect of paternal age on sperm DNA fragmentation and decondensation was determined in a retrospective study involving 1769 patients. TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling (TUNEL) assay was used to assess fragmentation, and DNA decondensation was measured with either chromomycin or aniline blue staining. The impact of atypical forms was also analysed. DNA fragmentation increases with age, but is independent of the percentage of atypical forms. Both staining techniques revealed a negative correlation between the quality of sperm packaging and the percentage of atypical forms. Decondensation increases with increasing age and fragmentation when measured with chromomycin; however, an inverse relationship is observed when testing is performed using aniline blue. These observations are discussed in relation to the specificity of the dyes, the deposition of protamines and the impact of age and reactive oxygen species on protamine cross-linking.     

立体视频的4维矩阵DCT编码算法

基于4维矩阵DCT变换理论提出了一种有效的立体视频编码方法。通常的方法是对每个立体对都进行视差估计和运动估计，该论文的方法采用4维矩阵DCT变换去除双目图像数据间的冗余，因此只需进行三分之一的运动估计计算而不需做任何视差估计。第一个立体对被称为“I立体对”，接下来的每三个相邻的立体对被称为一个“P立体对”，并且以4维单元的形式进行保存。仅对“P立体对”的中间时刻的块进行运动估计，中间时刻的运动矢量被视为4维单元的统一的运动矢量来计算运动补偿。然后，用4维矩阵DCT变换进一步的去除时域和空域上的冗余性。实验结果表明在计算复杂度大大降低的情况下该方法可以得到较好的编码性能。     

Cytogenetic and cryobiology of human cocultured embryos: A 3-year experience

Purpose Coculture, which allows good-quality human blastocysts with good yields to be obtained, has been designed mainly to select the best embryos for transfers.Methods In a first attempt during coculture, we have studied by fluorescent in situhybridization the chromosomic content of the in vitroblocked embryos, using centromeric probes for chromosomes 1, 12, and 18. Close to 37% of the arrested embryos show aneuploidymosaicism.Results Freezing cocultured blastocysts gives good recovery rates after transfer (83%). The ongoing pregnancy rates per transfer (19%) are high, and the implantation rate per embryo is 13%. This compares favorably with freezing at an early stage.Conclusions We observed that the quality of the endometrium is always the limiting step, as first of all we observed wide variations according to the hormonal preparation of the patients. Moreover the implantation per embryo in the pregnant patients is very high (57%), indicating that most of the losses are directly related to the receptivity of the endometrium.Presented at the 50th Annual Meeting of the American Fertility Society, San Antonio, Texas, November 5–10, 1994.