High responsiveness of HLA-B57-restricted Gag-specific CD8+ T cells in vitro may contribute to the protective effect of HLA-B57 in HIV-infection

HLA-B57 has been shown to be associated with long-term asymptomatic HIV-1 infection. To investigate the biological mechanism by which the HLA-B57 allele could protect from HIV-1 disease, we studied both the number of CD8(+) T cells as well as CD8(+) T cell responsiveness directed to different HIV-1 Gag peptides presented by HLA-A2, -B8 or -B57. T cells specific for the HLA-B57 peptide KAFSPEVIPMF responded more readily and to a higher extend to antigenic stimulation in vitro than T cells specific for the HLA-A2 peptide SLYNTVATL or the HLA-B8 peptide EIYKRWII. This phenomenon was reproducible with T cells from individuals expressing HLA-B57 in combination with one or both of the other alleles and was persistent during long-term follow-up. Lower reactivity of A2- and B8-restricted T cells was not explained by mutations in the B8- or A2-restricted Gag-peptides. Moreover, no correlation between peptide mutation frequency and IFN-gamma production by the corresponding Gag-specific T cells was observed. In conclusion, functional differences were observed between T cells specific for HIV epitopes derived from the same protein presented by different HLA molecules. B57-restricted KAFSPEVIPMF-specific CD8(+) T cells have relatively high responsiveness, which could contribute to the protective effect of HLA-B57 in HIV infection.     

Skin Cancer Risk Associated with Immunosuppressive Therapy in Organ Transplant Recipients

The aim of this review is to summarise the available literature regarding the epidemiology and proposed mechanisms of skin cancer development in organ transplant recipients who are receiving lifelong treatment with immunosuppressive therapy and to review the different strategies for managing complications in this group of patients. Organ transplantation is complicated by an increased incidence of certain cancers, of which non-Hodgkin's lymphoma, Kaposi's sarcoma and squamous cell carcinoma are the most common. The most important risk factor for these cancers is immunosuppressive therapy. The relative importance of different immunosuppressive therapy regimens in relation to the development of skin cancer is still unclear. Immunosuppression per se may play the most important role, but other mechanisms, which are independent of host immunity and which may be different for the various agents used, may also be of importance for the increased risk of cancer. Apart from immunosuppressive therapy, exposure to sunlight and infection with human papillomaviruses are believed to be the most important risk factors for the development of cutaneous squamous cell carcinoma in organ transplant recipients. Human papillomaviruses, no doubt, benefit considerably from immunosuppression, as is indicated by the large number of warts found in these patients, but many questions remain unanswered about their significance in cutaneous oncogenesis. The E6 protein from a range of cutaneous human papillomavirus types effectively inhibits apoptosis in response to ultraviolet light damage. It is, therefore, conceivable that the development of skin cancer in organ transplant recipients is the result of a complex interplay between exposure to ultraviolet radiation, human papillomavirus infection and genetic predisposition. Measures for protection from the sun are important for reducing the risk of skin cancer in organ transplant recipients. Regular surveillance of patients with skin problems and easy access to a dermatologist for these patients is advised. Changing the immunosuppressive regimen from azathioprine to cyclosporin or vice versa does not seem to relieve the skin problems. Tapering the immunosuppressive therapy to the lowest possible dose may be of some advantage. Oral retinoids, e.g. acitretin, have some effect in reducing the number of keratotic skin lesions and in the prevention of skin cancer in organ transplant recipients. Resurfacing the back of the hand can be a successful treatment for patients with multiple skin cancers on the back of the hand and can be used prophylactically in patients with severely actinically damaged skin.     

肝素酶和碱性成纤维细胞生长因子与非小细胞肺癌转移和预后的关系

目的 探讨肝素酶(heparanase)和碱性成纤维细胞生长因子(bFGF)在人非小细胞肺癌(NSCLC)组织中表达的临床意义及其与肺癌转移和预后的关系。方法 采用免疫组织化学、原位杂交和Western blot方法,检测115例人NSCLC石蜡切片和45例新鲜肺癌及对应癌旁正常组织中肝素酶和bFGF的表达情况。采用χ^2检验、t检验、生存曲线和Cox比例风险回归等方法分析肝素酶和bFGF分别表达及共表达的意义。结果 免疫组织化学染色证实肝素酶(91／115)和bFGF(89／115)主要表达在癌细胞质和(或)细胞膜中,在正常肺泡上皮和支气管上皮中则呈阴性表达。Western blot也证实肝素酶在肺癌中的表达明显增高(P=0．041)。统计分析结果显示：肝素酶和bFGF的表达具有明显的一致性(P：0．0001),二者单独表达和共表达均与肺癌的分期、血管侵袭、淋巴结转移、微血管密度和预后有关,其中,二者共表达时与分期和微血管密度的相关性更显著;另外,bFGF还与肺癌的分化程度有关。多因素分析结果显示,肺癌的分化程度、血管浸润、淋巴结转移和bFGF的表达可以作为判断肺癌预后的危险因素,但肝素酶不是影响预后的独立因素。结论 肝素酶和bFGF均与肺癌的转移、血管生成和预后密切相关。     

Enhanced responsiveness of human extravisual areas to photic stimulation in patients with severely reduced vision

Lesions in the primary visual cortex induce severe loss of visual perception. Depending on the size of the lesion, the visual field might be affected by small scotomas, hemianopia, or complete loss of vision (cortical blindness). In many cases, the whole visual field of the patient is affected by the lesion, but diffuse light-dark discrimination remains (residual rudimentary vision, RRV). In other cases, a sparing of a few degrees can be found (severely reduced vision, SRV).In a follow-up study, we mapped visually induced cerebral activation of three subjects with SRV using functional magnetic resonance imaging. We were especially interested in the visual areas that would be activated if subjects could perceive the stimulus consciously although information flow from V1 to higher visual areas was strongly reduced or virtually absent. Because subjects were only able to discriminate strong light from darkness, we used goggles flashing intense red light at a frequency of 3 Hz for full visual field stimulation. Besides reduced activation in V1, we found activation in the parietal cortex, the frontal eye fields (FEF), and the supplementary eye fields (SEF). In all patients, FEF activation was pronounced in the right hemisphere. These patterns were never seen in healthy volunteers. In a patient who recovered completely, we observed that extrastriate activation disappeared in parallel with the visual field restitution. This result suggests that damage to the primary visual cortex changes the responsiveness of parietal and extravisual frontal areas in patients with SRV. This unexpected result might be explained by increased stimulus-related activation of attention-related networks.     

Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer

Natural killer (NK) cells (CD56(+)/CD3(-)) in the circulation of cancer patients were reported to have low NK activity and undergo spontaneous apoptosis. A possible relationship between apoptosis and impaired NK activity was studied by Annexin V-binding and NK-cell assays performed with peripheral blood mononuclear cells of patients with head and neck cancer (HNC), breast cancer (BC) and normal controls (NC). Cells stained with Annexin V (Anx) and antibodies to CD56, CD3, CD95, CD25, CD122 or CD132 were examined by flow cytometry. NK activity was tested against K562 targets in 4-h (51)Cr-release assays. The ratio of CD56(dim)/CD56(bright) NK cells was significantly different in patients vs. controls (10 vs. 16; p<0.01). A significantly greater percentage of CD56(dim) NK cells bound Anx in HNC patients (27+/-17%, median +/- SD) or BC (46+/-18%) than in NC (15+/-18%, p<0.04 and p<0.0002, respectively). CD56(dim) NK cells were preferentially targeted for apoptosis. NK activity was significantly lower in patients with HNC and BC than in NC (p<0.009). An inverse correlation between NK activity and the percent of Anx(+)CD56(dim) NK cells was observed in cancer patients (p =0.002) but not in NC. In patients, circulating CD56(dim) NK cells were targeted for apoptosis, leading to low levels of NK activity.     

Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency

X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a severe inherited neurodegenerative disease, associated with the accumulation of very long-chain fatty acids (VLCFA). The recent unexpected observation that the accumulation of VLCFA in tissues of the Abcd1-deficient mouse model for X-ALD is not due to a deficiency in VLCFA degradation, led to the hypothesis that mitochondrial abnormalities might contribute to X-ALD pathology. Here, we report that in spite of substantial accumulation of VLCFA in whole muscle homogenates, normal VLCFA levels were detected in mitochondria obtained by organellar fractionation. Polarographic analyses of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between X-ALD and control mice. Moreover, analysis by electron microscopy, revealed normal size, structure and localization of mitochondria in muscle of both groups. Similar to the results obtained in skeletal muscle, the mitochondrial enzyme activities in brain homogenates of Abcd1-deficient and wild-type animals also did not differ. Finally, studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls revealed no abnormalities. Thus, we conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa-mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice.     

Culture of menstrual endometrium with peritoneal explants and mesothelial monolayers confirms attachment to intact mesothelial cells

BACKGROUND: To evaluate adhesion of menstrual endometrium (ME) to intact peritoneal mesothelium. METHODS: Explants of peritoneum were cultured for 1 h with ME (n = 6). Specimens were serially sectioned for haematoxylin and eosin stain and immunohistochemistry using an anti-cytokeratin antibody to label mesothelium. Confocal laser scanning microscopy (CLSM) was performed to identify an intact layer of mesothelial cells (MC) underlying sites of ME attachment. Also, ME and MC were labelled with Cell-Tracker dyes. ME was cultured with mesothelial monolayers for 1 h (n = 10). Cultures were examined with differential interference contrast and CLSM. Optical sections were taken and a three-dimensional model was constructed. RESULTS: In the peritoneal explants, ME adhered to intact mesothelium. There was no evidence of transmesothelial invasion. CLSM of sections of the explants demonstrated an intact monolayer of cytokeratin positive cells below the sites of ME implantation. Cytokeratin negative and positive ME cells adhered to mesothelial cells. Likewise, the ME attached to cultured mesothelium. Orthogonal sections and three-dimensional reconstruction confirmed an intact monolayer of mesothelium underlying ME attachment sites. CONCLUSIONS: This study confirms that ME adheres rapidly to intact peritoneal mesothelium. Further studies are needed that characterize the mechanisms of ME adhesion to, and migration through, mesothelial cells.     

Weight Status and BMI-Related Traits in Adolescent Friendship Groups and Role of Sociodemographic Factors: The European IDEFICS/I. Family Cohort

BackgroundDuring adolescence, health behaviors and weight status are increasingly influenced by friendship and peer networks. This paper examines resemblances in weight-related characteristics and how they differ by sociodemographic factors.MethodsOver 3,000 friendships were reported by 1,603 adolescents, aged 11–16 years, who participated in the school-based I. Family study in 6 European countries. Each “source child” named 1–10 friends for whom standardized weight-related traits were available in the same survey. The mean value of the friends'' traits weighted by time spent together was calculated, and related to the source child''s trait. Country, age and sex of the source child, parental education, and immigrant background were considered for confounding and moderation.ResultsSource children''s z-scores of body fat percent and BMI were positively associated with their friends'' characteristics, in particular if they had highly educated parents. Positive associations were also found regarding the frequency of fast-food consumption, impulsivity, screen time, preference for sugar-sweetened foods, and hours spent in sports clubs, in increasing order of effect size. Additionally, correlations were observed between friends'' cognitive and school functioning and being bullied. No associations were seen for a preference for high-fat foods, weight concerns, and health-related quality of life. Finally, parental education and immigrant background were associated between friends in all countries except Sweden, where no associations were observed.ConclusionAdolescent friends shared a number of weight-related characteristics. For weight measures per se, positive associations with friends'' characteristics were only observed in adolescents with high parental education. Associations regarding energy-balance behaviors and indicators of school-related well-being did not differ by parental education. Parental education and immigrant background correlated positively in friends in most countries showing that social aggregation is already occurring in adolescence. The wide spectrum of friendship associations in weight-related traits and behaviors suggests that health promotion initiatives in adolescents should be directed towards peer groups in both school-related and leisure-time environments.ISRCTN RegistryPan-European IDEFICS/I. Family children cohort (ID ISRCTN62310987; https://doi.org/10.1186/ISRCTN62310987).     

The effect of tyrphostin AG-556 on intimal thickening in a mouse model of arterial injury

BACKGROUND: Inflammation has been shown to play an important role in promoting the response to arterial injury and proinflammatory cytokines, such as tumor necrosis factor (TNF) alpha, are candidate mediators. AG-556 is a tyrosine kinase inhibitor proven to be effective in a model of multiple sclerosis-like syndrome in mice due to its immunomodulating effect. In the current study, we investigated the effect of the tyrphostin AG-556 on neointimal thickening and cytokine profile in a model of arterial injury in the mouse. METHODS: Injury was induced by external cuff placement on the left femoral artery of wild-type C57BL/6 mice. AG-556 dissolved in DMSO was injected intraperitoneally daily to the injured mice in a dosage of 2 mg/mouse. Control mice received DMSO injections. Histological analysis was carried out to assess neointimal formation. Splenocytes were cultured in the absence and presence of a mitogen for evaluation of thymidine incorporation and cytokine production. RESULTS: AG-556 treatment significantly attenuated intimal thickening (43,000+/-17,000 microm2; n=11) when compared to DMSO administration (286,000+/-127,000 microm2; n=10; P<0.05). Basal interferon-gamma production by splenocytes from AG-556-treated mice was increased by approximately 20-fold in comparison with levels in DMSO-treated animals, whereas Con-A induced secretion of the cytokine was similar between both groups. Levels of TNF-alpha, IL-4 and IL-10 in the culture supernatant from treated and non-treated animals did not differ significantly. CONCLUSION: The tyrosine kinase inhibitor AG-556 may have a role in the reduction of intimal thickening. The effect could be mediated via an immune modulating effect involving a significant increase in the smooth muscle cell inhibitory cytokine IFN-gamma.     

Metabolic polymorphisms and the micronucleus frequency in buccal epithelium of adolescents living in an urban environment

Micronuclei and other biomarkers were evaluated in oral cells from 11- to 16-year-old girls living in a foster home in the central area of México City. Variables analyzed for possible association with these biomarkers include smoking habits, body mass index, metabolic polymorphisms for NAT1 and GSTM1 and whether the cells were obtained from the cheek or pharynx. The results indicated that individuals having the NAT1*10 homozygous genotype showed a significant increase in chromatin buds and binucleated cells. When the damage in the cheek was compared with damage in the pharynx, a significant increase in micronuclei and binucleated cells was found for the latter tissue in all the individuals analyzed.