Individuals with X-linked hyper-IgM syndrome fail to express functional CD40 ligand (CD40L) and, as a consequence, are incapable of mounting protective antibody responses to opportunistic bacterial ...infections. To address the role of CD40L in humoral immunity, we created, through homologous recombination, mice deficient in CD40L expression. These mice exhibited no gross developmental deficiencies or health abnormalities and contained normal percentages of B and T cell subpopulations. CD40L-deficient mice did display selective deficiencies in humoral immunity; basal serum isotype levels were significantly lower than observed in normal mice, and IgE was undetectable. Furthermore, the CD40L-deficient mice failed to mount secondary antigen-specific responses to immunization with a thymus-dependent antigen, trinitrophenol-conjugated keyhole limpet hemocyanin (TNP-KLH). By contrast, the CD40L-deficient mice produced antigen-specific antibody of all isotypes except IgE in response to the thymus-independent antigen, DNP-Ficoll. These results underscore the requirement of CD40L for T cell-dependent antibody responses. Moreover, Ig class switching to isotypes other than IgE can occur in vivo in the absence of CD40L, supporting the notion that alternative B cell signaling pathways regulate responses to thymus-independent antigens.
In this study, we investigated the significance of MYC, BCL2 and BCL6 gene abnormalities in a cohort of 205 diffuse large B-cell lymphoma (DLBCL) patients studied by conventional and/or fluorescence ...in situ hybridization cytogenetic analysis. Combining these methods, 172 cases (84%) were classified as MYC-, 17 (8%) were MYC+/BCL2-/BCL6-, and 16 (8%) were double/triple-hit lymphomas (i.e. MYC+/BCL2+, MYC+/BCL6+, or MYC+/BCL2+/BCL6+). We found a significant difference in event-free survival (EFS) among the three groups (p = 0.02), with the double/triple-hit group having the worst EFS. Patients who were MYC+, but BCL2- and BCL6-, had the best EFS. We conclude that patients with MYC+ DLBCL, but without BCL2 or BCL6 abnormalities, do not have a worse outcome when compared to those who are MYC-. However, patients with double/triple-hit DLBCL have a very poor outcome and should be treated with aggressive or novel therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
There have been concerns that low blood cholesterol concentrations may cause non-vascular mortality and morbidity. Randomisation of large numbers of people to receive a large, and prolonged, ...reduction in cholesterol concentrations provides an opportunity to address such concerns reliably.
20,536 UK adults (aged 40-80 years) with vascular disease or diabetes were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified safety analyses were of cause-specific mortality, and of total and site-specific cancer incidence. Comparisons between all simvastatin-allocated versus all placebo-allocated participants (ie, "intention-to-treat") involved an average difference in blood total cholesterol concentration of 1.2 mmol/L (46 mg/dL) during the scheduled 5-year treatment period.
There was a highly significant 17% (95% CI 9-25) proportional reduction in vascular deaths, along with a non-significant reduction in all non-vascular deaths, which translated into a significant reduction in all-cause mortality (p = 0.0003). The proportional reduction in the vascular mortality rate was about one-sixth in each subcategory of participant studied, including: men and women; under and over 70 years at entry; and total cholesterol below 5.0 mmol/L or LDL cholesterol below 3.0 mmol/L. No significant excess of non-vascular mortality was observed in any subcategory of participant (including the elderly and those with pretreatment total cholesterol below 5.0 mmol/L), and there was no significant excess in any particular cause of non-vascular mortality. Cancer incidence rates were similar in the two groups, both overall and in particular subcategories of participant, as well as at particular primary sites. There was no suggestion that any adverse trends in non-vascular mortality or morbidity were beginning to emerge with more prolonged treatment.
These findings, which are based on large numbers of deaths and non-fatal cancers, provide considerable reassurance that lowering total cholesterol concentrations by more than 1 mmol/L for an average of 5 years does not produce adverse effects on non-vascular mortality or cancer incidence. Moreover, among the many different types of high-risk individual studied, simvastatin 40 mg daily consistently produced substantial reductions in vascular (and, hence, all-cause) mortality, as well as in the rates of non-fatal heart attacks, strokes and revascularisation procedures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This paper evaluates the contribution of (i) uncertainty in substance properties, (ii) lack of spatial variability, (iii) intermodel differences and (iv) neglecting sorption to black carbon (BC) to ...the uncertainty of Benzo
apyrene (BaP) concentrations in European air, soil and fresh water predicted by the multi-media fate model Simplebox. Uncertainty in substance properties was quantified using probabilistic modeling. The influence of spatial variability was quantified by estimating variation in predicted concentrations with three spatially explicit fate models (Impact 2002, EVn BETR and BETR Global). Intermodel differences were quantified by comparing concentration estimates of Simplebox, Impact 2002, EVn BETR and the European part of BETR Global. Finally, predictions of a BC-inclusive version of Simplebox were compared with predictions of a BC-exclusive version. For air concentrations of BaP, the lack of spatial variability in emissions was most influential. For freshwater concentrations of BaP, intermodel differences and lack of spatial variability in dimensions of fresh water bodies were the dominant sources of uncertainty. For soil, all sources of uncertainty were of comparable magnitude. Our results indicate that uncertainty in Simplebox can be as large as three orders of magnitude for BaP concentrations in the environment and would be substantially underestimated by focusing on one source of uncertainty only.
AIM On the basis of finalised data from the Corneal Transplant Follow up Study to identify and quantify factors influencing corneal graft outcome in terms of graft survival, rejection, visual acuity, ...and astigmatism. METHODS Multifactorial analysis of 2777 grafts registered by the UK Transplant Support Service from July 1987 to June 1991. RESULTS Several recipient factors influencing graft survival, rejection, and visual acuity were identified, but no donor factors. Of the operative factors amenable to change, mixed suturing was associated with reduced graft survival, and larger grafts with increased risk of rejection but better visual acuity when surviving. There was increased risk of rejection with poor matching at HLA class I antigens, but mismatched HLA-DR grafts suffered less rejection than those with zero HLA-DR mismatches. Recipient age below 10 years was associated with increased risk of both rejection and graft failure. However, whereas increasing age above 10 years was not associated with differential graft survival, it was significantly associated with decreasing risk of rejection. CONCLUSIONS While confirming possible benefits of HLA-A and B matching, the expense and delay involved in awaiting matched HLA-DR tissue is unlikely to be justified. Other donor factors are unrelated to graft outcome following screening of tissue by eye banks. The highest rates of graft failure and rejection happen in the early postoperative period, and factors influencing visual outcome are also apparent at this stage.
In children lacking influenza-specific adaptive immunity, upper respiratory tract innate immune responses may influence viral replication and disease outcome. We use trivalent live attenuated ...influenza vaccine (LAIV) as a surrogate challenge model in children aged 24–59 months to identify pre-infection mucosal transcriptomic signatures associated with subsequent viral shedding. Upregulation of interferon signaling pathways prior to LAIV is significantly associated with lower strain-specific viral loads (VLs) at days 2 and 7. Several interferon-stimulated genes are differentially expressed in children with pre-LAIV asymptomatic respiratory viral infections and negatively correlated with LAIV VLs. Upregulation of genes enriched in macrophages, neutrophils, and eosinophils is associated with lower VLs and found more commonly in children with asymptomatic viral infections. Variability in pre-infection mucosal interferon gene expression in children may impact the course of subsequent influenza infections. This variability may be due to frequent respiratory viral infections, demonstrating the potential importance of mucosal virus-virus interactions in children.
Display omitted
•Upregulated mucosal interferon prior to vaccination leads to reduced LAIV shedding•Asymptomatic respiratory viral infections were seen in 42% of children•Other respiratory viral infections contribute to higher interferon gene expression
Costa-Martins et al. show that in children seronegative to influenza vaccine strains, upregulated nasopharyngeal interferon genes prior to LAIV receipt associates with reduced vaccine strain shedding. Asymptomatic respiratory viral infections are common and result in higher interferon gene expression, highlighting the importance of virus-virus interactions in the upper respiratory tract.
Why are there so few hot Jupiters? Rice, W. K. M.; Armitage, Philip J.; Hogg, D. F.
Monthly notices of the Royal Astronomical Society,
March 2008, Letnik:
384, Številka:
3
Journal Article
Recenzirano
Odprti dostop
We use numerical simulations to model the migration of massive planets at small radii and compare the results with the known properties of ‘hot Jupiters’ (extrasolar planets with semimajor axes a < ...0.1 au). For planet masses Mpl sin i > 0.5MJ, the evidence for any ‘pile-up’ at small radii is weak (statistically insignificant), and although the mass function of hot Jupiters is deficient in high-mass planets as compared to a reference sample located further out, the small sample size precludes definitive conclusions. We suggest that these properties are consistent with disc migration followed by entry into a magnetospheric cavity close to the star. Entry into the cavity results in a slowing of migration, accompanied by a growth in orbital eccentricity. For planet masses in excess of 1 Jupiter mass we find eccentricity growth time-scales of a few ×105yr, suggesting that these planets may often be rapidly destroyed. Eccentricity growth appears to be faster for more massive planets which may explain changes in the planetary mass function at small radii and may also predict a pile-up of lower mass planets, the sample of which is still incomplete.
Background: High-dose therapy followed by autologous stem-cell transplantation (autoSCT) induces complete remissions in the majority of patients with advanced B-cell chronic lymphocytic leukemia or ...small lymphocytic lymphoma (B-CLL). However, the long-term utility of this therapy for B-CLL is unknown. Patients and methods: Sixteen previously treated patients with B-CLL were transplanted using autologous blood (n = 13) or bone marrow (n = 3). The median age of the patients was 49 years (range 44–60 years), and the median number of prior chemotherapy regimens was two. Patients were eligible for transplantation if they had chemosensitive disease and no morphologic evidence of malignant cells in the graft. Preparative regimens included cyclophosphamide and total-body-irradiation, with or without cytarabine, or BEAC. Results: All patients engrafted and achieved a complete remission posttransplant. Ten patients were alive at a median of 41 months (range 22–125 months), and five were disease-free. Eight patients have relapsed and six have died (three from progressive malignancy). The projected three-year overall survival, failure-free survival and relapse rates were 68%, 37%, and 56%, respectively. Conclusions: AutoSCT for advanced B-CLL is associated with a high relapse rate. Whether this therapy can prolong life or produce cures is uncertain.
The placenta is an essential organ that provides nutrients and oxygen to the developing fetus and removes toxic waste products from the fetal circulation. Maintaining placental blood osmotic pressure ...and blood flow is crucial for viable offspring. The renin-angiotensin system (RAS) in the placenta is a key player in the regulation of maternal-fetal blood flow during pregnancy. Therefore, the aim of this study was to determine if RAS genes are differentially expressed in mid to late gestation in rat placenta.
Whole placental tissue samples from pregnant Sprague Dawley rats at embryonic (E) days 14.25, 15.25, 17.25 and 20 (n = 6 for each gestational age) were used for genome-wide gene expression by microarray. RAS genes with expression differences of >2 fold were further analyzed. Quantitative Real-Time PCR (qPCR) was performed on independent samples to confirm and validate microarray data. Immunohistochemisty and Western blotting were performed on a differentially expressed novel RAS pathway gene (ANPEP).
Six out of 17 genes of the RAS pathway were differentially expressed at different gestational ages. Gene expression of four genes (Angiotensin converting enzyme (Ace), angiotensin converting enzyme 2 (Ace2), membrane metalloendopeptidase (Mme) and angiotensin II receptor 1A (Agtr1a)) were significantly upregulated at E20 whereas two others (Thimet oligopeptidase 1 (Thop1) and Alanyl aminopeptidase (Anpep)) were downregulated at E20 prior to the onset of labour. These changes were confirmed by qPCR. Western blots revealed no overall differences in ANPEP protein expression in the placentae. Immunohistochemical studies, however, indicated that the localization of ANPEP differed at E17.25 and E20 as ANPEP localization in the giant trophoblast cell of the junctional zone was no longer detectable at E20.
The current study investigated the expression of members of the RAS pathway in rat placentae and observed significantly altered expression of 6 RAS genes at 4 gestational ages. These findings present the need for further comprehensive investigation of RAS genes in normal and complicated pregnancies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
