Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

Human mannose-binding protein (MBL) is a component of innate immunity. To capture the common genetic variants of MBL2, we resequenced a 10.0 kb region that includes MBL2 in 102 individuals representing four major US ethnic groups. In all, 87 polymorphic sites were observed, indicating a high level of heterozygosity (total pi=18.3 x 10(-4)). Estimates of linkage disequilibrium across MBL2 indicate that it is divided into two blocks, with a probable recombination hot spot in the 3' end. Three non-synonymous SNPs in exon 1 of the encoding MBL2 gene and three upstream SNPs form common 'secretor haplotypes' that can predict circulating levels. Common variants have been associated with increased susceptibility to infection and autoimmune diseases. The high frequencies of B, C and D alleles in certain populations suggest a possible selective advantage for heterozygosity. There is limited diversity of haplotype structure; the 'secretor haplotypes' lie on a restricted number of extended haplotypes, which could include additional linked SNPs, which might also have possible functional implications. There is evidence for gene conversion in the region between the two blocks, in the last exon. Our data should form the basis for conducting MBL2 candidate gene association studies using a locus-wide approach.     

Prevalence,Clinical Significance and Risk Factors for Developing Scar Pain and Sensibility Disorders in Breast Cancer Patients after Breast-Conserving Therapy and Mastectomy

IntroductionThe aim of this study was to gather information on the prevalence and risk factors for scar pain and sensibility disorders after breast cancer surgery, as only limited information of these complaints are available.Material and MethodsA clinical cohort study using a non-validated questionnaire was conducted among women who presented to routine follow-up at the Breast Cancer Center Rostock, Germany. The subjects were informed that the subjective perception and sensation were in the foreground and that the questionnaire had to be filled out independently according to the current feeling.ResultsOverall 175 patients could be evaluated. The prevalence of scar pain was 30.8% after breast conserving therapy (BCT) and 34.5% after mastectomy. Following BCT 87.5%, respectively 81.8% of women after mastectomy were very satisfied or satisfied with the scarring. Sensory disorders were increased in the mastectomy group (p = 0.001). Scar pain after previous surgery was a risk factor to develop sensory disorders after BCT (p = 0.008) and mastectomy (p = 0.029). For patients receiving mastectomy, sensory disorders after previous breast surgeries increased the risk for sensory disorders (p = 0.029). Smoking was a risk factor for sensory disorders after mastectomy (p = 0.048). Multivariate analysis could not confirm any of the risk factors.ConclusionThis study demonstrated a high satisfaction with scarring after breast surgery and a low level of scar pain. A lack of postoperative information, as well as a low level of actually performed scar care after surgery were observed. Increased focus should be on improved information on postoperative scare care.     

Estimated GFR associates with cardiovascular risk factors independently of measured GFR

Estimation of the GFR (eGFR) using creatinine- or cystatin C-based equations is imperfect, especially when the true GFR is normal or near-normal. Modest reductions in eGFR from the normal range variably predict cardiovascular morbidity. If eGFR associates not only with measured GFR (mGFR) but also with cardiovascular risk factors, the effects of these non-GFR-related factors might bias the association between eGFR and outcome. To investigate these potential non-GFR-related associations between eGFR and cardiovascular risk factors, we measured GFR by iohexol clearance in a sample from the general population (age 50 to 62 years) without known cardiovascular disease, diabetes, or kidney disease. Even after adjustment for mGFR, eGFR associated with traditional cardiovascular risk factors in multiple regression analyses. More risk factors influenced cystatin C-based eGFR than creatinine-based eGFR, adjusted for mGFR, and some of the risk factors exhibited nonlinear effects in generalized additive models (P<0.05). These results suggest that eGFR, calculated using standard creatinine- or cystatin C-based equations, partially depends on factors other than the true GFR. Thus, estimates of cardiovascular risk associated with small changes in eGFR must be interpreted with caution.     

Headache and neck or shoulder pain--family learnt illnesses behaviour? The Bardu Muscoloskeletal Study, 1989-1990

OBJECTIVE: To explore the gender difference in reporting headache and neckor shoulder pain, we analysed the association between reportedown headache and reporting the same complaints among first graderelatives. Based on these associations we discuss ‘learning’of illnesses within the family structures. METHOD: A cross-sectional study based on a self-administered postalquestionnaire of musculoskeletal complaints in the total populationaged 20–70 years was carried out. A population based studywas conducted in the municipality of Bardu, northern Norway.A total population of men and women aged 20–70, altogether2409 people, were sent a questionnaire. After one postal reminder1939 questionnaires were returned, a response rate of 80.5%.The return rate was slightly higher among the eldest. The sexdistribution was the same in both the responders and the non-responders. RESULTS: The females in the family and the brothers and sisters werethe main family members imprinting the way in which the childrenwere deciphering symptoms like headache and neck or shoulderpain later in life. These illnesses were changed to a very littleextent by the impact from the spouse. Keywords. Headache, neck or shoulder pain, muscoloskeletal disorders, illness behaviour.     

Toponostics of invasive ductal breast carcinoma: combination of spatial protein expression imaging and quantitative proteome signature analysis

Due to enormous advances in quantitative proteomics and in immunohistochemistry (pathology), the two research areas have now reached the state to be successfully interwoven in order to tackle challenges in toponostics and to open tumor-targeted systems pathology approaches. In this study the differential expressions of candidate proteins nucleophosmin, nucleoside diphosphate kinase A/B (NDKA/B), osteoinducive factor (mimecan), and pyru-vate kinase M2 from a quantitative proteome signature for invasive ductal breast cancer were determined by immunohistochemistry on 53 tissue slices from formalin-fixed and paraffin-embedded tumor and control tissue samples from ten patients and fourteen controls. In addition, 87 images from the Human Protein Atlas representing seven tumor and nine normal breast tissue samples were investigated by computer-assisted semi-quantitative density measurements on nucleophosmin, nucleoside diphosphate kinase A/B (NDKA/B), osteoinducive factor (mimecan), pyruvate kinase M2, glyceraldehyde-3-phosphate dehydro-genase (GAP-DH), and mimecan (osteoinductive factor). Both IHC data sets match well to each other and support the quantitative proteome analysis data. Determining spatial distribution of signature protein expressions by protein imaging on morphologically intact tissue samples at the sub-cellular level and, hence, keeping all topological information, presents an added value to quantitative proteome data. Such comprehensive data sets are needed for both, pathway analyses and for "next generation clinical diagnostics" approaches.     

Eosinophils are required for the maintenance of plasma cells in the bone marrow

Plasma cells are of crucial importance for long-term immune protection. It is thought that long-lived plasma cells survive in specialized niches in the bone marrow. Here we demonstrate that bone marrow eosinophils localized together with plasma cells and were the key providers of plasma cell survival factors. In vitro, eosinophils supported the survival of plasma cells by secreting the proliferation-inducing ligand APRIL and interleukin-6 (IL-6). In eosinophil-deficient mice, plasma cell numbers were much lower in the bone marrow both at steady state and after immunization. Reconstitution experiments showed that eosinophils were crucial for the retention of plasma cells in the bone marrow. Moreover, depletion of eosinophils induced apoptosis in long-lived bone marrow plasma cells. Our findings demonstrate that the long-term maintenance of plasma cells in the bone marrow requires eosinophils.     

Reprogrammed quiescent B cells provide an effective cellular therapy against chronic experimental autoimmune encephalomyelitis

Activated B cells can regulate immunity and have been envisaged as a potential cell-based therapy for treating autoimmune diseases. However, activated human B cells can also propagate immune responses, and the effects resulting from their infusion into patients cannot be predicted. This led us to consider resting B cells, which in contrast are poorly immunogenic, as an alternative cellular platform for the suppression of unwanted immunity. Here, we report that resting B cells can be directly engineered with lentiviral vectors to express antigens in a remarkably simple, rapid, and effective way. Notably, this neither required nor induced activation of the B cells. With this approach we were able to produce reprogrammed resting B cells that inhibited antigen-specific CD4(+) T cells, CD8(+) T cells, and B cells upon adoptive transfer in mice. Furthermore, resting B cells engineered to ectopically express myelin oligodendrocyte glycoprotein antigen protected recipient mice from severe disability and demyelination in EAE, and even induced complete remission from disease in mice lacking functional natural Tregs, which otherwise developed chronic paralysis. In conclusion, our study introduces reprogrammed quiescent B cells as a novel tool for suppressing undesirable immunity.     

Correction to: Reducing chemotherapy use in clinically high-risk,genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective,randomised phase 3 West German Study Group (WSG) PlanB trial

Breast Cancer Research and Treatment - The article Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the...     

The 70-Gene Signature as Prognostic Factor for Elderly Women with Hormone Receptor-Positive, HER2-Negative Breast Cancer

BACKGROUND: The aim of this article was to evaluate the prognostic value of the MammaPrint(TM) signature in women $$ 60 years with invasive breast cancer. PATIENTS AND METHODS: 60 female patients were included in this prospective study. Eligibility criteria included: pT1c-3, pN0-1a, grade 2/3, hormone receptor-positive and HER2-negative tumor. The clinical risk was determined by Adjuvant! Online (AOL). RESULTS: 38 patients (63%) where considered to be low-risk patients by the 70-gene signature, while 22 (37%) were considered to be high-risk patients. No statistically significant differences between low- and high-risk groups could be detected for conventional prognostic parameters, particularly not for Ki-67. By AOL, 33 patients (55%) were considered to be at high risk, of which 20 had a discordant MammaPrint(TM) result. The discordance rate between the profile and AOL was 48%, which is higher than in previous publications. When the 70-gene signature was used in combination with the clinical risk assessment, the recommendation for adjuvant systemic treatment differed in 11 patients (18%). CONCLUSIONS: In the intermediate-risk subgroup, the 70-gene signature could be useful to decide in elderly patients whether they may benefit from adjuvant chemotherapy or not. Conventional clinicopathological factors were not suitable for a prediction of the 70-gene signature results in these patients.