The Binding Site for TRAF2 and TRAF3 but Not for TRAF6 Is Essential for CD40-Mediated Immunoglobulin Class Switching

AbstractTo define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40ΔTRAF6), TRAF2 and TRAF3 (CD40ΔTRAF2/3), or both (CD40ΔTRAFs) into B cells of CD40−/− mice. The in vivo isotype switch defect in CD40−/− mice was fully corrected by WT and CD40ΔTRAF6, partially by CD40ΔTRAF2/3, and not at all by CD40ΔTRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, and NFκB in B cells were normal in WT and CD40ΔTRAF6 mice, severely impaired in CD40ΔTRAF2/3, and absent in CD40ΔTRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential for CD40 isotype switching and activation in B cells

Mobility assemblages and lines of flight in women’s narratives of forced displacement

In this paper I take the notion of the mobility assemblage as a theoretical lens through which I consider entanglements between refugee and migrant women on the move, intense experiences of gendered labour, and affective encounters in crossing borders and following lines of flight. The analysis revolves around the life-story of a young refugee woman, who recounts her experiences of travelling to Greece. What emerges from her narrative is a whirl of lines of flight that deterritorialize her from patriarchal regimes, harsh border practices, labour exploitation and the pain of separation on a plane of remaking her present and re-imagining her future

Physicians’ Perspectives on the Diagnosis and Treatment of Chronic Nonbacterial Osteomyelitis

Background/Purpose. Understanding the practices of pediatric rheumatologists in diagnosing and treating chronic nonbacterial osteomyelitis (CNO) can provide important information to guide the development of consensus treatment plans. The objectives of this study were to determine physicians’ approaches to (1) diagnosing and monitoring CNO, (2) ordering a bone biopsy, and (3) making treatment decisions. Methods. A survey was distributed among members of the Childhood Arthritis and Rheumatology Research Alliance using a web-based questionnaire. Results. 121 of 277 (41%) attending physician members completed the survey. Plain radiographs (89%) were most commonly used followed by regional MRI (78%), bone scintigraphy (43%), and whole-body MRI (36%). The top three reasons for performing a biopsy were constitutional findings (66%), unifocal bone lesions (64%), and nocturnal bone pain (45%). Nearly all responders (95%) prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) as initial therapy. For patients who failed NSAID treatment, methotrexate (67%), tumor necrosis factor inhibitors (65%), and bisphosphonates (46%) were the next most commonly used treatments. The presence of a spinal lesion increased the use of bisphosphonate treatment. Conclusion. The diagnostic approach and disease activity monitoring for CNO varied among surveyed physicians. Our survey findings provided important background for the development of consensus treatment plans for CNO

The Ability to Generate Senescent Progeny as a Mechanism Underlying Breast Cancer Cell Heterogeneity

Background Breast cancer is a remarkably heterogeneous disease. Luminal, basal-like, "normal-like", and ERBB2+ subgroups were identified and were shown to have different prognoses. The mechanisms underlying this heterogeneity are poorly understood. In our study, we explored the role of cellular differentiation and senescence as a potential cause of heterogeneity. Methodology/Principal Findings A panel of breast cancer cell lines, isogenic clones, and breast tumors were used. Based on their ability to generate senescent progeny under low-density clonogenic conditions, we classified breast cancer cell lines as senescent cell progenitor (SCP) and immortal cell progenitor (ICP) subtypes. All SCP cell lines expressed estrogen receptor (ER). Loss of ER expression combined with the accumulation of p21Cip1 correlated with senescence in these cell lines. p21Cip1 knockdown, estrogen-mediated ER activation or ectopic ER overexpression protected cells against senescence. In contrast, tamoxifen triggered a robust senescence response. As ER expression has been linked to luminal differentiation, we compared the differentiation status of SCP and ICP cell lines using stem/progenitor, luminal, and myoepithelial markers. The SCP cells produced CD24+ or ER+ luminal-like and ASMA+ myoepithelial-like progeny, in addition to CD44+ stem/progenitor-like cells. In contrast, ICP cell lines acted as differentiation-defective stem/progenitor cells. Some ICP cell lines generated only CD44+/CD24-/ER-/ASMA- progenitor/stem-like cells, and others also produced CD24+/ER- luminal-like, but not ASMA+ myoepithelial-like cells. Furthermore, gene expression profiles clustered SCP cell lines with luminal A and "normal-like" tumors, and ICP cell lines with luminal B and basal-like tumors. The ICP cells displayed higher tumorigenicity in immunodeficient mice. Conclusions/Significance Luminal A and "normal-like" breast cancer cell lines were able to generate luminal-like and myoepithelial-like progeny undergoing senescence arrest. In contrast, luminal B/basal-like cell lines acted as stem/progenitor cells with defective differentiation capacities. Our findings suggest that the malignancy of breast tumors is directly correlated with stem/progenitor phenotypes and poor differentiation potential. © 2010 Mumcuoglu et al

Henoch-Schönlein nephritis associated with streptococcal infection and persistent hypocomplementemia: a case report

<p>Abstract</p> <p>Introduction</p> <p>Henoch-Schönlein purpura is a systemic disease with frequent renal involvement, characterized by IgA mesangial deposits. Streptococcal infection can induce an abnormal IgA immune response like Henoch-Schönlein purpura, quite similar to typical acute post-infectious glomerulonephritis. Indeed, hypocomplementemia that is typical of acute glomerulonephritis has also been described in Henoch-Schönlein purpura.</p> <p>Case presentation</p> <p>We describe a 14-year-old Caucasian Spanish girl who developed urinary abnormalities and cutaneous purpura after streptococcal infection. Renal biopsy showed typical findings from Henoch-Schönlein purpura nephritis. In addition, she had low serum levels of complement (C4 fraction) that persisted during follow-up, in spite of her clinical evolution. She responded to treatment with enalapril and steroids.</p> <p>Conclusion</p> <p>The case described has, at least, three points of interest in Henoch-Schönlein purpura: 1) Initial presentation was preceded by streptococcal infection; 2) There was a persistence of low serum levels of complement; and 3) There was response to steroids and angiotensin-converting enzyme inhibitor in the presence of nephrotic syndrome. There are not many cases described in the literature with these characteristics. We conclude that Henoch-Schönlein purpura could appear after streptococcal infection in patients with abnormal complement levels, and that steroids and angiotensin-converting enzyme inhibitor could be successful treatment for the disease.</p

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

The HSP70 Molecular Chaperone Is Not Beneficial in a Mouse Model of α-synucleinopathy

BACKGROUND: Aggregation and misfolded alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Heat-shock proteins (HSPs) that are involved in refolding and degradation processes could lower the aggregate load of alpha-synuclein and thus be beneficial in alpha-synucleinopathies. METHODOLOGY/PRINCIPAL FINDINGS: We co-overexpressed human A53T point-mutated alpha-synuclein and human HSP70 in mice, both under the control of Thy1 regulatory sequences. Behavior read-outs showed no beneficial effect of HSP70 expression in mice. In contrast, motor coordination, grip strength and weight were even worse in the alpha-synucleinopathy model in the presence of HSP70 overexpression. Biochemical analyses revealed no differences in alpha-synuclein oligomers/aggregates, truncations and phosphorylation levels and alpha-synuclein localization was unchanged in immunostainings. CONCLUSION/SIGNIFICANCE: Overexpressing HSP70 in a mouse model of alpha-synucleinopathy did not lower the toxic load of alpha-synuclein species and had no beneficial effect on alpha-synuclein-related motor deficits

DNA deaminases: AIDing hormones in immunity and cancer

It is well established that hormones can cause cancer, much less known is how they induce this change in our somatic cells. This review highlights the recent finding that estrogen can exert its DNA-damaging potential by directly activating DNA deaminases. This recently discovered class of proteins deaminate cytosine to uracil in DNA, and are essential enzymes in the immune system. The enhanced production of a given DNA deaminase, induced by estrogen, can lead not only to a more active immune response, but also to an increase in mutations and oncogenic translocations. Identifying the direct molecular link between estrogen and a mutation event provides us with new targets for studying and possibly inhibiting the pathological side-effects of estrogen

Ripples in a pond: Do social work students need to learn about terrorism?

In the face of heightened awareness of terrorism, however it is defined, the challenges for social work are legion. Social work roles may include working with the military to ensure the well-being of service-men and women and their families when bereaved or injured, as well as being prepared to support the public within the emergency context of an overt act of terrorism. This paper reviews some of the literature concerning how social work responds to confl ict and terrorism before reporting a smallscale qualitative study examining the views of social work students, on a qualifying programme in the UK, of terrorism and the need for knowledge and understanding as part of their education

The incidence of smoking and risk factors for smoking initiation in medical faculty students: cohort study

BACKGROUND: Medical education requires detailed investigation because it is a period during which the attitudes and behaviors of physicians develop. The purpose of this study was to calculate the yearly smoking prevalence and incidence rates of medical faculty students and to identify the risk factors for adopting smoking behaviour. METHODS: This is a cohort study in which every student was asked about their smoking habits at the time of first registration to the medical faculty, and was monitored every year. Smoking prevalence, yearly incidence of initiation of smoking and average years of smoking were calculated in analysis. RESULTS: At the time of registration, 21.8% of the students smoked. At the end of six years, males had smoked for an average of 2.6 ± 3.0 years and females for 1.0 ± 1.8 years (p < 0.05). Of the 93 medical students who were not smokers at the time of registration, 30 (32.3%) were smokers at the end of the 6 years of the course. CONCLUSION: The first 3 years of medical education are the most risky period for initiation of smoking. We found that factors such as being male, having a smoking friend in the same environment and having a high trait anxiety score were related to the initiation of smoking. Targeted smoking training should be mandatory for students in the Medical Faculty