Function of C3 in a humoral response: iC3b/C3dg bound to an immune complex generated with natural antibody and a primary antigen promotes antigen uptake and the expression of co-stimulatory molecules by all B cells,but only stimulates immunoglobulin synthesis by antigen-specific B cells

Previous studies have shown that an optimal humoral response to a primary protein antigen requires C3 and CR2 (CD21). Sera from non-immunized donors contain natural IgM and IgG antibodies to the primary antigen keyhole limpet haemocyanin (KLH), and these have been previously shown to form immune complexes (IC) that activate the classical pathway of C, fixing iC3b/C3dg onto the KLH antigen. Such KLH IC bind to CR2 on KLH-non-specific B lymphocytes, resulting in antigen processing and MHC class II-dependent presentation to KLH-specific helper T cells. KLH IC also induce B lymphocytes to express the CD80 co-stimulatory molecule via simultaneous CR2 ligation with C3 and FcγRII (CD32) stimulation by IgG natural antibody. The current study demonstrated that KLH IC ligation to either CR2 or FcγRII resulted in activation of a second co-stimulatory molecule, LFA-1 (CD11a, CD18). The possibility of polyclonal B cell stimulation by the presentation of KLH-iC3b/C3dg by antigen-non-specific B cells was excluded by demonstration that in vitro cultivation of peripheral blood mononuclear cells (PBMC) with KLH-iC3b/C3dg elicited only anti-KLH, and did not stimulate synthesis of antibodies to hepatitis C virus (HCV) or tetanus toxoid (TT). Of greatest significance, a specific anti-KLH response was only detectable in cultures stimulated with KLH-iC3b/C3dg and not in cultures stimulated with KLH alone or KLH-IgG. Thus, iC3b/C3dg that was bound to a primary protein antigen enhanced recognition and specific immunoglobulin synthesis by antigen-specific B cells, even though the antigen was taken up and processed via CR2 by both antigen-specific and non-specific B cells.     

Regulation of CR3 (CD11b/CD18)-dependent natural killer (NK) cell cytotoxicity by tumour target cell MHC class I molecules

Phagocyte and NK cell CR3 functions as both an adhesion molecule and an iC3b receptor mediating cytotoxic responses to microorganisms. Cytotoxic activation of iC3b receptor function requires ligation of both a CD11b I-domain site for iC3b and a lectin site located in the C-terminus of CD11b. Because tumours lack the CR3-binding polysaccharides of bacteria and fungi, iC3b-opsonized tumours do not stimulate CR3-dependent cytotoxicity. Previous studies showed that NK cells could be induced to kill iC3b-opsonized tumours with small soluble β-glucans that bound with high affinity to CR3, bypassing the absence of similar polysaccharides on tumour membranes. Because CR3 signalling requires several tyrosine phosphorylation events, it appeared possible that CR3-dependent killing of autologous tumour cells might be suppressed by NK cell inhibitory receptors for MHC class I (KIR and CD94/NKG2) whose action involves recruitment of SHP-1 and SHP-2 tyrosine phosphatases. In the current study, Epstein–Barr virus (EBV)-transformed B cells were used as targets following opsonization with iC3b. Soluble β-glucan primed CR3 for killing of iC3b-coated B cells, but autologous class I-bearing targets were 84% more resistant than class I-deficient Daudi cells. Blockade of target cell class I with a MoAb specific for a domain recognized by both KIR and CD94/NKG2 resulted in comparable killing of class I⁺ B cells. By contrast, another MoAb to class II had no effect on cytotoxicity. These data suggest that NK cell recognition of class I suppresses CR3/tyrosine kinase-dependent cytotoxicity in the same way as it suppresses cytotoxicity mediated by other tyrosine kinase-linked receptors such as FcγRIIIA (CD16).     

Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

Epstein Barr virus latent membrane protein-1 in Hodgkin's lymphoma in Nigerians

Background

The burden of lymphomas on the health care system in Nigeria is enormous. Correct diagnosis and identification of aetiological factor are important steps in reducing this burden.

Methods

Eight cases diagnosed as HL within a period of six years at the Obafemi Awolowo University teaching Hospital, Ile-Ife, Nigeria by haematoxylin and eosin (Hand E) only were immunophenotyped using the indirect immunoperoxidase method. Epstein-Barr virus latent membrane protein-1 (LMP-1), CD15 and CD30 immunohistochemistry was also performed. The clinical characteristics of each patient were documented.

Objectives

To document the frequency of involvement of Epstein-Barr virus in cases of HL seen in a university hospital in Nigeria.

Results

Out of the eight cases diagnosed by H&E as HL immunophenotyping showed only five were HL. The rest were non-Hodgkin''s lymphoma (2 diffuse large B-cell and 1 null cell ALCL). All were cases of classical HL with 60% being of the mixed cellularity (MC) subtype. There were 2 males and 3 females with ages ranging from 7 years to 40 years. All presented with cervical lymphadenopathy and three had splenomegaly in addition. 60% of the tumour was EBV positive, all of the MC subtype. Three patients had chemotherapy. Eventually all were lost to follow-up. There was no case of the nodular lymphocyte predominance variant.

Conclusion

Mixed cellularity is the most common subtype and is the only subtype associated with EBV positivity in this study. Epstein-Barr virus probably plays an important role in the aetiology of HL in Nigerians.Running title: Epstein-Barr virus, Hodgkin''s lymphoma in Nigerians     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.     

Induction of B cell apoptosis by co-cross-linking CD23 and sIg involves aberrant regulation of c-myc and is inhibited by bcl-2

A novel system to study the effects of co-cross-linking CD23/FceRII and sIg on murine B lymphocytes utilizes a highly multivalent form of anti- Ig prepared by covalently linking anti-Ig antibodies to a DNP-dextran backbone. CD23-sIg co-cross-linking is accomplished by the addition of DNP-specific monoclonal IgE. Previous studies demonstrated that co- cross-linking CD23 and sIg significantly inhibited mouse B cell proliferation, especially at high doses of the multivalent anti-Ig. Interestingly, examination of early activation signals reveals no difference in B cells subjected to co-cross-linking conditions as compared to B cells activated with anti-Ig alone. Total cellular protein tyrosine phosphorylation levels are unchanged by co-cross- linking. Analysis of B cell mRNA reveals that co-cross-linking the receptors does not alter the expression levels of ornithine decarboxylase 8 h after stimulation as compared to the controls. In contrast, levels of the proto-oncogene c-myc were significantly elevated 1 h after inducing B cell activation under co-cross-linking conditions. However, it remains unclear whether this aberrant c-myc regulation plays any role in inducing apoptosis. In addition, on day 3 after stimulation, the co-cross-linking of CD23 and sIg resulted in the formation of apoptotic B cells, determined by both photomicroscopy of the B cell cultures and FACS analysis of B cell nuclei. B cells obtained from bcl-2 transgenic mice proliferated as well as controls, and failed to undergo apoptosis when CD23 and sIg were co-cross-linked on their surface. These studies indicate that co-cross-linking of CD23 with B cell sIg inhibits B cell proliferation by a mechanism that is distinct from that seen by co-cross-linking of the Fc gamma RII and sIg. In addition, these results suggest a means by which antigen- specific IgE can down-regulate additional B cell activation and IgE synthesis.      

An International Comparison of Web-based Reporting About Health Care Quality: Content Analysis

Background

On more and more websites, consumers are provided with public reports about health care. This move toward provision of more comparative information has resulted in different information types being published that often contain contradictory information.

Objective

The objective was to assess the current state of the art in the presentation of online comparative health care information and to compare how the integration of different information types is dealt with on websites. The content analysis was performed in order to provide website managers and Internet researchers with a resource of knowledge about presentation formats being applied internationally.

Methods

A Web search was used to identify websites that contained comparative health care information. The websites were systematically examined to assess how three different types of information (provider characteristics and services, performance indicators, and health care user experience) were presented to consumers. Furthermore, a short survey was disseminated to the reviewed websites to assess how the presentation formats were selected.

Results

We reviewed 42 websites from the following countries: Australia, Canada, Denmark, Germany, Ireland, the Netherlands, Norway, the United Kingdom, the United States, and Sweden. We found the most common ways to integrate different information types were the two extreme options: no integration at all (on 36% of the websites) and high levels of integration in single tables on 41% of the websites). Nearly 70% of the websites offered drill down paths to more detailed information. Diverse presentation approaches were used to display comparative health care information on the Internet. Numbers were used on the majority of websites (88%) to display comparative information.

Conclusions

Currently, approaches to the presentation of comparative health care information do not seem to be systematically selected. It seems important, however, that website managers become aware of the complexities inherent in comparative information when they release information on the Web. Important complexities to pay attention to are the use of numbers, the display of contradictory information, and the extent of variation among attributes and attribute levels. As for the integration of different information types, it remains unclear which presentation approaches are preferable. Our study provides a good starting point for Internet research to further address the question of how different types of information can be more effectively presented to consumers.     

医药类专业本科物理课程的设置及目标与定位探讨

目的：探讨物理课程在高等医药类专业教育中的作用与地位。方法：对全国部分城市不同类别医院从业医务工作者进行调查，综合国际医学教育标准和我国现实医学教育以及医疗服务行业状况进行分析。结果：探讨了我国高等医药类专业教育中物理课程的设置及目标与定位问题，给出了明确的课程定位与设置标准。结论：现代医学高等教育不应忽视或淡化物理课程在医学人才培养中素质教育和专业水平提高的积极作用与基础地位，在有限的学时空间内合理安排基础性内容和与专业素质培养相关的应用内容。     

Whites and African-Americans in headache specialty clinics respond equally well to treatment

This study sought to determine if Whites and African-Americans respond similarly to headache treatment administered in 'real-world' headache specialty treatment clinics. Using a naturalistic, longitudinal design, 284 patients receiving treatment for headache disorders completed 30-day daily diaries that assessed headache frequency and severity at pretreatment and 6-month follow-up and also provided data on their headache disability and quality of life at pretreatment and 1-, 2- and 6-month follow-up. Controlling for socioeconomic status and psychiatric comorbidity, hierarchical linear models found that African-Americans and Whites reported significant reductions in headache frequency and disability and improvements in life quality over the 6-month treatment period. African-Americans, unlike Whites, also reported significant decreases in headache severity. Nevertheless, Africans-Americans had significantly more frequent and disabling headaches and lower quality of life after treatment relative to Whites. Although Whites and African Americans responded favourably to headache treatments, more efficacious treatments are needed given the elevated level of headache frequency that remained in both racial groups following treatment.     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.