Immune recognition of a molecule naturally presented as a monomeric or an oligomeric structure: the model of the human chorionic gonadotropin alpha subunit.

The immune recognition of a molecule naturally presented as a monomeric or an oligomeric structure is analyzed using the human chorionic gonadotropin alpha subunit (hCG-alpha) as a model. Indeed, hCG-alpha circulates as either a free subunit or combined to the beta subunit (hCG-beta) to form the dimeric hCG hormone. A T cell study was performed in BALB/c (H-2d) mice which were found to be high responders to hCG-alpha. Mice were immunized with the free hCG-alpha or the dimeric hCG alpha/beta, and their lymph node cells were challenged in vitro with either alpha subunits from different species, hCG or peptides spanning the entire primary structure of hCG-alpha. Proliferation and IL-2 assays demonstrated that hCG-alpha-primed lymph node cells responded equally well to hCG-alpha and hCG alpha/beta, suggesting that both the free and combined hCG-alpha subunits are processed in a similar way. Among the various synthetic peptides used, only those mimicking the hCG-alpha(59-92) C-terminus portion were able to stimulate hCG-alpha-primed lymph node cells, demonstrating that this region contains immunodominant T cell recognition site(s). The hCG-alpha(23-43) and (32-59) peptides, although incapable of stimulating T cells primed with hCG-alpha, elicited a T cell response when used as immunogens. These regions encompassed cryptic epitopes which were not generated during hCG-alpha processing in H-2d mice. The T cell epitopes of hCG-alpha above described as immunodominant or cryptic on the free alpha subunit, had similar characteristics when the alpha/beta dimer was used as the immunogen. In contrast, T cells primed with peptides mimicking immunodominant sites recognized differently the hCG-alpha and the hCG alpha/beta antigens. Moreover, the analysis of the B cell response to all the immunogenic hCG-alpha peptides indicated that they bear B and T cell epitopes as well. Antibodies elicited against the hCG-alpha(59-92) or (32-59) peptide were capable of recognizing the alpha subunit in its free form but not in the alpha/beta hCG dimer. Such study deserves attention for the comprehensive mechanisms of the immune response to hCG as well as for the design of anti-hCG vaccines.     

A monoclonal antibody against a synthetic peptide is specific for the free native human chorionic gonadotropin beta-subunit

A totally synthetic molecule (109-145 peptide) analogous to the beta-subunit carboxyl terminus was used as an antigen in the development of antibodies by the hybridoma technique. A monoclonal antibody (702 D7) specifically recognized the free native beta-human CG (beta hCG). 702 D7 was of the immunoglobulin G1 subclass and was directed against an antigenic site localized in a 10-amino acid sequence (109-118) or less. The recognition of an epitope located in the 109-118 region could explain the specific recognition of beta hCG observed with 702 D7, in contrast to monoclonal antibodies directed against a 118-145 region with a recognition of both beta hCG and whole hCG, as observed with a second monoclonal antibody (1032) to synthetic peptide. Immunohistochemical results and preliminary data obtained from the immunoradiometric assay show that 702 D7 provides a clinical tool for the detection of free beta-subunit secretion even at low concentrations, and could allow the study of this subunit or its metabolites produced by normal and tumoral cells.     

Effects of chronic noradrenaline on the nitric oxide pathway in human endothelial cells

Altered endothelium-dependent vasodilation has been observed in congestive heart failure (CHF), a disease characterized by a sustained adrenergic activation. The purpose of our study was to test the hypothesis that chronically elevated catecholamines influence the nitric oxide (NO) pathway in the human endothelium. Human umbilical vein endothelial cells (HUVEC) were exposed for 7 days to a concentration of noradrenaline (NA, 1 ng/mL) similar to that found in the blood of patients with CHF. Kinetics of endothelial constitutive NO synthase (ecNOS) and inducible NO synthase (iNOS) activity, measured by [³H]L-arginine to [³H]L-citrulline conversion, and protein expression of ecNOS and iNOS, assessed by Western blot analysis, were unaffected by chronic NA treatment. Furthermore, no changes in subcellular fraction-associated ecNOS were found; this indirectly shows that chronic NA did not cause phosphorylation of the enzyme. Moreover, [³H]L-arginine transport through the plasma membrane was conserved in chronically NA-treated cells. The data demonstrate that prolonged in vitro exposure to pathologic CHF-like NA does not affect the L-arginine NO pathway in human endothelial cells. Received: 11 July 1997, Returned for revision: 13 August 1997, Revision received: 6 October 1997, Returned for 2. revision: 17 November 1997, 2. Revision received: 5 January 1998, Accepted: 26 January 1998     

Skin complications of Bacillus Calmette-Guérin immunization

PURPOSE OF REVIEW: Bacillus Calmette-Guerin (BCG) vaccination has been performed since 1921, and remains the best method of preventing severe infections caused by Mycobacterium tuberculosis. Tuberculosis, in its various forms, remains a public health problem, and more than 100 countries continue BCG vaccination in an effort to control the disease. Since the initiation of BCG vaccination, numerous complications have been reported. In this review we will focus on the cutaneous complications of BCG vaccination. RECENT FINDINGS: Recent case reports detail the development of large keloids, and also of juvenile sarcoidosis after BCG vaccination. Adverse outcomes from inadvertent intradermal injection of the forearm and from revaccination with BCG have also been reported. Other recently described skin complications subsequent to BCG vaccination include lupus vulgaris, delayed granuloma formation, cutaneous BCG infection in immune disorders, anterior chest wall mass, acute erythroderma with multiple skin abscesses, ulceration at the BCG site during Kawasaki disease, fixed drug eruption, and cutaneous abscesses following mesotherapy. SUMMARY: BCG vaccination will continue to be a key method of preventing severe tuberculosis infections for the foreseeable future. The World Health Organization currently recommends BCG vaccination for all infants living in tuberculosis endemic areas. As such, it is important for health care providers to recognize the routinely anticipated cutaneous findings of the vaccination, in addition to complications relating to the injection. Subsequent care of these skin complications is of paramount importance to the health of these patients.     

Evaluating the efficiency of participatory epidemiology to estimate the incidence and impacts of foot-and-mouth disease among livestock owners in Cambodia

The economic and social impacts of foot-and-mouth disease (FMD) for livestock owners of developed countries have been extensively documented over the past few years. In developing countries such as Cambodia, this evaluation is often lacking due to the scarcity of accurate data. In the present study, we used a range of participatory tools to infer farmers' knowledge and perception, and the relative incidence of FMD from January 2009 to June 2010 in fifty-one villages of Svay Rieng province, Cambodia. In addition, the detection of non-structural protein at village level was used to cross-validate the results from the participatory epidemiology (PE) study. A quantitative assessment using Bayesian modeling was carried out to assess the ability of PE to retrospectively determine the FMD-infected status of a village in Cambodia. Our study shows that even if FMD is ranked second in the list of priority diseases, livestock owners did not see any benefit in reporting it since the disease entailed low direct losses. The average clinical incidence rates at individual level for cattle-buffaloes and pigs in infected villages were assessed by proportional piling at 18% and 11%, respectively for the year 2009. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PE study were estimated at 87%, 30%, 51% and 74%, respectively. This approach seems to largely overestimate the presence of the disease but proves useful in evaluating the impact of FMD at household level and in understanding the reasons for not reporting it. This information may be important in establishing well-adapted disease prevention and control strategies in Cambodia.     

Evaluating Twitter as a complementary data source for pharmacovigilance

Background: Social media are currently considered as a potential complementary source of knowledge for drug safety surveillance. Our primary objective was to estimate the frequency of adverse drug reactions (ADRs) experienced by Twitter users. Our secondary objective was to determine whether tweets constitute a valuable and informative source of data for pharmacovigilance purposes, despite limitations on character number per tweet.

Research design and methods: We selected a list of 33 drugs subject to careful monitoring due to safety concern in France and Europe, and extracted tweets using the streaming API from 30 September 2014 to 5 April 2015. Two pharmacovigilance centers classified these tweets manually as potential ADR case reports.

Results: Among 10,534 tweets, 848 (8.05%) implied or mentioned an ADR without meeting the four FDA criteria required for reporting an ADR, and 289 (2.74%) tweets were classified as ‘case reports.’ Among them 20 (7.27%) tweets mentioned an unexpected ADR and 33 (11.42%) tweets mentioned a serious ADR.

Conclusions: With the use of dedicated tools, Twitter could become a complementary source of information for pharmacovigilance, despite a major limitation regarding causality assessment of ADRs in individual tweets, which may improve with the new limitation to 280 characters per tweet.     

Implication of breast cancer phenotype for patients with leptomeningeal carcinomatosis

BackgroundWe aimed to study the implications of breast cancer (BC) subtypes for the development and prognosis of leptomeningeal carcinomatosis (LC).Patients and methodsData from the breast cancer patients diagnosed with LC between 2005 and 2010 were retrieved. Patients were classified in luminal A, B, HER2 positive and triple negative (TN) and their BC diagnosis, treatment, and outcome were analyzed according to each subtype. Pearson's chi-square and Fisher's exact test were used for categorical variables. Survival analyses were performed by Kaplan–Meier method and compared with the log-rank test.ResultsA total of 38 BC patients were identified, with a median age of 54.8 years (range 36–79). The proportion of luminal A, B, HER2 positive and TN was 18.4%, 31.6%, 26.3% and 23.7%, respectively. LC was the first evidence of metastatic disease in 5 BC patients. Twenty patients received the systemic chemotherapy, with 16 (80%) whole brain radiotherapy (WBRT). Nine patients received only WBRT. TN patients had the shorter interval between metastatic breast cancer diagnosis and the development of LC. Median survival after the diagnosis of LC (OSLC) was 2.6 months (range 1.2–6.4), and did not differ across breast cancer subtypes. In univariate analysis, performance status (ECOG = 0–2) and chemotherapy were prognostic for OSLC, but only the treatment stood as an independent prognostic factor in multivariate analysis.ConclusionsBreast cancer subtype influences the timing of LC appearance, but not OSLC. Patients with LC from breast cancer should be offered systemic treatment, as it appears to associate with the improved outcome. New therapeutic strategy, including, targeted and intrathecal therapy are deserved for BC patients with LC.