BCG Inoculation Research Articles

Blood routine risk factors for coronary artery aneurysm in infants younger than 8\u2009months with Kawasaki disease

ObjectiveThe aims of this study were to characterize the evolution of routine blood values within the first 10 days of illness and coronary artery outcome in infants < 8 months with Kawasaki disease (KD) and to identify risk factors for coronary artery aneurysm (CAA).MethodsLaboratory data, clinical features and coronary artery outcomes from 78 infants < 8 months old and 86 patients between 8 months and 7 years old were retrospectively analyzed. Logistic regression analysis was conducted to evaluate the potential risk factors for CAA.ResultsInfants < 8 months old were more likely to present with incomplete KD (37.2% vs 4.7%, P < 0.001), erythema and induration at the BCG inoculation site (24.4% vs 3.5%, P < 0.001) and CAA (47.4% vs 15.1%, P < 0.001) even with timely diagnosis and treatment with intravenous immunoglobulin (IVIG) compared with patients ≥8 months old. Clinical feature related to diagnostic criteria for KD including bilateral conjunctival injection, oral changes, unilateral cervical lymphadenopathy and extremity changes were less common in the younger group. During the acute phase, the percentage neutrophils and neutrophil to lymphocyte ratio [NLR] peaked on median illness day 3, followed by white blood cell (WBC) and CRP on median illness day 4, hemoglobin on median illness day 7 and platelet count on median illness day 9. CAA occurred on median illness day 6 and regressed on median illness day 28. Multivariate logistic regression analysis revealed that the peak percentage neutrophils (odds ratio [OR] per 0.1: 1.597, 95% confidence interval [CI]: 1.041–2.452, P = 0.032) and the peak platelet count (OR per 10 × 109/L: 1.029, 95% CI: 1.004–1.055, P = 0.024) were independent risk factors for CAA. Hemoglobin on the 5th day was associated with persistent CAA at 1 year after KD onset.ConclusionFactors associated with CAA include a high peak percentage neutrophils, increased peak platelet count, and reduced hemoglobin within 4–6 days during the acute phase of KD. Therefore, this population should receive primary therapy with IVIG and adjunctive anti-inflammatory medications.

Effects of thymulin 5cH in granuloma evolution and B1 cell differentiation: an experimental model to understand its biological mechanisms

In previous studies, we found that thymulin (a thymic hormone), when prepared in homeopathic 5cH potency, had the property to improve the productive performance of broiler chickens infected with reovirus, as well as modulate the development of Ehrlich tumor and granuloma inflammatory lesions in mice by immune-mediated mechanisms. The aim of the present work was to study the immunomodulatory mechanisms of thymulin 5cH in a granuloma experimental model, by subcutaneous inoculation of BCG in mice, focusing the B-1 cells and zinc involvement in this process. Three groups of male Balb/c SPF mice (group A treated with thymulin 5cH, group B treated with thymulin 5cH incubated in Chelex ® - a zinc chelant - and group C, control, treated with vehicle) were inoculated with BCG in the left footpad and subcutaneous granuloma and spleen were harvested for histomorphometry analysis, after 7, 14 and 21 days. Ziehl-Neelsen, HE and Prussia Blue staining methods were used. Flow cytometry was also used in the same times to characterize and quantify peritoneal cells. Positive cells for CD11b (activated phagocytes, B-1 cells), CD19 (B-1 and B-2 cells), CD23 (negative B-1 cells, positive B2 cells) and CD5 (B-1a cells) were analyzed in a FACS Calibur (BD) device. Statistical analysis was performed using Kruskal - Wallis / Dunn for nonparametric evaluations and ANOVA / Tuckey-Krammer for the parametric ones. The X² method was used to evaluate the cell count in flow cytometry. P values ≤ 0.05 were considered statistically significant. Mice treated with thymulin 5cH presented higher macrophage activity and increase in the follicular area were seen in spleen after 7 days. Increase in gross lesion diameter and decrease in local BCG infection were seen after 21 days. At this time, the flow cytometry demonstrated the increase in peritoneal phagocytes derived from B-1 cells in thymulin 5cH treated mice, independently of Chelex ® incubation. The incubation of thymulin 5cH with Chelex ® blocked its effects only upon the number of B2 cells in the peritoneum and reduces Mn levels in the medicine solution. We conclude that thymulin 5CH modulates the BCG-induced granuloma through more than one mechanism, especially by peritoneal B1 cell differentiation into phagocytes.

The Effect of Fluoxetine and Ibuprofen on BCG-Induced Alteration in Pain Sensitivity in Mice

Abstract Clinical observations recognized the co-existence and interactions of pain and depression a long time, ago. The aim of this work was to study the effect of ibuprofen and fluoxetine on BCGinduced depressive-like behaviour, on formalin-induced pain, as well as on mechanical allodynia after planter incision in mice. BCG induced a depressive behaviour that was seen in the forced swim test (FST) and the tail suspension test (TST). It also induced a decrease in pain-related behaviour in the formalin test, and an increase in the baseline in mechanical allodynia test compared to the control group. Fluoxetine (80 mg/L of drinking water) showed a significant decrease in the immobility time in the FST and TST and enhanced pain related behaviour in formalin test in the BCG-inoculated group. However, it did not affect the increase in the pain threshold in the planter incision allodynia model. Adding ibuprofen to drinking water (0.2 g/L of drinking water), reversed the depressive like behaviour induced by BCG and enhanced pain-related behaviour in formalin test, in both the total pain-related behaviour and phase 2. It also prevented the increase in the base line induced by BCG. On the other hand, the incisional pain model was not affected by BCG inoculation except at the 2-hour time point, where it showed hypoalgesia, as well.

Mycobacterium bovis BCG-mediated suppression of Th17 response in mouse experimental autoimmune encephalomyelitis

Introduction Multiple sclerosis (MS) is an autoimmune disease mediated by a pro-inflammatory immune response. Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with a myelin oligodendrocyte glycoprotein (MOG) peptide emulsified in killed Mycobacterium tuberculosis-containing complete Freund’s adjuvant (CFA-EAE) is used as a model of MS. Mycobacterium bovis BCG has been reported to ameliorate clinical symptoms of CFA-EAE, although the precise mechanism has not yet been documented. Since CFA-EAE uses adjuvant with mycobacterial antigens, mycobacterial antigen-specific T cells induced by CFA may cross-react with BCG and modulate EAE. Methods To exclude the influence of cross-reactivity, a modified murine EAE model (cell wall skeleton (CWS)-EAE) that does not induce mycobacterial antigen-specific T cells was established and used to reevaluate the therapeutic effects of BCG on EAE. Results Inoculation with BCG 6 d after CWS-EAE induction successfully ameliorated EAE symptoms, suggesting that the therapeutic effects of BCG are independent of the mycobacterial antigen-specific T cells induced by the CFA-EAE protocol. BCG inoculation into the CWS-EAE mice resulted in reduced levels of MOG-specific Th17 in the central nervous system (CNS) with reduced demyelinated lesions of the spinal cord. In the draining lymph nodes of the MOG-immunized sites, BCG inoculation resulted in an increase in MOG-specific Th17 and Th1 cells at an early stage of immune response. Conclusion The results suggest that BCG inoculation suppresses the Th17 response in the CNS of EAE mice via a mechanism that may involve the suppression of egress of encephalitogenic T cells from lymphoid organs.

Measles infection causing Bacillus Calmette-Gu\xe9rin reactivation: a case report

BackgroundReactivation of the Bacillus Calmette-Guérin (BCG), manifesting as erythema, induration, ulceration or crust formation at a previous BCG inoculation site, is a common and highly specific feature of Kawasaki disease (KD). We report the unusual finding of BCG reactivation in an infant with laboratory-confirmed measles.Case presentationA previously healthy 7-month old infant presented initially with fever, cough and coryza, and subsequently developed Koplik’s spots followed by a typical morbilliform skin rash. There was significant contact history with a household relative who had recently been diagnosed with measles. On examination, a 2.5 cm area of erythema and induration was seen at the previous BCG inoculation site, in addition to the widespread maculopapular rash. No other clinical features of KD were present. Measles virus was isolated from the throat swab and measles antibodies (IgM) were present in the serum. The patient recovered completely with oral vitamin A and supportive therapy, and had normal echocardiography examination on follow up.ConclusionsThis case report highlights the rare finding of BCG reactivation in a child with confirmed measles infection, and suggests that this clinical manifestation may occasionally occur in children with infections or conditions other than KD.

Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED50 of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.

Modest Expansion of Vß2+CD4+ T Cells and No Expansion of Vß7+CD4+ T Cells in a Subgroup of Kawasaki Disease Patients with Erythematic BCG Inoculation Site Lesions

Background: The similarities between Kawasaki disease (KD) and superantigen (SA) diseases indicate that a microbial SA might cause KD. Viral diseases can trigger an endogenous SA. Methods: We evaluated expression of Vs2 (responding to staphylococcal TSST-1) and Vs7 (responding to the endogenous SA induced by type-1 interferon or Epstein-Barr virus infection) on T cells from 70 KD patients along with the following control subjects: 18 non-vasculitic patients (NVs), 7 patients with anaphylactoid purpura (AP), and two with neonatal TSS-like exanthematous disease (NTED), a typical SA disease. We examined the correlation of clinical features of KD with Vs2 + or Vs7 + CD4 + T cell populations. Results: The Vs2 + CD4 + T cell rates were comparable between KD patients (9.9±2.9%) and NVs (9.0±1.8%), but were lower in AP patients (6.6±1.8%). However, the Vs2 + CD4 + T cell rate was significantly higher in KD patients with erythematic BCG inocula tion site lesions (10.8±3.2%) than in those without (8.8±2.1%) and NVs (9.0±1.8%), but much lower than in NTED patients (25.2%, 16.9%). Multivariate linear regression analysis with elevation of Vs2 expression as a dependent variable revealed significant correlations with BCG. In contrast, Vs7 + CD4 + T cell rates were not significantly different between KD patients and other study sub jects. Conclusion: While we were unable to find evidence supporting the involvement of the endogenous SA in the pathogenesis of KD in this study, modest expansion of the Vs2 + CD4 + T cell population in a subgroup of KD with erythematic BCG inoculation site lesions implies the involvement of a microbial agent(s) different from TSST-1 as well as immunopathological heterogeneity of KD. (249 words) ACTA MEDICA NAGASAKIENSIA 60: 13−19, 2015

Tuberculose latente em profissionais de saúde: concordância entre 2 testes diagnósticos

The diagnosis of latent tuberculosis infection (LTBI), namely in healthcare workers, has been done by tuberculin skin test (TST). Recently, Interferon‐ʎ Release Assays (IGRA tests) have been introduced. Unlike TST, they do not turn positive after BCG vaccine or after most of non‐tuberculous mycobacteria infections.In the absence of a gold standard for the diagnosis of LTB, the aim of this study was to analyze the correlation between the two LTB diagnostic techniques, by determining Kappa coefficient and concordance rate between TST and IGRA test, in healthcare workers of a Portuguese university hospital.We carried out a cross‐sectional and retrospective study, and we analysed TST and IGRA tests records, that are performed simultaneously (up to 15 days apart) in Occupational Health Department, in 2010 and 2011 (n137).Most of the sample did BCG and 44.5% did two or more inoculations. The average diameter of PT was 17.5mm (SD 4.3). Only two subjects reported TST<10mm, both showing a negative IGRA test. Only 53 (39.3%) of the 135 participants with positive PT had a positive IGRA test too.The level of agreement between TST and the IGRA test was determined by Kappa coefficient. Respectively to a cut off for PT of 10mm, 15mm and 20mm, the degree of agreement was 0.019 (p=0.26), 0,19 (p=0.001) and 0.26 (p=0.003). Concordance rates were respectively 40%, 54% and 65%.It was found that the concordance between the two methods increased as the cut off for TST also increased. Nevertheless, a higher concordance rate would be expected with cut off of 15mm, and particularly of 20mm, since BCG vaccine administered in childhood usually induce smaller reactions. The existence of more than one BCG inoculation in the sample, especially after childhood, can be partly responsible for the low concordance between the two methods. Nevertheless, we cannot also exclude IGRA test's false negatives.In the decision to treat LTB, it is necessary to take into account the limitations of both tests, their level of agreement and weighting individual, occupational and epidemiological factors.

Abstract O.35: BCGits as a Clinical Diagnosis Marker in Mexican Children with Kawasaki Disease

Background: Kawasaki disease (KD) is an acute febrile illness characterized by systemic vasculitis of unknown etiology. A BCG reactivation (BCGitis) is not included in the classical clinical criteria for KD. BCGitis recently has been recognized as a clinical marker of incomplete KS in younger children in countries where BCG vaccination is mandatory. Objectives: To assess the frequency of BCGitis in the clinical profile of patients diagnosed with KD in a Mexican third level Children’s Hospital and its association with the presence of coronary artery abnormalities. (CAA) Material and Methods: An observational, comparative, retrospective and case control study of all patients diagnosed with KD at our Institution between August 1995 and May 2014 was performed. The clinical presentation, laboratory results, treatment used and coronary artery abnormalities in the BCG-reactive [BCG(+)] and BCG-nonreactive [BCG(-)] groups were analyzed and compared. Results: We included 356 patients with KD diagnosed at our institution; 83 had BCGitis. (23.3%) The BCG(+) group was younger than the BCG(-) group, 21.2 ± 22.51 vs 44.33 ± 38.85 months (p &lt; 0.00001) There were 17 (20.48%) incomplete cases in the BCG(+) group compared with 52 (19.11%) in the BCG(-) group without statistical significance. The BCG(+) group had a slightly shorter fever duration before IVGG treatment than the BCG(-) group. Laboratory results showed lower hemoglobin counts, higher white blood cell counts, platelet counts, CRP counts, and ALT counts in the BCG(+) group. The BCG+ group developed CAA in 29 cases and the BCG- group developed CAA in 110 cases without statistical significance. Multivariate analysis showed that younger age at diagnosis (&lt; 24 months) was the only factor significantly associated with a reaction at the BCG inoculation site in KD patients Conclusions: In Mexico, as a country with a National BCG Vaccination Program and a low incidence of KD, a reaction at the BCG inoculation site could be a useful and early diagnostic sign of KD among younger patients, especially those younger than 24 months of age.

Disseminated BCG Infection (BCGosis) After BCG Vaccination

BCG vaccine has excellent safety profile. Disseminated BCG infection, so called BCGosis and death have occurred in few cases, mainly in those with impaired immunity. We are reporting a seven month old infant who developed BCGosis after BCG vaccination. She presented with weight loss, fever, axillary lymphadenopathy and hepato-splenomegaly. She did not respond to standard antitubercular treatment. In the context of increasing number of reported cases of BCGois in HIV era, inoculation of BCG might be postponed in a suspected case of immune-deficiency disease, until it is ruled out. DOI: http://dx.doi.org/10.3126/jnps.v34i1.9679 J Nepal Paediatr Soc 2014;34(1):62-64

Identification of Serum microRNA Biomarkers for Tuberculosis Using RNA-seq

Tuberculosis (TB) remains a significant human health issue. More effective biomarkers for use in tuberculosis prevention, diagnosis, and treatment, including markers that can discriminate between healthy individuals and those with latent infection, are urgently needed. To identify a set of such markers, we used Solexa sequencing to examine microRNA expression in the serum of patients with active disease, healthy individuals with latent TB, and those with or without prior BCG inoculation. We identified 24 microRNAs that are up-regulated (2.85–1285.93 fold) and 6 microRNAs that are down-regulated (0.003–0.11 fold) (P<0.05) in patients with active TB relative to the three groups of healthy controls. In addition, 75 microRNAs were up-regulated (2.05–2454.58 fold) and 11 were down-regulated (0.001–0.42 fold) (P<0.05) in latent-TB infected individuals relative to BCG- inoculated individuals. Of interest, 134 microRNAs were differentially-expressed in BCG-inoculated relative to un-inoculated individuals (18 up-regulated 2.9–499.29 fold, 116 down-regulated 0.0002–0.5 fold), providing insights into the effects of BCG inoculation at the microRNA level. Target prediction of differentially-expressed microRNAs by microRNA-Gene Network analysis and analysis of pathways affected suggest that regulation of the host immune system by microRNAs is likely to be one of the main factors in the pathogenesis of tuberculosis. qRT-PCR validation indicated that hsa-miR-196b and hsa-miR-376c have potential as markers for active TB disease. The microRNA differential-expression profiles generated in this study provide a good foundation for the development of markers for TB diagnosis, and for investigations on the role of microRNAs in BCG-inoculated and latent-infected individuals.

Tuberculin Positivity in Kawasaki Disease: An Unusual Occurrence

To the Editor:A 3-y-old girl presented with high grade fever, irritability, red eyes, lips and tongue and a pruritic rash. She had conjunctival injection, red, cracked lips, ‘strawberry tongue’, edematous hands and feet, and an erythematous, popular rash on the trunk, face and extremities, sparing the palms and soles with classical periungual desquamation. Mobile, non-tender, cervical lymph nodes were palpable. There was erythema and induration at the site where tuberculin had been administered 4 wk ago (Fig. 1). The BCG scar site was normal. Rest of the examination was unremarkable. She had anemia, leukocytosis, thrombocytosis and high erythrocyte sedimentation rate (57 mm) and C reactive protein (92.95 mg/L). Urine showed 7–8 leucocytes per high power field; culture was sterile. Echocardiogram did not reveal any coronary artery abnormalities. Due to the presence of typical features, a diagnosis of Kawasaki disease (KD) was made. Intravenous immunoglobulin was given followed by aspirin. Tomisaku Kawasaki, first reported reactivation of the BCG vaccination site in children with KD. Erythema at the BCG site is reported in upto 50 % of children with KD [1]. However, it has been an uncommon finding in reports from India. The first child with KD and erythema at both BCG and tuberculin administration sites was reported by Kadowaki et al. [2]. Beretto et al. reported tuberculin skin test to be a highly sensitive and specific diagnostic test for KD [3]. They observed that children with acute KD had swelling at the site of previous BCG vaccination or an erythematous reaction at BCG inoculation sites if given during acute KD. They compared tuberculin skin tests in typical KD patients and patients with other febrile illnesses and found that all KD patients had a positive tuberculin skin test. However, a similar study by Kollmann et al. did not support these findings [4]. Skin lesions at the site of BCG or tuberculin administration have been ascribed to molecular mimicry between a mycobacterial heat shock protein (HSP-65) and human homologue HSP 63. Mice inoculated with BCG followed by a crude extract ofMycobacterium intracellulare (cMI) developed coronary arteritis, whereas control animals inoculated with only cMI or BCG did not, suggesting that the immune response to the mycobacteria probably induced autoimmune damage to the vascular wall [5]. In countries with universal BCG vaccination, skin changes at the site of BCG or tuberculin inoculation can be a valuable aid in diagnosis of KD.

Erythema at BCG Inoculation Site in Kawasaki Disease Patients.

Introduction:Kawasaki disease is an acute, self-limiting childhood systemic vasculitis with unknown etiology. Because there is no diagnostic test for Kawasaki disease, the diagnosis is based on clinical criteria. An important clinical sign that is not included in the classical clinical criteria for Kawasaki disease is a reaction at the Bacille Calmette-Guérin inoculation site that are present in about 30-50% of Kawasaki disease patients.The aim:of this review was to highlight the usefulness of the inflammation at the Bacille Calmette-Guérin inoculation site for early diagnosis of Kawasaki disease, we conducted a literature review on Medline in PubMed area, Google scholar, Magiran and Scientific Information Database using the search terms “Kawasaki disease, Erythema, BCG, inoculation site, children, cardiac complications, coronary artery lesion, aneurysm, incomplete Kawasaki in 2013.Results and discussion:A total of 15 articles had been found. Erythema at the Bacille Calmette-Guérin inoculation site was found in 49.87% of Kawasaki disease patients. Coronary artery abnormalities were found in 10.3% of cases. According to this review, BCGitis is more prevalent than cervical lymphadenopathy and rash and it can be a useful criterion in the diagnosis of incomplete Kawasaki disease in cases not fulfills the classic criteria of at least four of the five findings.

A mathematical model to predict the risk of hepatitis B infection through needle/syringe sharing in mass vaccination

BackgroundThe Japanese Government settled a class litigation case with hepatitis B virus (HBV) carriers who claim to have been infected through needle/syringe sharing in childhood mass vaccination with a blanket compensation agreement. However, it is difficult to estimate how many of the present HBV carriers were infected horizontally from mass vaccination and how many were infected vertically from mothers.MethodsA mathematical model to predict the risk of infection through needle/syringe sharing in mass vaccination was proposed and a formula was developed. The formula was presented in a logarithmic graph enabling users to estimate how many people will be infected if a needle/syringe is shared by how many people for how many times under certain probability of infection. The formula was then applied to the historical data of mass tuberculin skin tests (TSTs) and BCG inoculation, from which a best estimate of how much needle/syringe sharing was practiced in different birth cohorts was determined.ResultsFor the oldest cohort born between 1951 and 1955, the prevalence of HBV carriers—0.65% at birth through vertical transmission—more than doubled in 1995 (1.46%) through horizontal transmission. If the probability of infection through needle/syringe sharing is assumed to be 10%, it is theoretically likely that an average of five or more people shared a needle/syringe four times to achieve the prevalence of HBV carriers in 1995. However, for the youngest cohort born between 1981 and 1985, the effects of needle/syringe sharing were negligible because the later prevalence of HBV carriers was lower than the prevalence at birth.ConclusionsMore than half of the HBV carriers born in the early 1950s might have contracted the disease by mass vaccinations. Japan’s experience needs to be shared with other countries as a caution in conducting mass vaccination programs under scarce needle/syringe supply (291 words).

Modulatory effects of acupuncture on murine depression-like behavior following chronic systemic inflammation

Depression associated with inflammatory immune responses may be an important medical problem from the perspective of quality of life in old age because chronic inflammation is recognized to have a close connection with the aging process. Activated proinflammatory cytokines induce depression-like behavior by stimulating the expression of indoleamine-2,3-dioxygenase, an enzyme catalyzing the conversion of tryptophan to kynurenine, and by reducing brain synaptic activities of serotonin and dopamine. Experimental inoculation of Bacillus Calmette-Guérin vaccine (BCG) in the mouse gradually and continuously elicits chronic inflammation-associated depression-like behavior. Despite extensive use of acupuncture therapy for treating various psychosomatic disorders in the Oriental medicine, an experimental study showing antidepressant-like activity of acupuncture stimulation has not been performed in the inflammation-associated depression-like animal behavior yet. In the present study, the antidepressant-like activity of acupuncture and its mechanism of action were investigated in BCG-inoculated mice. We confirmed that acupuncture stimulation significantly reduced depression-like behavior and that it lowered the kynurenine/tryptophan ratio and raised the serum kynurenic acid/3-hydroxykynurenine ratio. Acupuncture also relieved the hippocampal dopamine level that was lowered by BCG inoculation. Taken together, these findings may indicate that acupuncture has antidepressant-like effects on murine chronic inflammation-associated depression-like behavior due to its modulatory effects on tryptophan–kynurenine metabolism and dopamine metabolism in the brain.

Four-Month-Old Boy With Fever, Hepatosplenomegaly and Diffuse Pulmonary Infiltrations

: The (bacille Calmette-Gue´rin) BCG is widely practiced in many countries in pediatric group and is a part of routine vaccination program at birth in IR. IRAN for prophylaxis against tuberculosis, but its efficacy is a matter of debate in different geographic and ethnic regions. Adverse reactions induced by BCG vaccination ranges from BCG adenitis, osteitis, and cold abscess at vaccination site to rare occurrence of disseminated infection (BCG-osis). This Lethal disseminated disease specifically affects children with an immune deficiency and generally develops a few months after vaccination. We report one cases of disseminated BCG infection occurred in a 4 months old boy , with severe combined immunodeficiency and BCG-osis, which resulted from a consanguineous marriage with a history of two sibling death from severe infection . Inoculation of BCG as a live vaccine should be postponed for a few months in suspected neonates of primary immunodeficiency disease, until appropriate screening tests exclude this diagnosis.

Migratory sub-populations of afferent lymphatic dendritic cells differ in their interactions with Mycobacterium bovis Bacille Calmette Guerin

Understanding how pathogens or vaccine antigens are targeted to dendritic cell (DC) subsets is important for disease pathogenesis studies and vaccine design. We characterised the sub-populations of migrating bovine DC with functional and phenotypic diversity present in pseudoafferent lymph draining the skin. These skin draining DC exist as a series of maturation dependent subsets with differential capacities for antigen uptake and cytokine expression, and include both Langerhans' cells (LC) and dermal derived cells. Furthermore, Mycobacterium bovis Bacille Calmette Guerin, a vaccine which is administered by the intradermal route, was only taken up by a small number of the migrating DC, which were SIRPα(+) and expressed the mannose receptor and CD1b. This was evident following in vitro infection and also in vivo following inoculation of green fluorescent BCG over the lymphatic cannulation site. Only the SIRPα(+) DC were able to present antigen to T cells isolated from BCG vaccinated calves. Furthermore, presentation of BCG antigens by DC to T lymphocytes was ineffective compared to mycobacterial proteins. However, mycobacterial antigen 85 was delivered more effectively to DC via an adenoviral vector and the magnitude of the subsequent antigen-specific T cell response was significantly increased. This study further extends our understanding of the biology of migrating DC, identifies potential explanations for the modest success of BCG vaccination and demonstrates that targeted delivery of antigens via adenoviruses to DC can improve antigen presentation.

Incidence of various clinico-morphological variants of cutaneous tuberculosis and HIV concurrence: a study from the Indian subcontinent.

BACKGROUND AND OBJECTIVES:There are few reports of cutaneous tuberculosis with immunosuppressed states such as HIV, use of immunosuppressants or malignancy. Diagnosis is thus difficult and despite scientific advances such as polymerase chain reaction, it is frequently missed. Although rare, given its worldwide prevalence and the rising incidence of HIV, it is important for clinicians to recognize the variants and promptly treat the patient.DESIGN AND SETTING:Retrospective study of all cases of cutaneous tuberculosis diagnosed from October 2007 to November 2009 at an outpatient clinic of a tertiary-care hospital in northern India.METHODS:We collected information on the clinical form of disease, histopathology and HIV concurrence rates and looked for differences in presentation between mmunocompetent and immunocompromised states. We also looked for differences and HIV concurrence between immunocompetent and immunocomprised patients. Diagnosis was based on clinical, histopathological and microbiological tests for tuberculosis and a test for HIV.RESULTS:The overall incidence of cutaneous tuberculosis was 0.7% (131 of 18720 outpatients). HIV concurrence was 9.1% (12 cases) of all cutaneous tuberculosis cases. Most common variants seen were scrofuloderma (36.5%), lupus vulgaris (31%), tuberculosis verruca cutis (12.9%), lichen scrofulosorum (11.4%), papulonecrotic tuberculids (3.8%), erythema nodosum (2.2%) and erythema induratum of Bazin (1.5%).CONCLUSIONS:Cutaneous tuberculosis rates were slightly higher in our study than in other studies from India. HIV co-infection rates were similar to those in other studies. Many atypical morphological forms and presentations were observed in HIV co-infected patients. Due to the varied clinical presentations, physician awareness and a high index of suspicion are necessary to diagnose cutaneous forms of tuberculosis.

IL-15 protects antigen-specific CD8+ T cell contraction after Mycobacterium bovis bacillus Calmette-Guérin infection

We reported previously that IL-15 plays a critical role in protecting effector CD8(+) T cells from apoptosis during the contraction phase following acute infection with Listeria monocytogenes by inducing antiapoptotic molecules. In the present study, we examined the effects of in vivo administration of rIL-15 on contraction of CD8(+) T cells after chronic infection with Mycobacterium bovis BCG and on the efficacy of BCG vaccination against Mycobacterium tuberculosis infection. Antigen-specific CD8(+) T cells reached an expansion peak at approximately Day 21, followed by a contraction after inoculation with rBCG expressing OVA. In vivo administration of rIL-15 from Days 22 to 42 after BCG inoculation inhibited apoptosis of effector CD8(+) T cells by up-regulating their Bcl-2 expression, resulting in a significant increase of antigen-specific memory CD8(+) T cells producing IFN-gamma. However, the IL-15 treatment did not elicit improved efficacy of BCG vaccination against M. tuberculosis. These results suggest that IL-15 plays a critical role in protecting activated CD8(+) T cells from apoptosis during the contraction phase following BCG inoculation, although IL-15 administration alone at the contraction phase might not be sufficient to protect the efficient memory T cell responses against subsequent infection with M. tuberculosis.

Histopathological, immunohistochemical and ultraestructural evaluation of inflammatory response in Arius genus fish under experimental inoculation of BCG

The aim of this study was to evaluate the inflammatory response kinetics after experimental inoculation with BCG in the primitive Arius sp. fish. The BCG was applied through the intramuscular injection in the caudal peduncular region, and the samples were collected for the analyses at days 1, 3, 7, 14, 21, and 33 post-injection. Acute phase inflammatory infiltrate was characterized by the predominant mononuclear cells, intersticial edema, and muscular tissue necrosis. As the inflammatory response evolved, a large number of multinuclear giant cells were formed containing the BCG. These giant cells were positive for the S100 protein at the histochemical analysis, which demonstrate the macrofage activity, confirmed by the ultra-structural analysis showing the lack of the cytoplasmic membrane enveloping the many nuclei within the giant cell. These results led to the conclusion that Arius sp. fish injected with the BCG showed a difuse inflammatory response characterized by a large number of mononuclear cells, absence of granuloma formation, and predominant giant cells.