Advances in Bacillus Calmette-Guerin / 中国生物制品学杂志

@#Tuberculosis(TB) is a chronic and debilitating infectious disease caused by Mycobacterium tuberculosis(Mtb). It is a significant health concern that poses a serious threat to human well-being. Bacillus Calmette-Guerin(BCG)is the only approved vaccine for the prevention of TB. BCG is made from attenuated bovine Mtb and is highly effective in preventing tuberculous meningitis and granulomatous TB,which are particularly lethal in infants. However,BCG provides limited protection in both children and adults,and this protective effect decreases over time. Currently,there are ongoing improvements being made to BCG,which involve modifications in immunization routes and procedures. Additionally,researchers are working on the development of new TB vaccines. BCG is primarily used for the prevention of TB and the treatment of bladder cancer,although it also has other indications. This paper reviewed the recent research progress of BCG,focusing on its development history,improvements,and indications.

Infección diseminada por el bacilo vacunal Calmette-Guerin

RESUMEN Introducción: La infección diseminada por el bacilo vacunal Calmette-Guerin es una rara reacción adversa severa asociada a inmunodeficiencia. Objetivo: Describir una serie de cinco casos con infección vacunal diseminada. Presentación de casos: Se presentan cinco casos vacunados al nacer, predominio masculino 4 (80 %), promedio edad inicio: 8,4 meses 2 (15 %) y de edad al diagnóstico: 17,8 meses 6 (31 %). Cuadro clínico de huella vacunal ulcerada, linfadenitis axilar ipsilateral y en regiones distales, hepatosplenomegalia y afectación de otros órganos, con manifestaciones sistémicas y nutricionales. Existió consanguinidad en tres e historia familiar sospechosa de inmunodeficiencia en otros tres. Todos fallecieron: tres enfermos antes de los 3 años. Se realizaron estudios inmunológicos convencionales a todos los enfermos. Un paciente presentaba Inmunodeficiencia severa combinada, en los otros se sospechó enfermedad granulomatosa crónica en uno y síndrome de susceptibilidad mendeliana a micobacterias en tres. Conclusiones: Aunque la vacuna BCG raramente presenta diseminación del bacilo vacunal, debe sospecharse esta entidad en niños pequeños, con las características severas y sistémicas que se describen, con manifestaciones sugestivas de tuberculosis que no responden al tratamiento antituberculoso de primera línea.

ABSTRACT Introduction: The infection disseminated by the vaccine bacillus Calmette-Guerin is a rare severe adverse reaction associated with immunodeficiency. Objective: Describe a series of five cases with disseminated vaccine infection. Presentation of cases : There are five cases vaccinated at birth: predominance of the male sex in 4 (80%), average age onset: 8.4 months in 2 (15 %) and age at diagnosis: 17.8 months in 6 (31 %); clinical picture of ulcerated vaccine footprint, ipsilateral axillary lymphadenitis and in distal regions, hepatosplenomegaly, involvement of other organs, with systemic and nutritional manifestations. There was consanguinity in three of the patients and suspicious family history of immunodeficiency in three others. All died: three were sick before the age of 3. Conventional immunological studies were performed in all cases. One patient had severe combined immunodeficiency, chronic granulomatous disease was suspected in one, and Mendelian susceptibility syndrome to mycobacteria in three. Conclusions: Although the BCG vaccine rarely presents dissemination of the vaccine bacillus, this entity should be suspected in young children, with the severe and systemic characteristics described, with manifestations suggestive to tuberculosis that do not respond to first-line anti-tuberculous treatment.

Analysis of lymphocyte subsets and clinical characteristics in children with abnormal reaction to Bacillus Calmette-Guérin vaccination / 国际儿科学杂志

Objective:To investigate the lymphocyte subsets and clinical characteristics of children with abnormal reaction to Bacillus Calmette-Guérin(BCG)vaccination.Methods:A total of 35 children with BCG disease diagnosed in the Children′s Hospital Affiliated to Xi′an Jiaotong University from January 2013 to December 2019 were enrolled retrospectively.Patients with strong local reaction and lymphadenitis after vaccine injection were selected as the localized group, and with lymphadenitis complicated with distant organ involvement were classified as the disseminated group.The differences in clinical infection indicators, demographic data, lymphocyte subsets and prognosis between the two groups were compared.Results:There are 25 cases in the localized group and 10 cases in the disseminated group, male 20 cases and female 15 cases.Compared with the localized group, the incidence of cough, fever and growth retardation all increased in the disseminated group, with statistical significance(all P<0.05). Lymphocyte ratio[(61.14±18.61)% vs.(39.64±31.45)%], T lymphocytes [CD3 + (×10 6/L): (1 821±487)vs.(1 065±539)], helper/inducible T lymphocytes[CD3 + CD4 + (×10 6/L): (1 058±357)vs.(445±140)], double positive T lymphocytes[CD3 + CD4 + CD8 + (×10 6/L): (24.07±7.17)vs.(14.10±8.89)], CD4 + /CD8 + ratio[CD4 + /CD8 + (%): (1.65±0.73)vs.(1.00±0.25)], natural killer cells[CD16 + CD56 + (×10 6/L): (19.70±2.34)vs.(12.76±7.01)]were lower in the disseminated group than those in the localized group and the differences were significant(all P<0.05). In the disseminated group, 6 cases were diagnosed with immunodeficiency disease and 7 cases died during the follow-up period.All the children in the localized group were cured. Conclusion:Most BCG reaction have a good prognosis, while disseminated children combined with primary immune deficiency have worst prognosis.Early lymphocyte subsets analysis is effective for BCG disease screening.

Research progress of Bacillus Calmette-Guerin in the treatment of bladder cancer after renal transplantation / 中国综合临床

Kidney transplantation can improve the quality of life of end-stage renal disease patients and is the most effective treatment.But renal transplantation is also a high risk factor for bladder cancer.Bladder cancer is a common malignant tumor in department of urology.Bacillus Calmette-Guerin intravesical instillation is a first-line therapy for high-risk non muscle invasive bladder cancer, which can directly kill bladder cancer cells.We reviewed the mechanism and clinical application of BCG in the treatment of bladder cancer after renal transplantation, in order to provide references for better utilization of Bacillus Calmette-Guerin in adjuvant treatment of bladder cancer after renal transplantation.

Diagnostic value of the reaction at the bacillus calmette-guérin vaccination site in kawasaki disease / Utilidade diagnóstica da reação do sítio de vacinação bacillus calmette-guérin na doença de kawasaki

ABSTRACT Objective: To describe the case of an infant - diagnosed with incomplete Kawasaki disease - who developed BCG scar reactivation. Case description: A 6-month-old patient was admitted to hospital with fever associated with ocular hyperemia, cervical lymphadenopathy, and hyperemic lips, and remained hospitalized for 12 days. The physical examination revealed an inflammatory reaction at the site of the BCG scar, leading to the diagnosis of incomplete Kawasaki disease. The patient was treated with venous immunoglobulin, but presented recurrence of Kawasaki disease, with subsequent onset of coronary artery disease. Comments: BCG scar reactivation is an important finding in countries where the vaccine is routinely given and may be a useful marker for early diagnosis of Kawasaki disease, especially in its incomplete form.

RESUMO Objetivo: Descrever o caso de um lactente - com diagnóstico de Doença de Kawasaki incompleta - que desenvolveu reativação da cicatriz da vacina BCG. Descrição do caso: Um paciente de 6 meses de idade foi admitido no hospital com febre, associada à hiperemia ocular, linfadenomegalia cervical e fissuras labiais, permanecendo hospitalizado por 12 dias. Apresentava, no exame físico, reação inflamatória no local da cicatriz da vacina BCG, tendo sido feito o diagnóstico de Kawasaki incompleto. O paciente foi tratado com imunoglobulina venosa, mas apresentou recorrência da doença, com posterior surgimento de coronariopatia. Comentários: A reativação da BCG é um achado importante na doença de Kawasaki em países onde a vacina é aplicada de forma rotineira e pode ser um marcador útil para o diagnóstico precoce da doença de Kawasaki, principalmente em sua forma incompleta.

Tuberculosis extra-pulmonar en niños bajo 15 años de edad internados en el Centro Hospitalario Pereira Rossell, Uruguay / Extrapulmonary tuberculosis in children under the age of 15 hospitalized at the Pereira Rossell Hospital Center, Uruguay

Resumen Introducción: La tuberculosis es un problema de salud pública de alta prevalencia. Los niños constituyen una población de riesgo de enfermar y evolucionar a formas graves. Objetivo: Describir la frecuencia, características epidemiológicas, clínicas y evolutivas de los pacientes bajo 15 años de edad, internados por tuberculosis extra-pulmonar (TBCEP) en el Centro Hospitalario Pereira Rossell-Uruguay, durante 2009 a 2019. Pacientes y Métodos: Estudio descriptivo, retrospectivo, revisión de historias clínicas y registros de la Comisión Honoraria para la Lucha Antituberculosa. Variables: edad, sexo, nexo epidemiológico, clínica, confirmación diagnóstica, tratamiento y complicaciones. Resultados: Se registraron 77 casos de TBCEP, fueron hospitalizados en este centro 45 (58%). Media de edad 7 años, varones 25 (56%). Todos recibieron vacuna BCG. Se identificó nexo epidemiológico en 28 (62%). Las formas de TBCEP fueron: pleural 26 (58%), sistema nervioso central (SNC) 9 (20%), linfoganglionar 4 (9%), cutánea 2 (5%), ósea 1 (2%), peritoneal 1 (2%), pleural-peritoneal 1 (2%), ósea-SNC 1 (2%). Confirmación etiológica hubo en 23 (51%): mediante cultivo 16, GeneXpert 5, por ambos 2. Completaron tratamiento 36 (80%). Presentaron complicaciones 4 (9%): status convulsivo 2, hemorragia cerebral 1, fallo orgánico múltiple 1. Conclusiones: La TBCEP ocurrió en niños previamente sanos. El diagnóstico requiere alto índice de sospecha y la confirmación el empleo simultáneo de varias técnicas diagnósticas.

Abstract Background: Tuberculosis is a public health problem. Children constitute a population at risk of becoming ill and evolving into serious forms. Aim: To describe the frequency, epidemiological, clinical and evolutionary characteristics of children under 15 years of age hospitalized for extrapulmonary tuberculosis (EPTB) at the Pereira Rossell Hospital-Uruguay, during 2009-2019. Methods: Descriptive, retrospective study, review of medical records and records of the Honorary Commission for the Fight Against Tuberculosis. Variables: age, sex, epidemiological and clinical link, diagnostic confirmation, treatment and complications. Results: 77 cases of EPTB were registered, 45 (58%) were hospitalized in this center. Average age 7 years, males 25 (56%). All received the Bacillus Calmette-Guérin vaccine. An epidemiological link was identified in 28 (62%). The forms of EPTB were: pleural 26 (58%), central nervous system (CNS) 9 (20%), lymphoganglionic 4 (9%), cutaneous 2 (5%), bone 1 (2%), peritoneal 1 (2%), pleural- peritoneal 1 (2%), bone-CNS 1 (2%). Etiology was confirmed in 23 (51%): by culture 16, GeneXpert 5, by both 2. Thirty-six (80%) patients completed treatment. Four (9%) presented complications: convulsive state 2, cerebral hemorrhage 1, multiple organ failure 1. Conclusions: EPTB occurred in previously healthy children. The diagnosis requires a high index of suspicion and the confirmation of the simultaneous use of several diagnostic techniques.

SARS-CoV-2: previous coronaviruses, immune response, and development of vaccines / SARS-CoV-2: coronavirus previos, respuesta inmune y desarrollo de vacunas

Abstract Since the emergence of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China at the end of 2019, when its characteristics were practically unknown, one aspect was evident: its high contagion rate. This high infection rate resulted in the spread of the virus in China, Europe, and, eventually, the rest of the world, including Mexico. At present, around 9 million people are infected, and around 470,000 have died worldwide. In this context, the need to generate protective immunity, and especially the generation of a vaccine that can protect the world population against infection in the shortest possible time, is a challenge that is being addressed in different countries using different strategies in multiple clinical trials. This opinion article will present the evidence of the induction of immune response in some of the viruses of the coronavirus family before COVID-19, such as SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus). The information collected about the induction of an immune response by SARS-CoV-2 will be presented, as well as a description of the vaccine candidates reported to date in the various ongoing clinical trials. Finally, an opinion based on the evidence presented will be issued on the potential success of developing vaccine prototypes.

Resumen Desde el surgimiento del nuevo coronavirus SARS-CoV-2 (coronavirus tipo 2 del síndrome respiratorio agudo severo) en China a finales del año 2019, cuando todavía era desconocido prácticamente en todos los aspectos, una característica era evidente: el alto índice de contagio entre la población. Esto resultó en la expansión del virus en China, Europa y, finalmente, en el resto del mundo, incluyendo México. Actualmente, alrededor de 9 millones de personas están infectadas, y han muerto cerca de 500,000 en todo el mundo. En este contexto, la necesidad de generar inmunidad protectora y, sobre todo, el desarrollo de una vacuna que pueda proteger a la población mundial contra la infección en el menor tiempo posible, es un reto que se está abordando en distintos países utilizando diversas estrategias en múltiples ensayos clínicos. En este artículo de opinión se presentan las evidencias de la inducción de respuesta inmunitaria con algunos de los virus de la familia de coronavirus previos al SARS-CoV-2, como el SARS-CoV (coronavirus del síndrome respiratorio agudo severo) y el MERS-CoV (síndrome respiratorio por coronavirus de Oriente Medio). Además, se presenta lo reportado hasta el momento acerca de la inducción de respuesta inmunitaria por el SARS-CoV-2, así como una descripción de los candidatos a vacunas informados hasta el momento en los distintos ensayos clínicos en curso. Finalmente se emite una opinión, basada en las evidencias presentadas, acerca del éxito potencial de los prototipos de vacunas en desarrollo.

Assessment of vaccine wastage in an immunization clinic of a tertiary care hospital, Kolkata, West Bengal

Background: Universal Immunization Programme was launched by Government of India in 1985 with the aim of immunizing all children and pregnant women across the country free of cost. However high vaccine wastage and lack of proper vaccine management could not meet the demand and increased the cost.Methods: A descriptive record based study was conducted in the immunization clinic of KPC Medical College and Hospital. Vaccination records of all children and pregnant women attending clinic from 1st July 2018 to 30th June 2019 was retrieved from the immunization registers.Results: Wastage rate was found to be highest for bacillus Calmette–Guérin vaccine vaccine (68.9%) and lowest for oral polio vaccine (27.7%). Wastage rate was higher for 10 dose vial vaccine compared to 5 dose vial and 20 dose vial vaccine and the differences were statistically significant (p<0.00001).The wastage rate was higher for lyophilized vaccine compared to liquid vaccine and for injectable vaccine compared to oral vaccine. These differences were also statistically significant (p<0.00001).Conclusions: Thus regular monitoring of immunization sessions should be done to estimate the vaccine wastage in each session. Reducing wastage is expected to increase the quality and efficiency of the programme and also reduce the cost without compromising the coverage.

Enfermedad por bacilo de Calmette-Guérin a distancia en un lactante: Presentación de un caso / Distant bacillus Calmette-Guérin disease in an infant: Case report

La vacuna con el bacilo de Calmette-Guérin es una vacuna atenuada utilizada para prevenir formas graves de tuberculosis. Se aplica a los recién nacidos en países con alta prevalencia de tuberculosis. Pueden presentarse, después de su aplicación, complicaciones a nivel local, como supuración o adenopatías regionales. La enfermedad por diseminación del bacilo es infrecuente y ocurre, por lo general, en pacientes con alteraciones inmunitarias subyacentes. Se presenta el caso de un niño de 5 meses que ingresó por un cuadro de 2 meses de evolución con detención del aumento de peso y nódulos subcutáneos. Se sospechó enfermedad por diseminación del bacilo y se diagnosticó por la biopsia de las lesiones. Se realizó el tratamiento con tres drogas antituberculosas, y se recuperó clínicamente. Si bien se realizaron estudios inmunológicos, no logró demostrarse ninguna inmunodeficiencia como afección predisponente.

The bacillus Calmette-Guérin vaccine is an attenuated vaccine historically used to prevent severe forms of tuberculosis. It is applied to all newborns in countries with high prevalence of tuberculosis. Local complications, such as suppuration or regional adenopathies, may occur after application. Disease due to the spread of the bacillus is infrequent, usually occurring in a patient with an underlying immune alteration. We present the case of a 5-month-old child who was admitted due to a 2-month evolution with weight loss and subcutaneous nodules. Disease was suspected to be due to bacillus Calmette-Guérin dissemination, being diagnosed by biopsy of the lesions. Treatment was carried out with three antituberculous drugs, evolving towards clinical recovery. Although immunological studies were carried out, no immunodeficiency could be demonstrated as a predisposing condition.

Cross-reactive immune responses to Mycobacterium vaccae, Mycobacterium tuberculosis and Bacillus Calmette-Guerin / 中华微生物学和免疫学杂志

Objective To investigate the cross-reactive immune responses to Mycobacterium vac-cae (M. vaccae), Mycobacterium tuberculosis (M. tuberculosis, H37Rv) and Mycobacterium bovis Bacillus Calmette-Guerin ( BCG) for providing reference for the development of new vaccines with M. vaccae. Meth-ods M. vaccae (ATCC95051), M. tuberculosis (H37Rv) and BCG (China strain) were cultured on L-J solid media and harvested. Total bacterial protein antigens prepared by ultrasonic disruption were used to im-munize BALB/c mice. IgG antibodies in serum samples were detected with enzyme-linked immunosorbent assay ( ELISA) to evaluate humoral immune responses. Cellular immunity was assessed by detecting various cytokines with cytokine release assay ( CRA) . Results The mice that were respectively immunized with the three mycobacterial antigens could produce high titers of antibodies ( IgG) and high levels of IFN-γand IL-2, but low levels of IL-4 and IL-10. Results of the cross reactivity tests showed that ATCC95051, H37Rv and BCG were able to cross-react with the immunized mice, and all of them induced high levels of IFN-γ, IL-2 and IgG antibodies. Conclusions The three Mycobacteria mainly elicited Th1 immune responses. There were cross-reactive immune responses to M. vaccae, M. tuberculosis and BCG, which might provide ref-erence for using M. vaccae in the development of new anti-tuberculous vaccines.

Bacillus Calmette-Guérin (BCG)-Cell Wall Skeleton as Immunotherapeutic Option for BCG-Refractory Superficial Bladder Cancer

Although intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most successful cancer immunotherapy for superficial bladder cancer, the serious side effects are frequently arisen by using live mycobacteria. To allow less toxic and more potent immunotherapeutic agents following intravesical BCG treatment for superficial bladder cancer, noninfectious immunotherapeutic drug instead of live BCG would be highly desirable. Recently, immune-enhancing adjuvants are considered an effective vaccine immunotherapy for cancer, providing enhanced antitumor effects and boosted immunity. The BCG-cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate as a noninfectious immunotherapeutic drug instead of live BCG against bladder cancer. However, the most limited application for anticancer therapy, it is difficult to formulate a water-soluble BCG-CWS due to the aggregation of BCG-CWS in both aqueous and nonaqueous solvents. To overcome the insolubility and improve the internalization of BCG-CWS into bladder cancer cells, it should be developed the lipid nanoparticulation of BCG-CWS, resulting in improved dispensability, stability, and small size. In addition, powerful technology of delivery systems should be applied to enhance the internalization of BCG-CWS, such as encapsulated into lipid nanoparticles using novel packaging methods. Here, we describe the progress in research on effects of BCG-CWS for cancer immunotherapy, development of lipid-based solvent, and packaging method using nanoparticles with drug delivery system.

Lymphadenitis associated with Bacillus Calmette-Guérin vaccination / 中华实用儿科临床杂志

Bacillus Calmette- Guérin(BCG) is still an effective way to prevent tuberculosis, but BCG vaccination reaction has various forms, mainly including lymphadenitis associated with BCG vaccination and disseminated BCG disease, the latter is relatively rare, lymphadenitis associated with BCG vaccination is relatively common, it is unclear that diagnosis and treatment, especially the timing of treatment and the choice of treatment methods, and lack of authoritative guidelines.Through further understanding of the pathogenesis, risk factors, clinical classification and diagnosis of this disease, clinicians can choose the optimized treatment plan for this disease.At the same time, the development and use of new vaccines are expected to reduce the occurrence of this disease.

Regulation of il-1 and TNF-α on metabolic enzyme cyp2e1 in immunological liver injury in rats / 中国药理学通报

Aim To investigate the regulation and mechanism of inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) on the drug metabolism enzyme cytochrome P450 2E1 (CYP2E1) during immune-mediated liver injury. Methods By injection of Bacillus Calmette-Guerin(BCG, 125 mg·kg-1) prepared rat model of immunological liver damage. To detection of CYP2E1 probe drug chlorzoxazone in blood concentration changes of rats over time reflects its metabolic activity by high-performance liquid chromatography (HPLC) assay. The changes of IL-1β and TNF-α in liver tissue of rats were detected by ELISA. The expression of CYP2E1 protein was determined by Western blot analysis. Results After 14 days of BCG injection of rats, a large number of mononuclear cells and lymphocytes infiltrated around the liver parenchyma and the portal area, resulting in a large number of granuloma masses with different sizes and diffuse distribution, IL-1β and TNF-α high expression (P < 0.01), CYP2E1 metabolic activity and protein expression were significantly decreased (P < 0.05). The protein content of CYP2E1 was significantly negatively correlated with IL-1β (r=0.222, P=0.027). Activation of PDTC-mediated nuclear factor-kappa B (NF-κB) inhibited the high expression of IL-1β and TNF-α in liver tissue and slowed down the down-regulation of CYP2E1 metabolism and protein expression. Conclusions NF-κB may be involved in the regulation of CYP2E1 by regulating the inflammatory cytokines IL-1β and TNF-α.

The efficacy and safety of BCG in the prevention of postoperative recurrence of intermediate and high-risk non-muscle invasive bladder cancer: a randomized, controlled, multi-center clinical trial (mid-term report) / 中华泌尿外科杂志

Objective To investigate the efficacy and safety of intravesical instillation of BCG vaccine in the prevention of early recurrence of middle and high risk non-muscle invasive bladder cancer.Methods From July 2015,patients with non-muscle invasive bladder cancer aged 18-75 years with informed consent were screened and underwent transurethral resection of bladder tumor (TURBT).Immediately intravesical instillation of epirubicin 50 mg was given postoperatively.After pathology was comfirmed,patients was enrolled in group 1 (BCG15) or group 2 (BCG 19) or the control group (epirubicin 18) randomly with SAS 9.3 software.Data of follow-up and Adverse event was collected and analyzed.Results By May 31,2019,531 patients were enrolled in the study.The drop-off rate was 20.1％.167 patients (143 males and 24 females)in group 1,172 patients (141 males and 31 females)in group2 and 84(75 males and 9 females) in the control group with follow-up data were analyzed.There were no significant differences in age,gender,BMI,ECOG score,risk stratification between the three groups (P =0.8641,P =0.2906,P =0.9384,P =0.6126).The median follow-up time makes no statistical difference between the groups (P =0.9251),12.0 (6.0,22.5) months,13.0 (6.0,22.3) months,and 13.0 (7.0,22.3) months.The median recurrence time of the three groups was 4.0 (3.0,6.0) months,4.5 (3.0,9.8) months,4.5 (3.0,8.8) months.There was no statistical difference between the three groups (P =0.2852).Risk stratification in the patients got no significant difference between the three groups (P ＞ 0.05).The 1-year recurrence-free survival rates were 80.0％ in the group 1 and 88.3％ in the group 2 and 73.7％ in the control group.The group 2 was superior to the group 1 and the control group (P =0.0281,P =0.0031).There was no significant difference between group 1 and control group (P =0.2951).There was no significant difference in the cumulative recurrence-free survival between the experimental group 1 and the experimental group 2,(95％ CI 0.80-2.43,P =0.2433).The cumulative recurrence-free survival in the group 1 and the group 2 was better than the control group (95 ％ CI 0.31-0.92,P =0.0266;95 ％ CI 0.20-0.65,P =0.0008).All the cases underwent instillation were analyzed for adverse events.The incidence of overall AE(adverse events) in group 1 was 68.5％ (152/222),the incidence of grade Ⅰ-Ⅱ AE was 53.2％ (118/222),the incidence of grade Ⅲ-Ⅳ AE was 15.3％ (32/222).The incidence of overall AE in the group 2 was 71.8％ (160/223),the incidence of grade Ⅰ-Ⅱ AE was 60.1％ (134/223),and the incidence of grade Ⅲ-Ⅳ AE was 11.7％ (26/223).The overall AE rate in the control group was 53.2％ (59/111),of which the incidence of grade Ⅰ-Ⅱ AE was 42.4％ (47/111),and the incidence of grade Ⅲ-Ⅳ AE was 10.8％ (12/111).There was no difference in the incidence of overall AE between the group 1 and the group 2 (P =0.4497).The incidence of AE in the two experimental groups was higher than that in the control group (P =0.0062,P =0.0008).There was no difference in the incidence of grade Ⅲ-Ⅳ AE between the three groups (P =0.3902).Conclusions BCG(19 instillation schedule) has a better effect on preventing recurrence after 1 year of bladder surgery,which is superior to epirubicin group.The long-term efficacy of BCG in preventing recurrence and the efficacy of different schedules need to be further followed up.The lower urinary tract symptoms,which are mainly urinary frequency,are one of the causes of case fallout and should be fouced in future.Compared with epirubicin,BCG perfusion does not increase the incidence of grade Ⅲ-Ⅳ adverse reactions,and is safe to use.

Lymphadenitis associated with Bacillus Calmette-Guérin vaccination / 中华实用儿科临床杂志

Bacillus Calmette-Guérin(BCG) is still an effective way to prevent tuberculosis,but BCG vaccination reaction has various forms,mainly including lymphadenitis associated with BCG vaccination and disseminated BCG disease,the latter is relatively rare,lymphadenitis associated with BCG vaccination is relatively common,it is unclear that diagnosis and treatment,especially the timing of treatment and the choice of treatment methods,and lack of authoritative guidelines.Through further understanding of the pathogenesis,risk factors,clinical classification and diagnosis of this disease,clinicians can choose the optimized treatment plan for this disease.At the same time,the development and use of new vaccines are expected to reduce the occurrence of this disease.

Short-term efficacy and predictive factors of BCG instillation in high risk non-muscle invasive bladder cancer / 中华泌尿外科杂志

Objective To investigate the short-term efficacy,safety and factors affecting the efficacy of BCG intravesical therapy in high risk non-muscle-invasive bladder cancer (NMIBC) patients.Methods A total of 161 high-risk non-muscle invasive bladder cancer (NMIBC) patients were reviewed in our hospital from March 2014 to December 2017.They were all treated with BCG instillation after transurethral resection of bladder tumor (TURBT).There were 121 males (75.2％) and 40 females (24.8％).Median age was 65 years old,including 17 cases (10.6％) ＜50 years old,23 cases (14.3％) within 50-59 years old,72 cases (44.7％) within 60-69 years old,49 cases ≥70 years old (30.4％).There were 112 patients (69.6％) with primary bladder cancer and 49 (30.4％) patients with recurrent bladder cancer.56 cases (34.8％) had single tumor and 105 cases (65.2％) had multiple tumors.The tumors size in 106 cases (65.8％) was less than 3 cm,and tumor size in 55 cases (34.2％) was more than 3 cm.43 patients (26.7％) suffered carcinoma in situ.10 patients (6.2％) suffered urothelial carcinoma with variant types.According to the American Joint Commission for Cancer (AJCC) version 7 TNM staging system,25 cases (15.5％) were classified into Ta stage,129 cases (80.1％) were classified into T1 stage,and 7 cases (4.3％) were classified into Tis stage.There were 8 cases (5％) with low-grade cancer and 153 cases (95％) with high-grade cancer.69 patients (42.9％) received chemo-instillation before.43 cases were directly perfused without re-TURBT and 118 cases were perfused after re-TURBT.They were all treated with BCG instillation after transurethral resection of bladder tumor (TURBT).The 120 mg BCG were dissolved into 50 ml saline for instillation and were kept for 2 hours.Induction scheme of six-weekly and three fortnightly instillations started two weeks after the initial TUR or re-TUR.Maintenance instillations were then be offered in a scheme of ten monthly instillations.During treatment,patients were offered cystoscopy and cytology every three months,while CT and chest radiographs were reviewed every 6-12 months.Recurrence status and adverse effects were recorded.Univariate and multivariate regression analyses were performed to predict risk factors for failure of BCG instillation in bladder cancer.Results A total of 161 patients were followed up.The median follow-up time was 13 months,ranging 7-22 months.The overall recurrence rate was 26.1％ (42/161) and the 1-year recurrence-free survival rate was 79.0％.On univariate analysis,recurrence history,history of instillation chemotherapy application and history of re-staging transurethral resection influenced recurrence.Multivariate regression analysis showed recurrence status was an independent prognostic factor regarding recurrence-free survival.The incidence of adverse events in all 161 instillation patients was 40.4％ (26/65).Grade 1,grade 2 and grade 3 adverse events accounted for 53.8％ (35/65),40.0％ (26/65) and 6.2％ (4/65) respectively.6 cases (3.7％) reduced the dose of BGC and 1 case stop the instillation due to the intolerance of BCG.Conclusion Short-term efficiency and safety were confirmed in BCG-treated high-risk NMIBC patients.And recurrence status was an independent prognostic factor for recurrence-free survival.

Efficacy and complications of intravesical instillation of BCG for prevention of recurrence of moderate and high-risk non muscle invasive bladder cancer / 中华泌尿外科杂志

Objective To assess the efficacy and side effects of intravesical instillation of BCG after transurethral resection of the bladder tumor (TURBT) in non-muscle invasive bladder cancer (NMIBC) patients.Methods The clinical data of patients treated with BCG 120 mg per course induced perfusion or more after TURBT from December 2013 to October 2016 in 18 hospitals of northeast China region,were analyzed retrospectively.The first part,data of 106 patients with moderate,high-risk NMIBC were collected.A total of 83 patients were male,while the other 23 patients were female.The average age was 66.7 years old.The clinical staging were T1 in 86(81.1％) cases,Ta in 20(18.9％) cases and carcinoma in situ in 6 (5.7％) patients.Intravesical instillation of BCG was executed after transurethral resection of the bladder tumor.The incidence rate of recurrence and progression during more than 6 months' follow-up time were observed.Multivariate analyses were done by using logistic analysis and Cox proportional hazards regression model with Kaplan-Meier method.The second part,treatment compliance of 276 patients with bladder cancer,including moderate/high-risk NMIBC in 263 cases,moderate/high-risk NMIBC followed with renal pelvis/ureteral carcinoma in 8 cases were and moderate/high-risk NMIBC with renal pelvis/ureteral carcinoma in 5 cases who treated with BCG after the surgeries,were observed.Patients consisted of 211 males and 65 females with average age of 68.3 years.Results With a median follow-up of 12 months,9 (8.5％) patients experienced tumor recurrence and 2 (1.9％) patients were found progression in the first part.The one-year cancer free recurrence rate of the patients was 91.5％.Statistically significant prognostic factors for recurrence identified by multivariable analyses were prior recurrence of the tumors (OR =3.214,95％CI0.804-12.845,P =0.099).In the second port,an incidence rate of adverse effects was 64.1％ (177/276).The Ⅲ/Ⅳ degree complications were occurred in 11 patients and satisfactory outcomes achieved with active treatment.A total of 36 patients withdrawal with the major causes were recurrence and progression of bladder tumor in 12 cases (4.4 ％),9 cases (3.3 ％) with economic reasons and 11 cases (4.0％) with serious complications.Conclusions NMIBC patients treated with intravesical BCG therapy have approving cancer free recurrence rates and acceptable adverse effects.Prior recurrence may be prognostic factor of recurrence after intravesical BCG therapy.

Transcriptome sequencing and analysis of bovine alveolar macrophages infected with BCG / 吉林大学学报(医学版)

Objective:To reveal the differentially expressed genes and long non-coding RNAs (lncRNAs) by sequencing the transcriptome of bovine alveolar macrophages (BAM) infected with Bacillus Calmette-Guérin (BCG) and analyzing their bioinformations, and to provide theoretical foundation for the research on immune regulation mechanism of anti-infection of Mycobacteriumtuberculosisof macrophages.Methods:The BAM were collected by pulmonary lavage and centrifugation and cultured and divided into infected group and uninfected group.After infection for 12hin infected group, the expression profiles of mRNA and lncRNA in infected group and uninfected group were detected by RNA-Seq, and bioinformatics analysis was carried out.Results:compared with uninfected group, there were 119differentially expressed lncRNAs and 1111differentially expressed mRNA in infected group (P＜0.05) .Gene Ontology functional enrichment analysis showed that the most significant enrichment was immune response (GO:0006955, P＜0.05) , including 125genes, in which 63 were up-regulated and 62 were downregulated, and the expressions of proinflammatory factors interleukin-1 (IL-6) , interleukin-7 (IL-7) , and interleukin-23A (IL-23A) were up-regulated.Cis target gene prediction and KEGG pathway analysis showed that the differentially expressed lncRNAs were involved in the regulation of transforming growth factor-β (TGF-β) signaling pathway and ATP-binding cassette transporter (ABC transporter) signaling pathway (P＜0.05) .Conclusion:The host cells are stimulated to produce a strong immune response after the BAM are infected by BCG and results in the changes of lncRNA and mRNA expression profiles.

Detection of IL-35-expressing monocytes in mice infected with BCG and its clinical significance / 中国免疫学杂志

Objective:To detect IL-35 in mononuclear cells of peripheral blood and lung tissue with BCG infected mouse,and to analyze its effect on the tuberculosis immune mechanism and pathology.Methods: Mycobacterium tuberculosis infecting animal model was made by BCG injection in wild type C57BL/6 mouse.Then,mice were sacrificed in different time points.The peripheral blood and lung tissue were isolated.The bacterial load and histopathological analysis in lung tissue were performed,and the expression of IL-35 subunits P35 and EBI3 in monocytes were detected by flow cytometry.Furthermore,the correlation of IL-35-expressing monocytes with the load of bacterium was analyzed.Results:The expression of P35 and EBI3 in monocytes in peripheral blood and lung tissue of BCG-infected mice was significantly higher than that of the control group,and the peripheral blood of the experimental group was significantly increased at 4 weeks after infection.The expression of EBI3 in lung tissue diaplayed significant rising trend.The correlation analysis showed that the P35 expression was positively correlated with the expression of EBI3 in monocyte,and the IL-35-ex-pressing monocyte in lung tissue was negatively correlated with the load of bacteria.The IL-35-expressing monocyte in peripheral blood and lungs increased significantly at 2-week and 4-week,while it increased in lung tissue at 8 week,significantly.Conclusion: BCG-infects mouse monocytes with high expression of IL-35,it may participate in anti-tuberculosis immune regulation.

Expression of IFN-γ,IL-4 and IL-17A in asthmatic mice vaccinated with BCG and HepB in neonatal period / 中国病理生理杂志

AIM:To investigate the expression of IFN-γ,IL-4 and IL-17A in asthmatic mice vaccinated with bacillus Calmette-Guérin(BCG)and hepatitis B(HepB)in the neonatal period.METHODS: BALB/c mice were ran-domly divided into BGG+HepB+ovalbumin(OVA)group(B/H/O group),B/O group,H/O group,B/H group,OVA group,BCG group,HepB group and normal saline(NS)group(n=6).The mice in B/H/O group and B/H group at 0, 7 and 14 d received subcutaneous injection of 1×105CFU BCG for 3 times,while at 0 and 28 d received intramuscular in-jection of 1.5 μg HepB on the hindlimb twice.The mice in other groups were individually vaccinated with BCG or HepB. OVA sensitization and aerosol inhalation were performed to establish the asthma model.The lung tissues were collected for HE staining.Bronchoalveolar lavage fluid(BALF)and peripheral blood(PB)were collected,and the number of eosino-phils(EOS)in BALF was counted.The serum levels of IFN-γand IL-4,and the level of IL-17A in lung tissue homoge-nate were measured by ELISA.RESULTS: The pathological changes of the lung in OVA group, B/O group, B/H/O group and H/O group were observed.There were extensive inflammatory cell infiltration around the bronchus,and epithe-lial cell hypertrophy.Those in B/H/O group and H/O group were worse than those in OVA group, while those in B/O group was better than those in OVA group.Total BALF cell counts in B/H/O group,B/O group and H/O group were de-creased(P<0.05)as compared with OVA group.The BALF EOS count in B/H/O group was higher than that in B/H group,that in B/O group was higher than that in BCG group,and that in H/O group was higher than that in HepB groups (P<0.05).Compared with H/O group, OVA group and NS group, the serum IFN-γ/IL-4 ratio in HepB group was in-creased(P<0.05),and compared with B/H/O group,B/O group,OVA group and NS group,that in B/H group was al-so increased(P<0.05).Compared with OVA group, the level of IL-17A in the lung tissues of B/H/O group and B/O group was decreased(P <0.05), and compared with B/O group, that in B/H/O group was further decreased(P <0.05).CONCLUSION:Combined vaccination of BCG and HepB reduces the inflammotory responses in the lung tissues of asthmatic mice.The mechanism may be related with the decrease in the release of IL-4, the increase in IFN-γ/IL-4, and the inhibition of IL-17A expression.