Mast cells accumulate in the anogenital region of somatosensory thalamic nuclei during estrus in female mice

Mast cells are located in the mammalian thalamus where their numbers are sensitive to reproductive hormones. To evaluate whether differences between sexes and over the estrus cycle influence the nuclear distribution of mast cells in mice, we mounted a comprehensive analysis of their distribution in males compared to females and in females over the estrus cycle. Compared to males, mast cells were more numerous in the lateral intralaminar and posterior nuclei of females during estrus and in the ventral posterolateral (VPL) and medial geniculate nuclei during proestrus. During estrus, mast cells were especially concentrated in those regions within the VPL and posterior thalamic nuclei that receive somatosensory information from the anogenital region. Treatment of ovariectomized mice with estrogen increased the number and the percent of mast cells that were degranulated compared to that after ovariectomy alone, an effect that was most apparent in the lateral intralaminar, VPL and posterior nuclei. In estrogen-primed, ovariectomized females, progesterone delivered 5 h before tissue collection counteracted the effects of estrogen. Cromolyn, a mast cell stabilizer, injected centrally 1 h prior to and 24 h after estrogen in ovariectomized mice, prevented the increase in number of mast cells in the whole thalamus and in the intralaminar, VPL and posterior nuclei. This suggests that estrogen induces hyperplasia by a mechanism that involves mast cell degranulation. Based on the discrete anatomical location of mast cells in areas of somatosensory nuclei that receive anogenital input together with the temporal correspondence of these cells with estrus, mast cells are well situated to influence sensory input in females during mating.     

Newborn screening for cystic fibrosis is associated with reduced treatment intensity

OBJECTIVES: To determine whether the improved clinical status after newborn screening (NBS) for cystic fibrosis (CF) segregates with increased therapeutic intervention compared with presentation by clinical diagnosis (CD). STUDY DESIGN: In 2002, two populations (1 to 9 years of age) who presented (excluding meconium ileus) by NBS < or = 3 months of age or by CD were compared in an observational, cross-sectional design. NBS and CD populations (184 and 950 patients, respectively) were divided into 3-year age groups (1 to 3, 4 to 6, and 7 to 9 years). Therapies of duration >3 months were compared together with Pseudomonas aeruginosa infection status. RESULTS: NBS patients < or = 6 years of age received significantly fewer and less demanding therapies not explained by age, genotype, geography, or social deprivation. In 7- to 9-year-olds, significantly fewer NBS patients received intravenous antibiotics. NBS patients without P aeruginosa infection received significantly fewer therapies, but no differences were found between intermittently or chronically infected NBS and CD populations. Comparable results were found in deltaF508/deltaF508 subpopulations. CONCLUSIONS: CF populations diagnosed by NBS are associated with reduced treatment compared with age- and genotype-matched CD control subjects.     

降钙素基因相关肽家族的新成员-intermedin/adrenomedullin2的生物学效应

降钙素基因相关肽（Calcitonin gene-related peptide,CGRP）是1982年Amara在研究甲状腺髓样癌的降钙素基因表达时发现的,是人类直接运用分子生物学发现的第一个血管活性肽.1983年,Rosefeld等证实了CGRP在人和动物体内的存在.现己研究发现的降钙素基因相关肽超家族包括五个成员：降钙素（Calcitonin,CT）,胰淀粉酶（Amylin）,两种降钙素基因相关肽和肾上腺髓质素（Adrenomedullin,ADM）.     

阿托伐他汀联合缬沙坦对原发性高血压伴早期肾损伤患者血清IMD、FGF23及CysC的影响

目的 观察阿托伐他汀联合缬沙坦对原发性高血压伴早期肾损伤患者的降压效果,并探讨血清中叶素(IMD)、胱抑素C(CysC)及成纤维细胞生长因子23(FGF23)水平的变化.方法 将120例原发性高血压患者随机分为试验组及对照组,各60例.对照组口服缬沙坦160 mg,1次/d;试验组在对照组的基础上联合阿托伐他汀治疗,20 mg/次,1次/d,睡前服用,疗程12月.比较用药前后血压变化、达标率(血压＜ 140/90 mmHg)(1 mmHg=0.133 kPa).同时采集患者外周静脉血,应用生化分析仪检测血清IMD、CysC及FGF23水平.结果 治疗前,两组血压比较差异无统计学意义(t=-0.958,P=0.340;t=-0.737,P=0.463),治疗12月后,两组收缩压、舒张压均较治疗前降低(P＜0.001);与对照组相比,试验组降压效果更明显(t=2.403,P=0.018;t=2.107,P=0.037).对照组达标率73.33％,试验组达标率88.33％,差异有统计学意义(x2=4.357,P=0.037).两组治疗前血清IMD、FGF23及CysC水平比较,差异无统计学意义(t=-0.578,P=0.564;t=-0.698,P=0.487;t=-0.179,P=0.858);治疗12月后,两组血清IMD、FGF23及CysC表达水平均较治疗前明显降低,差异有统计学意义(P＜0.01);与对照组相比,试验组血清IMD、FGF23及CysC表达水平明显下调,差异有统计学意义(t=4.755,P＜0.001;t=-4.230,P＜0.001;t=3.417,P=0.001).结论 阿托伐他汀联合缬沙坦对原发性高血压伴早期肾损伤患者降压效果明显,血清IMD、FGF23、CysC水平的下调可能是其缓解肾损伤的机制之一.     

The role of pediatricians as key stakeholders in influencing immunization policy decisions for the introduction of meningitis B vaccine in Canada: The Ontario perspective

As key stakeholders in immunization policy decisions, the Pediatricians of Ontario held an accredited conference on January 18, 2014, to discuss prevention of invasive meningococcal disease. Five key recommendations were put forth regarding immunization strategies to protect children from meningococcal serogroup B disease. The recently approved four-component meningococcal B (4CMenB) vaccine should be recommended and funded as part of Ontario’s routine immunization schedule and should also be mandated for school attendance. Public funding for 4CMenB immunization is justified based on current MenB epidemiology, vaccine coverage, cost effectiveness and acceptability, as well as legal, political and ethical considerations related to 4CMenB immunization, particularly because routine recommendations and funding are currently in place for vaccination against meningococcal serogroups that cause significantly less disease in Canada than MenB. Broadly, the goals are to assist individual practitioners in advocating the benefits of 4CMenB vaccination to parents, and to counterbalance recommendations from the National Advisory Committee on Immunization and the Canadian Paediatric Society.     

Drosophila as a model for intestinal dysbiosis and chronic inflammatory diseases

The association between deregulated intestinal microbial consortia and host diseases has been recognized since the birth of microbiology over a century ago. Intestinal dysbiosis refers to a state where living metazoans harbor harmful intestinal microflora. However, there is still an issue of whether causality arises from the host or the microbe because it is unclear whether deregulation of the gut microbiota community is the consequence or cause of the host disease. Recent studies using Drosophila and its simple microbiota have provided a valuable model system for dissecting the molecular mechanisms of intestinal dysbiosis. In this review, we examine recent exciting observations in Drosophila gut-microbiota interactions, particularly the links among the host immune genotype, the microbial community structure, and the host inflammatory phenotype. Future genetic analyses using Drosophila model system will provide a valuable outcome for understanding the evolutionarily conserved mechanisms that underlie intestinal dysbiosis and chronic inflammatory diseases.     

The epidemiology of invasive meningococcal disease in EU/EEA countries, 2004–2014

BackgroundInvasive meningococcal disease (IMD) is a major cause of bacterial meningitis and septicaemia although infection by some serogroups may be prevented through vaccination. We aimed to describe the epidemiology of IMD in EU/EEA countries during 2004–2014 to monitor serogroup- and age-specific trends, and compare country trends by the period of meningococcal C conjugate (MCC) vaccine introduction.MethodsWe analysed IMD surveillance data by age, gender, serogroup, country and outcome. We estimated the percentage change in annual notification rate (NR), using linear regression analysis of the log of the annual NR. We grouped countries by the year they introduced MCC vaccination into their routine immunisation programmes.ResultsThe overall NR was 0.9/100 000 population, and decreased 6.6% (95%CI: −8.0%;−5.1%) annually. Infants had the highest NR (16.0/100 000), and there were decreasing trends in all age groups <50 years. Serogroup B (SgB) caused 74% of all cases, and the majority of cases in all age groups. There were decreasing trends in SgB and serogroup C (SgC) and an increasing trend in serogroup Y. Countries that introduced MCC vaccination before, and between 2004 and 2014, had decreasing trends in NR of SgC, but not countries without routine MCC vaccination.ConclusionsOur findings support evidence that routine MCC vaccination was the driving force behind the decreasing SgC trend. Vaccinating against SgB in the first year of life could help reduce the burden of IMD due to this serogroup. Changing serogroup-specific NR trends highlight the need for high-quality surveillance data to accurately assess the changing epidemiology of IMD, the effectiveness and impact of implemented vaccines, and the need for future vaccines.     

Immunogenicity and safety of the 4CMenB and MenACWY-CRM meningococcal vaccines administered concomitantly in infants: A phase 3b,randomized controlled trial

BackgroundInvasive meningococcal disease has its highest incidence in infants. Co-administration of serogroup B (4CMenB) and quadrivalent conjugate (MenACWY-CRM) vaccines could protect against 5 clinically-relevant meningococcal serogroups.MethodsThis phase 3b, open, multicenter study (NCT02106390), conducted in Mexico and Argentina, enrolled and randomized (1:1:1) 750 healthy infants to receive either 4CMenB co-administered with MenACWY-CRM (4CMenB/MenACWY group), 4CMenB (4CMenB group), or MenACWY-CRM alone (MenACWY group) at ages 3, 5, 7 and 13 months. Non-inferiority of immune responses of co-administration to single administration of vaccines was assessed at 1 month post-booster dose (primary objective). Immunogenicity was evaluated pre- and 1 month post-primary and booster vaccinations using human serum bactericidal assay (hSBA). Safety was assessed.ResultsAt 1 month post-booster vaccination, between-group hSBA geometric mean titer (GMT) ratios ranged from 0.89 to 1.03 for serogroup B strains (group 4CMenB/MenACWY over 4CMenB), and from 1.05 to 2.48 for ACWY serogroups (group 4CMenB/MenACWY over MenACWY). The lower limit of the 2-sided 95% confidence intervals for all GMT ratios was >0.5; the primary objective was demonstrated. Across all groups and serogroup B strains, 68–100% and 87–100% of children had hSBA titers ≥5 at 1 month post-primary and booster vaccination, respectively. For serogroups ACWY, ≥96% (post-primary vaccination) and ≥98% (post-booster vaccination) of children in all groups had hSBA titers ≥4. Post-booster vaccination, GMTs increased ≥5.99-fold from pre-booster values for each strain/serogroup. Solicited adverse events (AEs) were more frequent in groups 4CMenB/MenACWY and 4CMenB than in MenACWY; incidence of all other AEs was similar between groups. Serious AEs were reported for 6, 13, and 11 participants in groups 4CMenB/MenACWY, 4CMenB, and MenACWY, respectively; 1 (group 4CMenB) was considered vaccine-related.ConclusionImmune responses elicited by co-administration of 4CMenB and MenACWY-CRM was non-inferior to single immunization. Co-administration of vaccines was immunogenic and well tolerated in infants.ClinicalTrials.gov: NCT02106390.An Audio Summary linked to this article that can be found on Figshare https://figshare.com/articles/Immunogenicity_and_safety_of_the_4CMenB_and_MenACWY-CRM_meningococcal_vaccines_administered_concomitantly_in_infants_-_A_phase_3b_randomized_controlled_trial/9945050.     

Immunogenicity and safety of the quadrivalent meningococcal vaccine MenACWY-TT co-administered with a combined diphtheria-tetanus-acellular pertussis vaccine versus their separate administration in adolescents and young adults: A phase III,randomized study

BackgroundThis study evaluated the immunogenicity and safety of quadrivalent meningococcal conjugate vaccine using tetanus (T) toxoid as carrier protein (MenACWY-TT) co-administered with combined diphtheria-tetanus-acellular pertussis vaccine (Tdap) versus their separate administration in adolescents and young adults.MethodsIn this phase III, randomized, partially-blind study (NCT01767376), healthy 11–25-year-olds (N = 660) were randomized (1:1:1) to receive MenACWY-TT and Tdap at Month 0 (Co-ad group), MenACWY-TT at Month 0 and Tdap at Month 1 (ACWY_Tdap group) or Tdap at Month 0 and MenACWY-TT at Month 1 (Tdap_ACWY group). Immune responses to MenACWY-TT were measured by serum bactericidal assay using rabbit complement (rSBA). Anti-diphtheria (D), anti-tetanus (T), anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations were assessed using enzyme-linked immunosorbent assays. Non-inferiority of immunogenicity was assessed using pre-defined clinical criteria. Safety was also evaluated.ResultsNon-inferiority of immunogenicity of MenACWY-TT and Tdap when co-administered versus their separate administration was demonstrated in terms of rSBA geometric mean titers (GMTs) for 4 meningococcal serogroups and of the percentage of participants with antibody concentrations >1 IU/ml for D and T. Among the pertussis antigens, non-inferiority criteria for geometric mean concentrations (GMCs) were reached for PT, but not met for FHA and PRN. Across all groups, ≥93.2% of participants had vaccine responses to each meningococcal serogroup, ≥99.1% were seroprotected against T and D, and ≥85.5% had booster responses to each pertussis antigen. Robust increases in antibody GMTs/GMCs were observed for all antigens between pre-and post-vaccination. Both vaccines had clinically acceptable safety profiles.ConclusionImmune responses to MenACWY-TT and to the T and D antigens from Tdap were not impacted by their co-administration. The lower antibody concentrations observed against the pertussis components may be of limited clinical relevance since robust anti-pertussis booster responses were observed. This study supports concurrent administration of the 2 vaccines in adolescents.