[Penile glans amputation during circumcision: causes, treatments and preventive measures].

INTRODUCTION: Penile glans amputation during circumcision is a rare but potentially devastating complication. The mechanism and causes are poorly understood and incomprehensible. It is important to identify the causes of these complications, to suggest a mechanism and to propose prevention measures. MATERIALS: Between 2005 and 2019, six patients with penile glans amputationafter circumcision were analyzed. All were operated without medical evidence, for religious reasons. THE RESULTS: The operations were performed by local anesthesia, at home - in 5 patients, in 1 child - at polyclinic. All children were circumcised by scalpel with guillotine method, without visualization of glans. Partial amputation of penile glans was observed in 2 children (33.3%). Complete cut-off of the glans at the level of the coronal sulcus was revealed in 4 boys (66.6%). Meatoplasty with urethral mobilizations was performed 2 patients (33.3%) with partial amputation. The tops of corpus cavernous was covered of with the remnants of the skin of penile shaft in two boys (33.3%). Glansplasty was performed in 2 other patients (33/3%), using a labial mucosa graft to reconstruct the shape of glans and glanular groove. The follow up have showed meatostenosis in two boys (33.3%) in the first 2 months after surgery. One child required repeated meatoplasty (16.6%), another had a recovery of normal urine flow rates after urethral dilatation and stenting (4 weeks). CONCLUSION: Visual control of the glans position during circumcision will prevent the amputation. "Guillotine" techniques including, Mogen clamp-type devices, are considered potentially dangerous. Circumcision in newborns, without general anesthesia, in the presence of swelling of the foreskin have an increased risk of glans damage. Preliminary examination of the glans and adequate release of preputial adhesions help to prevent complication of circumcision and to identify combined malformations (hypospadia, epispadia, concealed penis.).

Elevated adiponectin predicts the development of rheumatoid arthritis in subjects with obesity.

Objective The aim of the current study is to determine whether baseline serum adiponectin levels predict the development of rheumatoid arthritis (RA). Method The current report includes 3693 individuals from the Swedish Obese Subjects (SOS) study. The original SOS study is a longitudinal non-randomized controlled study aiming to assess the effect of bariatric surgery on obesity-related mortality and morbidity. Participants included in the present report had adiponectin measurement available at baseline and no prevalent RA. The diagnosis of RA was retrieved through the Swedish National Patient Register. Results During a follow-up for up to 29 years, 82 study participants developed RA. Elevated baseline adiponectin levels were associated with a higher risk of developing RA independently of other factors, including C-reactive protein (CRP) and smoking [hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.12-2.60 for an increase in adiponectin of 10 mg/L, p = 0.01]. After stratifying the population according to adiponectin and CRP median at baseline, study participants with both adiponectin and CRP above the median had a higher risk of developing RA compared to subjects with adiponectin and CRP below the median (HR 2.80, 95% CI 1.25-6.31, p = 0.01). Conclusions In this cohort of subjects with obesity followed up for up to 29 years, high serum adiponectin levels at baseline were associated with an increased risk for RA. Moreover, subjects with both high adiponectin and CRP levels at baseline were at particular risk of developing RA. ClinicalTrials.gov Identifier: NCT01479452.

Allergic disease in 8-year-old children is preceded by delayed B cell maturation.

BACKGROUND: We previously reported that exposure to a farming environment is allergy-protective, while high proportions of neonatal immature/naïve CD5+ B cells and putative regulatory T cells (Tregs) are risk factors for development of allergic disease and sensitization up to 3 years of age. OBJECTIVE: To examine if B and T cell maturation are associated with allergic disease and farming environment over the first 8 years in life. METHODS: In the prospective FARMFLORA study, including both farming and non-farming families, 48 of 65 children took part in the 8-year follow-up study. Various B and T cell maturation variables were examined in blood samples obtained at several occasions from birth to 8 years of age and related to doctors' diagnosed allergic disease and sensitization, and to farming environment. RESULTS: We found that the incidence of allergic disease was lower among farmers' compared to non-farmers' children during the 8-year follow-up period, and that farmers' children had higher proportions of memory B cells at 8 years of age. Moreover, a high proportion of neonatal CD5+ B cells was a risk factor for and may predict development of allergic disease at 8 years of age. A high proportion of Tregs was not protective against development of these conditions. CONCLUSION AND CLINICAL RELEVANCE: High proportions of neonatal naïve B cells remained as a risk factor for allergic disease in school-aged children. Thus, the accelerated B cell maturation observed among farmers' children may be crucial for the allergy-protective effect of a farming environment.

High proportions of FOXP3(+) CD25(high) T cells in neonates are positively associated with allergic sensitization later in childhood.

BACKGROUND: The role of FOXP3(+) regulatory T cells in the prevention against sensitization and allergy development is controversial. OBJECTIVE: We followed 65 newborn Swedish children from farming and non-farming families from birth to 3 years of age and investigated the relation between CD4(+) T cell subsets in blood samples and development of sensitization and allergic disease. METHODS: The proportions of FOXP3(+) CD25(high) , CTLA-4(+) CD25(+) , CD45RO(+) , HLA-DR(+) , CCR4(+) or α4ß7(+) within the CD4(+) T cell population were examined by flow cytometry of blood samples at several time-points. Mononuclear cells were isolated from blood and stimulated with birch allergen, ovalbumin or the mitogen PHA, and the levels of IL-1ß, IL-6, TNF, IFN-γ, IL-5 and IL-13 were measured. A clinical evaluation regarding the presence of allergen-specific IgE and allergy was performed at 18 and 36 months of age. RESULTS: Multivariate discriminant analysis revealed that children who were sensitized at 18 or 36 months of age had higher proportions of FOXP3(+) CD25(high) T cells at birth and at 3 days of life than children who remained non-sensitized, whereas allergy was unrelated to the neonatal proportions of these cells. The proportions of CTLA-4(+) CD25(+) T cells were unrelated to both sensitization and allergy. The association between higher proportions of FOXP3(+) CD25(high) T cells and sensitization persisted after exclusion of farmer's children. Finally, a farming environment was associated with lower proportions of FOXP3(+) CD25(high) T cells in early infancy and to a more prominent T cell memory conversion and cytokine production. CONCLUSION & CLINICAL RELEVANCE: Our results indicate that high proportions of FOXP3(+) CD25(high) T cells in neonates are not protective against later sensitization or development of allergy.

Enveloped virus but not bacteria block IL-13 responses in human cord blood T cells in vitro.

Infections that occur early in life may have a beneficial effect on the immune system and thereby reduce the risk of allergen sensitization and/or allergic disease. It is not yet clear to what extent specific virus and/or bacteria can mediate this effect. The purpose of this study was to assess the role of virus and bacteria in CD4(+) T cell-derived cytokine production in newborns. We compared the effects of five bacteria (Staphlococcus aureus, Escherichia coli, Clostridium difficile, Lactobacillus rhamnosus and Bifidobacterium bifidus) and seven virus (adenovirus, coronavirus, cytomegalovirus, herpes simplex virus, influenza virus, morbillivirus and poliovirus) on the Th1/Th2 cytokine production in mixed lymphocyte reactions using CD4(+) T cells from cord blood cocultured with allogenic myeloid or plasmacytoid dendritic cells. When comparing the baseline cytokine production prior to microbial stimulation, we observed that cord plasmacytoid DC were stronger inducers of Th2 cytokines (IL-5 and IL-13) compared with cord myeloid DC and to adult DC. When adding microbes to these cultures, bacteria and virus differed in two major respects; Firstly, all enveloped viruses, but none of the bacteria, blocked Th2 (IL-13) production by cord CD4(+) cells. Secondly, all Gram-positive bacteria, but none of the virus, induced IL-12p40 responses, but the IL-12p40 responses did not affect Th1 cytokine production (IFN-γ). Instead, Th1 responses were correlated with the capacity to induce IFN-α secretion, which in cord cells were induced by S. aureus and influenza virus alone. These data imply that enveloped virus can deviate Th2 responses in human cord T cells.

Early fish introduction is associated with less eczema, but not sensitization, in infants.

OBJECTIVE: To investigate if the development of allergic diseases during the child's first 18 months of life is influenced by the time at which different food items were introduced into the child's diet. METHOD: A birth cohort of 184 children was followed to 18 months of age. Diaries were used to document feeding practices, and parental interviews were performed at 6 and 12 months of age, probing for symptoms suggesting allergic disease, general health-related issues and food introduction regimes. Symptoms promoted prompt clinical examination, and all children were examined clinically, and tested for sensitization to common airborne and food allergens at 18 months of age. RESULTS: The earlier the fish was introduced into the child's diet the lower was the frequency of eczema. This association remained after control for confounding factors. The timing of fish introduction and asthma development showed a similar pattern, but did not reach statistical significance. Sensitization was not influenced by the timing of fish introduction. Other food items or feeding practices did not seem to influence allergy development. CONCLUSION: Early introduction of fish into the child's diet was associated with less eczema development, and a tendency to less asthma. Sensitization was not associated with the timing of fish introduction.

Infection of infants with human herpesvirus type 6 may be associated with reduced allergic sensitization and T-helper type 2 development.

BACKGROUND: Epidemiological studies point to an inverse relationship between microbial exposure and the prevalence of allergic diseases. The underlying mechanism for this observation remains largely unknown, as well as the nature of the microbes involved. OBJECTIVE: To investigate the effects of early infection with human herpesviruses (HHVs) on IgE formation and T-helper type 2 (Th2) development in infants. METHODS: Serum was collected from children aged 18 months and assessed for IgE to common allergens and IgG to five common herpesviruses. Cord blood plasmacytoid dendritic cells (pDC) were exposed to HHV type 6 in vitro and mixed with allogeneic cord blood CD4(+) T cells. Cytokine levels were determined by ELISA and by flow cytometry. RESULTS: We found that children seropositive at 18 months of age to HHV type 6 were significantly less often IgE sensitized than seronegative children [odds ratio (OR): 0.08, 95% confidence interval (CI): 0.009-0.68]. HHV type 6 also decreased the production of the Th2-associated cytokines IL-5 and IL-13 by CD4(+) T cells when co-cultured with allogeneic cord blood pDC. This was associated with an increased production of IFN-alpha by pDC exposed to HHV type 6. CONCLUSION: These data indicate that an early childhood infection with HHV type 6 could down-regulate Th2 responses and reduce IgE formation to common allergens in a young child.

High circulating immunoglobulin A levels in infants are associated with intestinal toxigenic Staphylococcus aureus and a lower frequency of eczema.

BACKGROUND: Intestinal bacteria trigger IgA production and delayed maturation of mucosal IgA response is linked to allergy development. OBJECTIVE: Our aim was to investigate if plasma levels of IgA or APRIL (a proliferation inducing ligand), an important factor for IgA class switch recombination, in infancy correlates with intestinal colonization by any specific bacteria or yeast. We also examined if plasma IgA or APRIL levels are related to sensitization and the development of eczema. METHODS: IgA was quantified in plasma obtained from infants at birth and at 4 and 18 months of age and APRIL was measured at 4 months of age. Colonization by major bacterial groups and yeast was followed in the first 8 weeks of life by quantitative culture of stool samples. A clinical evaluation regarding the presence of allergen-specific IgE or eczema and eosinophil counts in blood was performed at 18 months of age. RESULTS: In multiple linear regression analysis, only colonization by Staphylococcus aureus strains producing toxins with superantigen function (SEA-D or TSST-1) made an independent contribution to plasma IgA levels at 4 months of age. Further, increased levels of APRIL in plasma at 4 months were negatively associated with sensitization while IgA plasma levels were inversely correlated to eczema development and blood eosinophil counts at 18 months of age. CONCLUSION: Early intestinal colonization by toxigenic S. aureus strains seems to promote systemic IgA responses. Furthermore, high levels of APRIL and IgA in the circulation at 4 months of age seem to correlate negatively with allergy development.

Could benefits of epidural analgesia following oesophagectomy be measured by perceived perioperative patient workload?

BACKGROUND: A controversy exists whether beneficial analgesic effects of epidural analgesia over intravenous analgesia influence the rate of post-operative complications and the length of hospital stay. There is some evidence that favours epidural analgesia following major surgery in high-risk patients. However, there is a controversy as to whether epidural analgesia reduces the intensive care resources following major surgery. In this study, we aimed at comparing the post-operative costs of intensive care in patients receiving epidural or intravenous analgesia. METHODS: Clinical data and rates of post-operative complications were extracted from a previously reported trial following thoraco-abdominal oesophagectomy. Cost data for individual patients included in that trial were retrospectively obtained from administrative records. Two separate phases were defined: costs of pain treatment and the direct cost of intensive care. RESULTS: Higher calculated costs of epidural vs. intravenous pain treatment, 1,037 vs. 410 Euros / patient, were outweighed by lower post-operative costs of intensive care 5,571 vs. 7,921 Euros / patient (NS). CONCLUSION: Higher costs and better analgesic effects of epidural analgesia compared with intravenous analgesia do not reduce total costs for post-operative care following major surgery.

Prediction of post-operative pain after a laparoscopic tubal ligation procedure.

BACKGROUND: Pre-operative identification of reliable predictors of post-operative pain may lead to improved pain management strategies. We investigated the correlation between pre-operative pain, psychometric variables, response to heat stimuli and post-operative pain following a laparoscopic tubal ligation procedure. METHODS: Assessments of anxiety, mood, psychological vulnerability and pre-operative pain were made before surgery using the State-Trait Anxiety Inventory (STAI), the Hospital Anxiety Depression Scale (HADS), a psychological vulnerability test and the Short-Form McGill Pain Questionnaire (SF-MPQ), respectively. Pre-operative assessments of thermal thresholds and pain response to randomized series of heat stimuli (1 s, 44-48 degrees C) were made with quantitative sensory testing technique. Post-operative pain intensity was evaluated daily by a visual analogue scale during rest and during standardized dynamic conditions for 10 days following surgery. Univariate and multivariate regression analyses were used to construct prediction models. RESULTS: Fifty-nine patients completed the study. Post-operative pain was significantly correlated with pre-operative pain (SF-MPQ), heat pain perception, psychological vulnerability, STAI and HADS. In the multiple regression model pre-operative pain and heat pain perception were significant predictive factors (R=0.537-0.609). CONCLUSION: The study indicates that pre-surgical pain and heat pain sensitivity are important pre-operative indicators of post-operative pain intensity, while psychological factors like vulnerability and anxiety seem to contribute to a lesser degree after laparoscopic tubal ligation. The prediction model accounted for 29-43% of the total variance in post-operative movement-related pain.

Increased levels of circulating soluble CD14 but not CD83 in infants are associated with early intestinal colonization with Staphylococcus aureus.

BACKGROUND: Soluble forms of the monocyte marker CD14 and the mature dendritic cell marker CD83 are plasma proteins with immunoregulatory functions. The physiological stimulus for their production is unclear and their possible role in allergy development is unknown. METHODS: We measured the plasma levels of soluble CD14 (sCD14) and soluble CD83 (sCD83) in 64 Swedish children in relation to intestinal bacterial colonization pattern in a prospective birth cohort. Soluble CD14 and sCD83 levels were quantified by enzyme linked immunosorbent assay in plasma obtained at birth and at 4, 18 and 36 months of age. All major aerobic and anaerobic bacteria were quantified in faecal samples obtained regularly over the first 8 weeks of life. Clinical allergy and IgE levels were evaluated at 18 months of age. RESULTS: Soluble CD14 in plasma increased during the first 18 months of life while sCD83 peaked at 4 months of age. Children who were perinatally colonized with Staphylococcus aureus had significantly higher levels of sCD14 in plasma at 4 months of age relative to non-colonized children. The levels of sCD14 were unrelated to colonization with Escherichia coli, other enterobacteria, enterococci, clostridia, Bacteroides, bifidobacteria or lactobacilli. Further, children with food allergy by 18 months tended to have lower levels of sCD14 than healthy children. Plasma levels of sCD83 were not related to either bacterial colonization pattern or allergy development. CONCLUSIONS: Perinatal colonization with S. aureus may trigger the occurrence of sCD14 in plasma, which may influence development of the infantile immune system and risk of allergy development.

FOXP3 identifies regulatory CD25bright CD4+ T cells in rheumatic joints.

Regulatory T cells have recently been implicated in a number of human diseases, including rheumatoid arthritis. To investigate whether the presence of CD25+CD4+ regulatory T cells is a general finding in arthritic joints, synovial fluid of patients with different rheumatic diseases such as undifferentiated arthritides, systemic rheumatic diseases and reactive arthritis were investigated for the presence of such cells. In 95% of the patients, a higher frequency of CD25(bright)CD4+ T cells was found in synovial fluid as compared with peripheral blood. Both in vitro suppression experiments and FOXP3 mRNA analysis confirmed these cells to be natural regulatory T cells. Together with our previous data, we conclude that arthritic joints, irrespective of precise diagnosis and disease duration, are enriched with natural regulatory T cells. These results suggest that suppressor cells migrate to and/or multiply at the sites of inflammation as part of the immune responses' effort to combat injurious inflammation.

Cat allergen induces proinflammatory responses by human monocyte-derived macrophages but not by dendritic cells.

BACKGROUND: The upper airway mucosa of healthy humans contains a dense network of cells with dendritic morphology of which the majority express a macrophage-like phenotype (CD14+CD64+CD68+), whereas the smaller population are immature dendritic cells (DC; CD11c+CD14-). Our aim was to study the proinflammatory response of human monocytes and in vitro-generated macrophages and DC after contact with cat allergens. METHODS: Monocyte-derived DC and monocyte-derived macrophages were exposed to cat allergen extract or Escherichia coli. Purified monocytes were stimulated with allergen extracts from cat or house dust mite (HDM) or the major allergenic protein Fel d 1 and induction of proinflammatory cytokines by monocytes was analyzed before and after blocking CD14. RESULTS: We show that cat allergen extract induced tumor necrosis factor (TNF) and interleukin (IL)-6 production by CD14-positive macrophages but not by CD14-negative DC. Moreover, monocytes produced significantly higher levels of TNF in response to cat allergens than in response to HDM allergens. We observed no differences in levels of TNF and IL-6 from either macrophages or monocytes after exposure to cat allergen when comparing healthy and cat-allergic individuals. Finally, the proinflammatory cytokine production from monocytes in response to cat allergen extract but not to HDM allergen was significantly reduced by blocking CD14. CONCLUSION: These results indicate that closely related innate immune cells from the myeloid lineage respond differentially to cat allergen extract and that the pattern-recognition receptor CD14 might be one of the mediators involved in the inflammatory responses to inhalant allergens.

CD4+CD25+-regulatory T cells from mouse to man.

Immunological tolerance is one of the fundamental concepts of the immune system. During the past decade, CD4+CD25+-regulatory T cells have emerged as key players in the development of tolerance to autoantigens as well as to foreign antigens. Still many questions remain illusive regarding the basic properties of CD4+CD25+-regulatory T cells. This review aims to recapitulate some of the current understandings about the phenotype, function and clinical relevance of murine and human CD4+CD25+-regulatory T cells.

Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season.

BACKGROUND: CD4(+)CD25+ regulatory T cells suppress proliferation and cytokine production by human T cells both to self-antigens and exogenous antigens. Absence of these cells in human newborns leads to multiple autoimmune and inflammatory disorders together with elevated IgE levels. However, their role in human allergic disease is still unclear. OBJECTIVE: This study aimed to evaluate the capacity of CD4(+)CD25+ regulatory T cells to suppress proliferation and cytokine production outside and during birch-pollen season in birch-allergic patients relative to non-allergic controls. METHODS: CD4+ cells were obtained from blood of 13 birch-allergic patients and six non-allergic controls outside pollen season and from 10 birch-allergic patients and 10 non-allergic controls during birch-pollen season. CD25+ and CD25- fractions were purified with magnetic beads and cell fractions, alone or together in various ratios, were cultured with antigen-presenting cells and birch-pollen extract or anti-CD3 antibody. Proliferation and levels of IFN-gamma, IL-13, IL-5 and IL-10 were measured by thymidin incorporation and ELISA, respectively. Numbers of CD25+ cells were analysed by flow cytometry. RESULTS: CD4(+)CD25+ regulatory T cells from both allergics and non-allergics potently suppressed T cell proliferation to birch allergen both outside and during birch-pollen season. However, during season CD4(+)CD25+ regulatory T cells from allergic patients but not from non-allergic controls were defective in down-regulating birch pollen induced IL-13 and IL-5 production, while their capacity to suppress IFN-gamma production was retained. In contrast, outside pollen season the regulatory cells of both allergics and non-allergic controls were able to inhibit T-helper 2 cytokine production. CONCLUSION: This is the first study to show differential suppression of Th1 and Th2 cytokines, with CD4(+)CD25+ regulatory T cells from birch-pollen-allergic patients being unable to down-regulate Th2, but not Th1 responses during birch-pollen season.

Pain relief and safety after major surgery. A prospective study of epidural and intravenous analgesia in 2696 patients.

BACKGROUND: Adverse effects may still limit the use of continuous epidural and intravenous analgesia in surgical wards. This study postulated that postoperative epidural analgesia was more efficient, and had fewer side-effects than intravenous morphine. The aim was to investigate efficacy, adverse effects and safety of the treatments in a large patient population. METHODS: During a five-year period 2696 patients undergoing major surgery, received either epidural or intravenous analgesia for postoperative pain relief. The patients were prospectively monitored in surgical wards. Pain was evaluated with a numeric rating scale (0-10) at rest/mobilization. Treatment duration, respiratory depression, sedation/hallucinations/nightmares/confusion, nausea/vomiting, pruritus, orthostatism/leg weakness, and insufficient pain relief were registered. Pain relief for all patients aimed at a pain scoring of less than 4 at rest. RESULTS: Epidural analgesia was used in 1670 patients, and intravenous morphine in 1026 patients. Patients with epidural analgesia experienced less pain both at rest and during mobilization. Insufficient treatment effects such as dose adjustments, orthostatism/leg weakness, and pruritus were more common in the epidural group. Respiratory depression and sedation/hallucinations/nightmares/confusion occurred more often in the intravenous group. Thoracic epidural catheters caused a lower incidence of motor blockade compared to lumbar catheter placements. CONCLUSION: In a large patient population the use of epidural and intravenous postoperative analgesia was considered safe in surgical wards, and the incidence of adverse effects was low. Patients with epidural analgesia experienced overall less pain, while opioid related side-effects were more common with intravenous morphine analgesia.

"Bystander" amplification of PBMC cytokine responses to seasonal allergen in polysensitized atopic children.

BACKGROUND: Atopic children show increased expression and production of the Th2-associated cytokines IL-4, IL-5, IL-13, and IL-9 from PBMCs after stimulation with allergen, but it has previously not been clearly determined whether the Th2-cytokine production is restricted to the inhalant allergen the child is sensitized to, and whether perennial or seasonal allergens induce different cytokine responses. Our purpose was to determine whether in vitro Th2 cytokine production is specific to the sensitizing allergen, and to compare the cytokine responses to a perennial and a seasonal allergen in monosensitized and polysensitized children. METHODS: Using semiquantitative RT-PCR, we analyzed the expression of the cytokines IL-4, IL-5, IL-13, IL-9, IL-10, and IFN-gamma after stimulation of PBMCs with house-dust-mite (HDM) or ryegrass allergen. The cells were sampled from groups of 6-year-old children sensitized to either HDM (n=20) or ryegrass (n=24), or to both allergens (n=20), as well as from a nonatopic group (n=20). RESULTS: After stimulation with HDM allergen, PBMCs from children sensitized only to HDM expressed increased mRNA levels of the Th2 cytokines, but not of IL-10 and IFN-gamma, whereas ryegrass stimulation did not result in increased cytokine expression. PBMCs from children sensitized to HDM and ryegrass expressed increased Th2 cytokines after stimulation with either of the two allergens. In contrast, PBMCs from children sensitized only to ryegrass did not express increased levels after stimulation with either of the allergens. CONCLUSIONS: The expression of Th2 cytokines after in vitro stimulation of PBMCs from atopic children is specific to the sensitizing allergen, indicating that atopic status per se does not affect the type of T-cell response. In addition, T cells specific to seasonal allergens circulate in the blood out of season only if the child is concomitantly sensitized to a perennial allergen.

Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans.

Sexually transmitted diseases are a major health problem worldwide, but there is still a lack of knowledge about how to induce an optimal immune response in the genital tract of humans. In this study we vaccinated 21 volunteers nasally or vaginally with the model mucosal antigen cholera toxin B subunit and determined the level of specific immunoglobulin A (IgA) and IgG antibodies in vaginal and cervical secretions as well as in serum. To assess the hormonal influence on the induction of antibody responses after vaginal vaccination, we administered the vaccine either independently of the stage in the menstrual cycle or on days 10 and 24 in the cycle in different groups of subjects. Vaginal and nasal vaccinations both resulted in significant IgA and IgG anti-cholera toxin B subunit responses in serum in the majority of the volunteers in the various vaccination groups. Only vaginal vaccination given on days 10 and 24 in the cycle induced strong specific antibody responses in the cervix with 58-fold IgA and 16-fold IgG increases. In contrast, modest responses were seen after nasal vaccination and in the other vaginally vaccinated group. Nasal vaccination was superior in inducing a specific IgA response in vaginal secretions, giving a 35-fold increase, while vaginal vaccination induced only a 5-fold IgA increase. We conclude that a combination of nasal and vaginal vaccination might be the best vaccination strategy for inducing protective antibody responses in both cervical and vaginal secretions, provided that the vaginal vaccination is given on optimal time points in the cycle.

Development of immunologic memory against tetanus toxoid and pertactin antigens from the diphtheria-tetanus-pertussis vaccine in atopic versus nonatopic children.

BACKGROUND: Recent findings suggest that a hallmark of the atopic phenotype is reduced capacity to respond to vaccine antigens, as well as to environmental allergens, during infancy. This deficiency, which is most marked for the cytokine IFN-gamma, appears transient but can result in a long-lasting imbalance within T helper cell (T(H)) memory responses to allergens. Indirect evidence suggests that parallel effects may occur within immunologic memory responses against vaccine antigens in atopic children. OBJECTIVE: Our purpose was to compare vaccine antigen-specific T(H) memory responses in atopic and nonatopic children. METHODS: We analyzed specific serum IgG and cytokine responses to pertactin and tetanus antigens as well as to mitogen (PHA) and house dust mite (HDM) allergen in 25 HDM-sensitized atopic and 25 nonatopic 6-year-old children who were vaccinated and boosted with diphtheria-tetanus-pertussis (DTP) vaccine. RESULTS: PBMCs from the atopic subjects produced higher levels of T(H)1 and T(H)2 cytokines to HDM allergen and PHA. Vaccine antibody titers were normal in the atopic subjects; vaccine-specific T(H)2 responses were rarely detectable, yet T(H)1 (IFN-gamma) responses, in particular against tetanus, were frequent and higher in the atopic subjects (121.5 [SE 64.3] vs 8.0 [3.5] pg/mL culture fluid, P =.04). Corresponding pertactin responses were comparable in both groups. CONCLUSIONS: At the completion of the full primer-booster DTP vaccination regimen, levels of vaccine-specific immunity in atopic 6-year-old children are at least equivalent to their nonatopic counterparts, indicating that the transient atopy-associated deficiency in T(H)1 function in childhood can be successfully overcome by appropriate vaccination and boosting regimens.

Antibody responses in the lower respiratory tract and male urogenital tract in humans after nasal and oral vaccination with cholera toxin B subunit.

Nasal vaccine delivery is superior to oral delivery in inducing specific immunoglobulin A (IgA) and IgG antibody responses in the upper respiratory tract. Although an antibody response in the nasal passages is important in protecting against primary colonization with lung pathogens, antibodies in the lungs are usually required as well. We immunized 15 male volunteers twice nasally or orally with cholera toxin B subunit (CTB) and determined the specific antibody levels in serum, bronchoalveolar lavage (BAL) fluid, and urine before and 2 weeks after immunization. Nasal immunization induced fivefold increases in the levels of specific IgA antibodies in BAL fluid of most volunteers, whereas there were no significant specific IgA responses after oral immunization. The specific IgG antibody level increased eightfold in BAL fluid in the nasally vaccinated subjects, and the major part of IgG had most probably been transferred from serum. Since the specific IgG response in serum was lower in the individuals vaccinated orally, the IgG response in BAL fluid in this group was also lower and not significant. In conclusion, nasal immunization is also preferable to the oral route when vaccinating against lower respiratory tract infections, and a systemic immune response is considerably more important in the lower than in the upper respiratory tract. Moreover, both nasal and oral immunizations were able to stimulate 6- to 10-fold specific IgA and IgG responses in urine in about half of the individuals, which indicates that distant mucosal vaccination might be used to prevent adhesion of pathogens to the urogenital tract.