The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach.
Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks.
After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions.
Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants.
asthma; Bayesian network; genetic association; eczema; innate immunity
A vaginal gel containing 1% tenofovir (TFV) was found to be safe and effective in reducing HIV infection in women when used pericoitally. Because of the long intracellular half-life of TFV and high drug exposure in vaginal tissues, we hypothesized that a vaginal gel containing TFV may provide long-lasting protection. Here, we performed delayed-challenge experiments and showed that vaginal 1% TFV gel protected 4/6 macaques against vaginal simian-human immunodeficiency virus (SHIV) exposures occurring 3 days after gel application, demonstrating long-lasting protection. Despite continued gel dosing postinfection, neither breakthrough infection had evidence of drug resistance by ultrasensitive testing of SHIV in plasma and vaginal lavage. Analysis of the active intracellular tenofovir diphosphate (TFV-DP) in vaginal lymphocytes collected 4 h to 3 days after gel dosing persistently showed high TFV-DP levels (median, 1,810 fmol/106 cells) between 4 and 24 h that exceed the 95% inhibitory concentration (IC95), reflecting rapid accumulation and long persistence. In contrast to those in peripheral blood mononuclear cells (PBMCs) following oral dosing, TFV-DP levels in vaginal lymphocytes decreased approximately 7-fold by 3 days, exhibiting a much higher rate of decay. We observed a strong correlation between intracellular TFV-DP in vaginal lymphocytes, in vitro antiviral activity, and in vivo protection, suggesting that TFV-DP above the in vitro IC95 in vaginal lymphocytes is a good predictor of high efficacy. Data from this model reveal an extended window of protection by TFV gel that supports coitus-independent use. The identification of protective TFV-DP concentrations in vaginal lymphocytes may facilitate the evaluation of improved delivery methods of topical TFV and inform clinical studies.
Letrozole, a selective aromatase inhibitor, reduces the total dose of gonadotrophin required for inducing follicular maturation. We evaluated if incorporation of letrozole could be an effective alternative for low-cost in vitro fertilization (IVF) protocol particularly in intracytoplasmic sperm injection (ICSI) cycles where male factor infertility is the sole indication for IVF.
MATERIALS AND METHODS:
It is a randomized controlled single-blind trial. 94 women with history of severe male factor infertility were selected. 42 women (study group) received letrozole, 5 mg daily from day 3-7 and recombinant FSH (rFSH) 75IU/day from day 5 continuously till hCG injection. 52 women (control group) underwent continuous stimulation by rFSH (150-225IU/day) from day 2. GnRH-antagonist (Inj. Orgalutran 0.25 ml sub-cutaneous) was started at maximum follicle size of 14 in both groups. Ovulation was triggered by 10,000IU of hCG followed by IVF-ET. Main outcome measures were total dose of rFSH (IU/cycle), terminal E2 (pg/ml), number of mature follicles, number of oocyte retrieved, transferable embryo, endometrial thickness, pregnancy rate and mean expenditure. Statistical analysis is done by using SPSS11.
As compared to control group (1756 ± 75IU), the study group i.e., Let-rFSH received (625 ± 98IU) significantly lower (P = 0.0001) total dose of rFSH. Terminal E2 was significantly lower (P = 0.0001) in study group than control (830 ± 36 vs. 1076 ± 41 pg/ml) with significant increment in endometrial thickness (P = 0.0008) in study group, (9.1 ± 0.32 vs. 8.7 ± 0.69) which maintained an improved pregnancy rate though nonsignificant. The risk of hyperstimulation had significantly (P = 0.01) reduced in study group than control (0 vs. 7).Treatment outcome in all other aspects including pregnancy rate were statistically comparable. Per cycle mean expenditure was reduced by 34% in study group than control.
Adjunctive use of letrozole may be an effective mean of low-cost IVF therapy.
Antagonist; ICSI; letrozole; low-cost IVF; male factor infertility
The aim of this study is to examine meiotic spindle in oocytes along with reactive oxygen species (ROS) levels in follicular fluid of women undergoing IVF and to correlate these findings with embryo quality and pregnancy outcome.
MATERIALS AND METHODS:
167 women aged 25–35 years with endometriosis (Group A), polycystic ovarian syndrome (PCOS) (Group B) and tubal block (Group C) were included. Long protocol downregulation using recombinant follicular stimulating hormone was used for ovarian stimulation. Aspirated follicular fluid containing mature oocytes were analyzed for ROS levels and the oocytes were assessed for the presence of meiotic spindle using Cri-Oosight™ Polscope. Fertilization, embryo quality, endometrial assessment, and final pregnancy outcome were assessed.
Meiotic spindles were visualized in a higher proportion of mature oocytes retrieved from women with endometriosis (66%) as compared to those with PCOS (50.5%) and tubal block (62.3%). ROS levels were also observed to be significantly less in the follicular fluid of oocytes in women with endometriosis (Group A) as compared to the other two groups (P ≤ 0.001). However, pregnancy rates were observed to be lower in Group A (32%) than Groups B (39%) and C (44%), respectively. Within each group, oocytes with spindle visualization yielded a higher number of Grade 1 embryos (P < 0.05) as well as lower ROS levels in follicular fluid (P ≤ 0.001) as compared to those where spindle could not be visualized.
There was good correlation between spindle imaging and ROS levels as reliable predictors of oocyte assessment. Women with endometriosis had low ROS levels and good spindle imaging results suggesting a possible role of endometrial receptivity accounting for lower pregnancy rates in these women. Poor oocyte quality, as reflected by higher mean ROS levels and low number of oocytes with spindle visualization, could be the factor impeding pregnancy in women with PCOS as compared to women with tubal block.
Endometriosis; meiotic spindle imaging; oocyte quality; PCOS; reactive oxygen species
Polymorphisms in the endotoxin-mediated TLR4 pathway genes have been associated with asthma and atopy. We aimed to examine how genetic polymorphisms in innate immunity pathways interact with endotoxin to influence asthma risk in children.
In a previous analysis of 372 children from the Boston Home Allergens and the Connecticut Childhood Asthma studies, 7 SNPs in 6 genes (CARD15, TGFB1, LY96, ACAA1, DEFB1 and IFNG) involved in innate immune pathways were associated with asthma, and 5 SNPs in 3 genes (CD80, STAT4, IRAK2) were associated with eczema. We tested these SNPs for interaction with early life endotoxin exposure (n = 291), in models for asthma and eczema by age 6.
We found a significant interaction between endotoxin and a SNP (rs156265) in ACAA1 (p = 0.0013 for interaction). Increased endotoxin exposure (by quartile) showed protective effects for asthma in individuals with at least one copy of the minor allele (OR = 0.39 per quartile increase in endotoxin, 95% CI 0.15 to 1.01). Endotoxin exposure did not reduce the risk of asthma in children homozygous for the major allele.
Our findings suggest that protective effects of endotoxin exposure on asthma may vary depending upon the presence or absence of a polymorphism in ACAA1.
Wilson’s disease is a rare inherited disorder of copper metabolism causing severe damage to vital organs. Liver and brain disorders are the main manifestations. Severe hemolytic anemia is an unusual complication of Wilson’s disease. We present a case who developed spherocytic acute hemolytic anemia (Coomb’s negative) as the initial manifestation of Wilson’s disease. On examination Kayser- Fleischer ring was found. Laboratory data supported a diagnosis of Wilson’s disease.
Wilson’s disease (WD); Spherocytic anemia
Perivascular epithelioid cell tumors are a family of rare mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. They can originate in any visceral organ or soft tissue and include a range of lesions such as angiomyolipoma, clear cell 'sugar' tumor of the lung, lymphangioleiomyomatosis and clear cell myomelanocytic tumors of the falciparum ligament/ligament teres. Due to their rarity and varied sites and presentation, management of these tumors remains highly challenging.
A 46-year-old para 2 Caucasian woman initially presented to the general surgeons at our hospital in North West London with abdominal pain. Laparoscopy revealed a right broad ligament hematoma, which was thought to be iatrogenic in origin, from insertion of the Veress needle at the time of surgery, and was managed conservatively. Upon her re-presentation two months later with severe pain, ultrasound scanning revealed the hematoma had increased in size and she underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histology results from necrotic tissue from the hematoma led to a diagnosis of perivascular epithelioid cell tumor. She was then referred to a tertiary oncology center, where she underwent several further operations in an attempt to debulk the tumor for symptomatic relief of her pain, with limited success. She is now taking the immunosuppressive drug sirolimus, which has produced a modest reduction in tumor size. She is now 47 months on from initial presentation.
A literature search has revealed only six other case reports of broad ligament perivascular epithelioid cell tumors, with varied presentations and management. The longest duration of follow-up was 21 months. Only five other cases of perivascular epithelioid cell tumor managed with sirolimus have been reported. We therefore feel that this report highlights some of the difficulties in diagnosing perivascular epithelioid cell tumors, and sheds light on management strategies for a very rare gynecological tumor in addition to sharing our experience in the use of sirolimus in its treatment.
The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis.
Methods and Principal Findings
In this study, a comparison of intranasal (i.n.) and subcutaneous (s.c.) vaccination with the BCG vaccine demonstrated that a single moderate dose delivered intranasally induced a stronger and sustained M. tuberculosis-specific T-cell response in lung parenchyma and cervical lymph nodes of BALB/c mice than vaccine delivered subcutaneously. Both BCG and a multicomponent subunit vaccine composed of nine M. tuberculosis recombinant proteins induced strong antigen-specific T-cell responses in various local and peripheral immune compartments. Among the nine recombinant proteins evaluated, the alanine proline rich antigen (Apa, Rv1860) was highly antigenic following i.n. BCG and immunogenic after vaccination with a combination of the nine recombinant antigens. The Apa-induced responses included induction of both type 1 and type 2 cytokines in the lungs as evaluated by ELISPOT and a multiplexed microsphere-based cytokine immunoassay. Of importance, i.n. subunit vaccination with Apa imparted significant protection in the lungs and spleen of mice against M. tuberculosis challenge. Despite observed differences in the frequencies and location of specific cytokine secreting T cells both BCG vaccination routes afforded comparable levels of protection in our study.
Conclusion and Significance
Overall, our findings support consideration and further evaluation of an intranasally targeted Apa-based vaccine to prevent tuberculosis.
The association of systemic lupus erythematosus (SLE) and myeloproliferative and lymphoproliferative malignancies is widely reported. There is scarce information available with regards to the association of SLE and malignancy in children. Usually, SLE precedes the onset of lymphoproliferative disease, but the neoplasia can occur earlier or even simultaneously. There are only five pediatric cases of SLE and associated acute lymphoblastic leukemia (ALL) reported in literature. All of these except one satisfied the revised American College of Rheumatology Criteria for SLE. Three of these cases developed SLE several years after successful treatment of ALL. While two cases reported had simultaneous onset of SLE and ALL, one of the cases in this two-patient series, did not fulfill ≥4 criteria for diagnosis of SLE. We present a case of a 3-year-old boy with SLE and coexistent ALL. To the best of our knowledge, only two such cases of simultaneous presentation of both these diseases are present in literature.
Acute lymphoblastic leukemia; myeloproliferative disorder; systemic lupus erythematosus
Little is known about the role of most asthma susceptibility genes during human lung development. Genetic determinants for normal lung development are not only important early in life, but also for later lung function.
To investigate the role of expression patterns of well-defined asthma susceptibility genes during human and murine lung development. We hypothesized that genes influencing normal airways development would be over-represented by genes associated with asthma.
Asthma genes were first identified via comprehensive search of the current literature. Next, we analyzed their expression patterns in the developing human lung during the pseudoglandular (gestational age, 7-16 weeks) and canalicular (17-26 weeks) stages of development, and in the complete developing lung time series of 3 mouse strains: A/J, SW, C57BL6.
In total, 96 genes with association to asthma in at least two human populations were identified in the literature. Overall, there was no significant over-representation of the asthma genes among genes differentially expressed during lung development, although trends were seen in the human (Odds ratio, OR 1.22, confidence interval, CI 0.90-1.62) and C57BL6 mouse (OR 1.41, CI 0.92-2.11) data. However, differential expression of some asthma genes was consistent in both developing human and murine lung, e.g. NOD1, EDN1, CCL5, RORA and HLA-G. Among the asthma genes identified in genome wide association studies, ROBO1, RORA, HLA-DQB1, IL2RB and PDE10A were differentially expressed during human lung development.
Our data provide insight about the role of asthma susceptibility genes during lung development and suggest common mechanisms underlying lung morphogenesis and pathogenesis of respiratory diseases.
Asthma; Development; Expression; Genetics; Lung
The relationships between total serum IgE levels and gene expression patterns in peripheral blood CD4+ T cells (in all subjects and within each sex specifically) are not known.
Peripheral blood CD4+ T cells from 223 participants from the Childhood Asthma Management Program (CAMP) with simultaneous measurement of IgE. Total RNA was isolated, and expression profiles were generated with Illumina HumanRef8 v2 BeadChip arrays. Modeling of the relationship between genome-wide gene transcript levels and IgE levels was performed in all subjects, and stratified by sex.
Among all subjects, significant evidence for association between gene transcript abundance and IgE was identified for a single gene, the interleukin 17 receptor B (IL17RB), explaining 12% of the variance (r2) in IgE measurement (p value = 7 × 10-7, 9 × 10-3 after adjustment for multiple testing). Sex stratified analyses revealed that the correlation between IL17RB and IgE was restricted to males only (r2 = 0.19, p value = 8 × 10-8; test for sex-interaction p < 0.05). Significant correlation between gene transcript abundance and IgE level was not found in females. Additionally we demonstrated substantial sex-specific differences in IgE when considering multi-gene models, and in canonical pathway analyses of IgE level.
Our results indicate that IL17RB may be the only gene expressed in CD4+ T cells whose transcript measurement is correlated with the variation in IgE level in asthmatics. These results provide further evidence sex may play a role in the genomic regulation of IgE.
Upper extremity deep vein thrombosis commonly refers to thrombosis of the axillary and/or subclavian veins. This condition may lead to some serious complications like pulmonary embolism if the diagnosis and treatment are delayed. We introduce here one such case where the diagnosis of this rare condition was difficult because of the atypical clinical manifestation but the chylous ascites provided a valuable clue which led to early diagnosis and treatment of this patient.
Chylous ascites; Paget-Schroetter syndrome; upper extremity deep vein thrombosis
Rationale: Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.
Objectives: We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma.
Methods: Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV1, FVC, and FEV1/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study.
Measurements and Main Results: Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7–16 wk) and the canalicular (gestational age: 17–26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P < 0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV1 (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV1/FVC (combined P = 0.003).
Conclusions: Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma.
asthma; lung development; lung function; genetic variation; gene expression
Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion.
We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of asthmatic children in Costa Rica. Significant findings were replicated in white and African-American participants in the Childhood Asthma Management Program, in African Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children’s Health Study, and in whites in the Framingham Heart Study (FHS).
Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (p values of 2×10−5 and 1×10−5, respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (p= 3×10−6). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (p= 2×10−4). Findings for rs2289276 were consistent in all cohorts except the FHS.
TSLP variants are associated with asthma in a sex-specific fashion.
asthma; genetic association; sex-specific; thymic stromal lymphopoietin; TSLP
The glutathione S-transferase M1 (GSTM1) null variant is a common copy number variant associated with adverse pulmonary outcomes, including asthma and airflow obstruction, with evidence of important gene-by-environment interactions with exposures to oxidative stress.
To explore the joint interactive effects of GSTM1 copy number and tobacco smoke exposure on the development of asthma and asthma-related phenotypes in a family-based cohort of childhood asthmatics.
We performed quantitative PCR-based genotyping for GSTM1 copy number in children of self-reported white ancestry with mild to moderate asthma in the Childhood Asthma Management Program. Questionnaire data regarding intrauterine (IUS) and postnatal, longitudinal environmental tobacco smoke exposure were available. We performed both family-based and population-based tests of association for the interaction between GSTM1 copy number and tobacco smoke exposure with asthma and asthma-related phenotypes.
Associations of GSTM1 null variants with asthma (p= .03), younger age of asthma symptom onset (p=.03), and greater airflow obstruction (reduced FEV1/FVC, p=.01) were observed among the 50 children (10% of the cohort) with exposure to IUS. In contrast, no associations were observed between GSTM1 null variants and asthma-related phenotypes among children without IUS exposure. Presence of at least one copy of GSTM1 conferred protection.
These findings support an important gene-by-environment interaction between two common factors: increased risk of asthma and asthma-related phenotypes conferred by GSTM1-null homozygosity in children is restricted to those with a history of IUS exposure.
Asthma; GSTM1; copy number variation (CNV); gene by environment; intrauterine smoke exposure; tobacco smoke
Among asthmatics, bronchodilator response (BDR) to inhaled ß2- adrenergic agonists is variable, and the significance of a consistent response over time is unknown.
We assessed baseline clinical variables and determined the clinical outcomes associated with a consistently positive BDR over 4 years in children with mild-moderate persistent asthma.
In the 1,041 participants in the Childhood Asthma Management Program (CAMP), subjects with a change in FEV1 of 12% or greater (and 200mLs) after inhaled ß2 agonist at each of their yearly follow-up visits (consistent BDR) were compared with those who did not have a consistent BDR.
We identified 52 children with consistent BDR over the 4-year trial. Multivariable logistic regression modeling demonstrated that baseline pre-bronchodilator FEV1 (OR=0.71, p<0.0001), log 10 IgE level (OR=1.97, p=0.002), and lack of treatment with inhaled corticosteroids (OR=0.31, p=0.009) were associated with a consistent BDR. Individuals who had a consistent BDR had more hospital visits (p=0.007), required more prednisone bursts (p=0.0007), had increased nocturnal awakenings due to asthma (p<0.0001), and missed more days of school (p=0.03) than non-responders during the 4-year follow-up.
We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.
asthma; consistent bronchodilator response; outcomes
A large prospective clinical trial was conducted to compare the efficacy of single dose uFSH and clomiphene citrate combination with clomiphene citrate alone for ovulation induction to improve the pregnancy rate.
MATERIALS AND METHODS:
The study was a randomized, prospective clinical trial. Totally, 1527 infertile women (4381 cycles) with polycystic ovarian syndrome (PCOS) (n=911/2573 cycles) and unexplained infertility (n=616/1808 cycles) were randomized into two groups. Group A received single dose of uFSH on D3 of menstrual cycle along with clomiphene. Group B received clomiphene only for ovulation induction. We compared the pregnancy rate and miscarriage rate between two groups.
Group A had a pregnancy rate of 17% compared to 8.3% of Group B which was significantly higher (P=0.0001). The miscarriage rate was 11% in Group A and 10% in Group B which was not significant (P=0.99). Pregnancy rates in PCOS women were 22% in Group A and 9.3% in Group B which shows significantly higher pregnancy rate (P=0.0001) in anovulatory infertility. But in unexplained infertility, there was no significant difference in pregnancy rate between Group A (11%) and Group B(6.3%). Miscarriage rates were 8.8% and 9.5% in Group A and Group B, respectively, in PCOS women and 14% and 13% in women with unexplained infertility.
Addition of single dose of uFSH improves pregnancy outcome particularly in anovulatory infertility (WHO II). Correction of unexplained infertility may need more than simple correction of possible subtle ovulatory effect.
Clomiphene citrate; fecundity; miscarriage; ovulation induction; uFSH
New-generation gels that deliver potent antiretroviral drugs against human immunodeficiency virus type 1 have renewed hopes for topical prophylaxis as a prevention strategy. Previous preclinical research with monkey models suggested that high concentrations and drug combinations are needed for high efficacy. We evaluated two long-acting reverse transcriptase inhibitors, tenofovir (TFV) and emtricitabine (FTC), by using a twice-weekly repeat challenge macaque model and showed that a preexposure vaginal application of gel with 1% TFV alone or in combination with 5% FTC fully protected macaques from a total of 20 exposures to simian-human immunodeficiency virus SF162p3. FTC and TFV were detected in plasma 30 min after vaginal application, suggesting rapid absorption. FTC was detected more frequently than TFV and showed higher levels, reflecting the fivefold-higher concentration of this drug than of TFV. Two of 12 repeatedly exposed but protected macaques showed limited T-cell priming, which did not induce resistance to infection when macaques were rechallenged. Thus, single drugs with durable antiviral activity can provide highly effective topical prophylaxis and overcome the need for noncoital use or for drug combinations which are more complex and costly to formulate and approve.
Rationale: Polymorphisms in the gene for transforming growth factor-β1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma.
Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood.
Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity.
Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P = 0.0006) and CAMP (P = 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P ≤ 0.01). Dust mite exposure modified the effect of the C allele of exonic SNP rs1800471 on airway responsiveness (P = 0.03 for interactions in both cohorts). The T allele of a coding SNP (rs1982073) was associated with a reduced risk of asthma exacerbations in Costa Rica (P = 0.009) and CAMP (P = 0.005). Dust mite exposure also significantly modified the effect of the A allele of the promoter SNP rs2241712 on asthma exacerbations in both cohorts.
Conclusions: SNPs in TGFB1 are associated with airway responsiveness and disease exacerbations in children with asthma. Moreover, dust mite exposure may modify the effect of TGFB1 SNPs on airway responsiveness and asthma exacerbations.
airway responsiveness; asthma; dust mite allergen; single nucleotide polymorphisms; transforming growth factor-β1
Endocrine mutant mice have proven invaluable toward the quest to uncover mechanisms underlying longevity. Growth hormone (GH) and insulin like-growth factor (IGF) have been shown to be key players in physiological systems that contribute to aging processes including glucose metabolism, body composition and cellular protection. Examination of these mutant mice across several laboratories has revealed that differences exist in both the direction and magnitude of change, differences that may result in variation in life span. Growth hormone receptor knock out mice lack a functional GH receptor, therefore GH signaling is absent. These mice have been shown to lack the heightened oxidative defense mechanisms observed in other GH mutants yet live significantly longer than wild type mice. In this study, glutathione (GSH) and methionine (MET) metabolism was examined to determine the extent of variation in this mutant in comparison to the Ames dwarf, a mouse that exhibits delayed aging and life span extension of nearly 70%. Components of GSH and MET were altered in GHR KO compared to wild type controls. The results of these experiments suggest that these pathways may be partially responsible for differences observed in stress resistance and the capacity to respond to stressors, that in the long term, affect health and life span.
aging; metabolism; glutathione; methionine; stress resistance
Hypercholesterolemia increases levels of β-amyloid (Aβ), a peptide that accumulates in Alzheimer’s disease brains. Because cholesterol in the blood does not cross the blood brain barrier (BBB), the link between circulating cholesterol and Aβ accumulation is not understood. In contrast to cholesterol, the oxidized cholesterol metabolite 27-hydroxycholestrol can cross the BBB, potentially increasing Aβ levels. However, the mechanisms by which cholesterol or 27-hydroxycholesterol regulate Aβ levels are not known. The insulin-like growth factor-1 (IGF-1) regulates the glycogen-synthase kinase-3α (GSK-3α) and the insulin degrading enzyme (IDE). While GSK-3α increases Aβ production, IDE is a major Aβ-degrading enzyme. We report here that feeding rabbits with a cholesterol-enriched diet increases Aβ levels in the hippocampus, an effect that is associated with reduced IGF-1 levels. 27-hydroxycholestrol also increases Aβ and reduces IGF-1 levels in organotypic hippocampal slices from adult rabbits. We suggest that hypercholesterolemia-induced Aβ accumulation may be mediated by 27-hydroxycholesterol, involving IGF-1 signaling.
Akt; Alzheimer's disease; β-amyloid; Cholesterol; CREB; GSK-3α; hippocampus; insulin degrading enzyme; 27-hydroxycholesterol
Modified vaccinia Ankara (MVA) is being tested in humans as an alternative to the current smallpox vaccine Dryvax. Here, we compare the magnitude and longevity of protective immune responses elicited by a DNA/MVA HIV-1 vaccine with those elicited by Dryvax using a monkeypox virus/macaque model. The DNA/MVA vaccine elicited similar levels of vaccinia virus (VV)-specific antibody and 5–10-fold lower levels of VV-specific cellular responses than Dryvax. This MVA-elicited cellular and humoral immunity was long lived. A subset of the DNA/MVA - and Dryvax- vaccinated macaques were subjected to a lethal monkeypox virus challenge at 3 years after vaccination. All of the vaccinated monkeys survived, whereas the unvaccinated controls succumbed to monkeypox. The viral control correlated with early post challenge levels of monkeypox-specific neutralizing antibody but not with VV-specific cellular immune response. Thus, our results demonstrate the elicitation of long lasting protective immunity for a lethal monkeypox challenge by a DNA/MVA HIV-1 vaccine.
HIV; Modified vaccinia virus Ankara; DNA/MVA vaccine; Smallpox; Monkeypox; CD8 T cells; Rhesus macaque
In this study, we monitored the temporal breadths, frequencies, and functions of antiviral CD4 and CD8 T cells in 2 of 22 DNA/modified vaccinia virus Ankara-vaccinated macaques that lost control of a simian-human immunodeficiency virus 89.6P challenge by 196 weeks postchallenge. Our results show that both mutation and exhaustion contributed to escape. With the reappearance of viremia, responding CD8 and CD4 T cells underwent an initial increase and then loss of breadth and frequency. Antiviral gamma interferon (IFN-γ)- and interleukin 2-coproducing cells were lost before IFN-γ-producing cells and CD4 cells before CD8 cells. At euthanasia, all CD8, but no CD4, Gag epitopes detected during long-term control contained mutations.