Mesenchymal stem cells (MSCs) are multipotent progenitors that can undergo osteogenic differentiation under proper stimuli. We demonstrated that BMP9 is one of the most osteogenic BMPs. However, the molecular mechanism underlying BMP9-initiated osteogenic signaling in MSCs remains unclear. Through gene expression profiling analysis we identified several candidate mediators of BMP9 osteogenic signaling. Here, we focus on one such signaling mediator and investigate the functional role of cysteine-rich with EGF-like domains 2 (Creld2) in BMP9-initiated osteogenic signaling. Creld2 was originally identified as an ER stress-inducible factor localized in the ER-Golgi apparatus. Our genomewide expression profiling analysis indicates that Creld2 is among the top up-regulated genes in BMP9-stimulated MSCs. We confirm that Creld2 is up-regulated by BMP9 in MSCs. ChIP analysis indicates that Smad1/5/8 directly binds to the Creld2 promoter in a BMP9-dependent fashion. Exogenous expression of Creld2 in MSCs potentiates BMP9-induced early and late osteogenic markers, and matrix mineralization. Conversely, silencing Creld2 expression inhibits BMP9-induced osteogenic differentiation. In vivo stem cell implantation assay reveals that exogenous Creld2 promotes BMP9-induced ectopic bone formation and matrix mineralization, whereas silencing Creld2 expression diminishes BMP9-induced bone formation and matrix mineralization. We further show that Creld2 is localized in ER and the ER stress inducers potentiate BMP9-induced osteogenic differentiation. Our results strongly suggest that Creld2 may be directly regulated by BMP9 and ER stress response may play an important role in regulating osteogenic differentiation.
Certain saponins are bioactive compounds with anticancer, antivirus and antioxidant activities. This paper discussed inhibitory effects of saponins from Xanthoceras Sorbifolia on tyrosinase, through the research of the rate of tyrosinase catalyzed L-DOPA oxidation. The inhibition rate of tyrosinase activity presented non-linear changes with the saponins concentration. The rate reached 52.0% when the saponins concentration was 0.96 mg/ml. Antioxidant activities of saponins from Xanthoceras Sorbifolia were evaluated by using hydroxyl and superoxide radical scavenging assays. The hydroxyl radical scavenging effects of the saponins were 15.5–68.7%, respectively at the concentration of 0.18–2.52 mg/ml. The superoxide radical scavenging activity reduced from 96.6% to 7.05% with the time increasing at the concentration of 1.44 mg/ml. All the above antioxidant evaluation indicated that saponins from Xanthoceras Sorbifolia exhibited good antioxidant activity in a concentration- dependent manner.
Parent of origin effect is important in understanding the genetic basis of childhood allergic diseases and to improve our ability to identify high risk children.
To investigate parent of origin effect in childhood allergic diseases.
The Isle of Wight Birth Cohort (n=1,456) has been examined at 1, 2, 4, 10 and 18-years. Information on prevalence of asthma, eczema, rhinitis and environmental factors was obtained using validated questionnaires. Skin prick tests were carried out at ages 4, 10 and 18 year, and total IgE at 10 and 18 years. Parental history of allergic disease was assessed soon after the birth of the child when maternal IgE was also measured. Prevalence ratios (PR) and their 95% confidence intervals (CI) were estimated, applying log-linear models, adjusted for confounding variables.
When stratified for sex of the child, maternal asthma was associated with asthma in girls [PR:1.91 (CI:1.34–2.72), p=0.0003], but not in boys [PR:1.29 (CI:0.85–1.96), p=0.23), while paternal asthma was associated with asthma in boys [PR:1.99 (CI:1.42–2.79), p<0.0001], but not in girls [PR: 1.03 (0.59–1.80) p=0.92). Maternal eczema increased the risk of eczema in girls [PR: 1.92 (CI: 1.37–2.68); p=0.0001] only, while paternal eczema did the same for boys (PR: 2.07 (CI:1.32–3.25); P=0.002). Similar trends were observed when the effect of maternal and paternal allergic disease was assessed for childhood atopy and when maternal total IgE was related to total IgE in children at age 10 and 18 years.
The current study indicates a sex dependent association of parental allergic conditions with childhood allergies; maternal allergy increasing the risk in girls and paternal allergy in boys. This has implications for childhood allergy prediction and prevention.
maternal; paternal; sex; cohort; parent of origin; atopy; asthma; eczema; rhinitis; allergy; IgE
Eczema is a prevalent skin disease that is mainly characterized by systemic deviation of immune response and defective epidermal barrier. Th2 cytokines, such as IL-13 and transcription factor STAT6 are key elements in the inflammatory response that characterize allergic disorders, including eczema. Previous genetic association studies showed inconsistent results for the association of single nucleotide polymorphisms (SNPs) with eczema. Our aim was to investigate whether SNPs in IL13 and STAT6 genes, which share a biological pathway, have an interactive effect on eczema risk.
Data from two independent population-based studies were analyzed, namely the Isle of Wight birth cohort study (IOW; n = 1,456) and for the purpose of replication the Swansea PAPA (Poblogaeth Asthma Prifysgol Abertawe; n = 1,445) cross-sectional study. Log-binomial regressions were applied to (i) account for the interaction between IL13 (rs20541) and STAT6 (rs1059513) polymorphisms and (ii) estimate the combined effect, in terms of risk ratios (RRs), of both risk factors on the risk of eczema.
Under a dominant genetic model, the interaction term [IL13 (rs20541) × STAT6 (rs1059513)] was statistically significant in both studies (IOW: adjusted Pinteraction = 0.046; PAPA: Pinteraction = 0.037). The assessment of the combined effect associated with having risk genotypes in both SNPs yielded a 1.52-fold increased risk of eczema in the IOW study (95% confidence interval (CI): 1.05 – 2.20; P = 0.028) and a 2.01-fold higher risk of eczema (95% CI: 1.29 – 3.12; P = 0.002) in the PAPA study population.
Our study adds to the current knowledge of genetic susceptibility by demonstrating for the first time an interactive effect between SNPs in IL13 (rs20541) and STAT6 (rs1059513) on the occurrence of eczema in two independent samples. Findings of this report further support the emerging evidence that points toward the existence of genetic effects that occur via complex networks involving gene-gene interactions (epistasis).
Eczema; Gene-gene Interaction; Epistasis; STAT6; IL13; Genetic Association Study
Neovascularization (NV) in the cornea is a major cause of vision impairment and corneal blindness. Hemangiogenesis and lymphangiogenesis induced by inflammation underlie the pathogenesis of corneal NV. The current mainstay treatment, corticosteroid, treats the inflammation associated with corneal NV, but is not satisfactory due to such side effects as cataract and the increase in intraocular pressure. It is imperative to develop a novel therapy that specifically targets the hemangiogenesis, lymphangiogenesis and inflammation pathways underlying corneal NV. Histone deacetylase inhibitors (HDACi) have been in clinical trials for cancer and other diseases. In particular, HDACi suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) has been approved by the FDA for the treatment of cutaneous T-cell lymphoma. The functional mechanism of SAHA in cancer and especially in corneal NV remains unclear. Here, we show that topical application of SAHA inhibits neovascularization in an alkali-burn corneal injury model. Mechanistically, SAHA inhibits corneal NV by repressing hemangiogenesis, inflammation pathways and previously overlooked lymphangiogenesis. Topical SAHA is well tolerated on the ocular surface. In addition, the potency of SAHA in corneal NV appears to be comparable to the current steroid therapy. SAHA may possess promising therapeutic potential in alkali-burn corneal injury and other inflammatory neovascularization disorders.
corneal neovascularization; HDAC; HDAC inhibitor; hemangiogenesis; lymphangiogenesis; inflammation; alkali-burn injury
To determine whether DNA methylation (DNA-M) of the leptin receptor genotype (LEPR/LEPROT) links gestational smoking and leptin serum levels and BMI later in life, we focused on female offspring, 18 years of age, from the Isle of Wight Birth Cohort (IOWBC). Leptin binds to the leptin receptor encoded by the LEPR/LEPROT genotype. Using general linear models, we tested a two-stage model. First, we investigated whether single nucleotide polymorphisms (SNPs) acting as methylation quantitative trait loci (methQTLs) depending on gestational smoking were related to differentially methylated cytosine-phosphate-guanine (CpG) sites. In stage 2, we tested whether the selected CpG sites, in interaction with other SNPs (modifiable genetic variants, modGV), are associated with serum leptin and BMI (stage 2). Children from the IOWBC were followed from birth to age 18. Information on gestational smoking was gathered upon delivery. SNPs tagging LEPR and LEPROT genes were genotyped. Data on LEPR/LEPROT DNA-M and leptin were obtained from blood samples drawn at age 18; to determine BMI, height and weight were ascertained. Blood samples were provided by 238 girls. Of the 21 CpG sites, interactions between gestational smoking and SNPs were detected for 16 CpGs. Methylation of seven of the 16 CpGs were, in interaction with modGVs, associated with leptin levels at age 18 years. Two CpGs survived a multiple testing penalty and were also associated with BMI. This two-stage model may explain why maternal smoking has a long-term effect on leptin levels and BMI in girls at age 18 years.
LEPR; LEPROT; leptin; CpG sites; in utero smoking exposure; rs12059300; BMI
Identification of cancer stem cells (CSCs) and their behaviors will provide insightful information for the future control of human cancers. This study investigated CD44 and CD24 cell surface markers as breast cancer CSC markers in vitro and in vivo.
Flow cytometry with CD44 and CD24 markers was used to sort breast cancer MCF7 cells for scanning electron microscopy (SEM), tumor cell invasion assay, and nude mouse xenograft assay.
Flow cytometry assay using CD44 and CD24 markers sorted MCF7 cells into four subsets, i.e., CD44+/CD24-/low, CD44-/CD24+, CD44+/CD24+, and CD44-/CD24-. The SEM data showed that there were many protrusions on the surface of CD44+/CD24-/low cells. CD44+/CD24-/low cells had many microvilli and pseudopodia. The CD44+/CD24-/low cells had a higher migration and invasion abilities than that of the other three subsets of the cells. The in vivo tumor formation assay revealed that CD44+/CD24- cells had the highest tumorigenic capacity compared to the other three subsets.
CD44 and CD24 could be useful markers for identification of breast CSCs because CD44+/CD24-/low cells had unique surface ultrastructures and the highest tumorigenicity and invasive abilities.
Breast cancer stem cells; Ultrastructure; Tumorigenicity; Invasive ability
Police officers are required to work irregular hours, which induces stress, fatigue, and sleep disruption, and they have higher rates of chronic disease and mortality. Cortisol is a well-known “stress hormone” produced via activation of the hypothalamic-pituitary-adrenal axis. An abnormal secretion pattern has been associated with immune system dysregulation and may serve as an early indicator of disease risk. This study examined the effects of long- and short-term shiftwork on the cortisol awakening response among officers (n = 68) in the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) pilot study (2001–2003). The time each officer spent on day (start time: 04:00–11:59 h), afternoon (12:00–19:59 h), or night (20:00–03:59 h) shifts was summarized from 1994 to examination date to characterize long-term (mean: 14 ± 9 yrs) and short-term (3, 5, 7, or 14 days prior to participation) shiftwork exposures. The cortisol awakening response was characterized by summarizing the area under the curve (AUC) for samples collected on first awakening, and at 15-, 30-, and 45-min intervals after waking. Data were collected on a scheduled training or off day. The cortisol AUC with respect to ground (AUCG) summarized total cortisol output after waking, and the cortisol AUC with respect to increase (AUCI) characterized the waking cortisol response. Officers also completed the Center for Epidemiologic Studies Depression scale. Waking cortisol AUC values were lower among officers working short-term night or afternoon shifts than day shifts, with maximal differences occurring after 5 days of shiftwork. The duration of long-term shiftwork was not associated with the cortisol awakening response, although values were attenuated among officers with more career shift changes.
Cortisol awakening response; Police; Shiftwork; Stress
This study evaluated whether measures of waking or diurnal cortisol secretion, or self-reported psychological disturbances differed among police officers with a Period3 (PER3) clock gene length polymorphism.
The cortisol awakening response was characterized via the area under the salivary cortisol curve with respect to the increase (AUCI) or total waking cortisol (AUCG). Diurnal cortisol measures included the slope of diurnal cortisol and the diurnal AUCG. Psychological disturbances were characterized using the Center for Epidemiologic Studies Depression Scale, Impact of Events Scale, and Life Events Scale.
Officers with a 4/5 or 5/5 genotype had higher awakening AUCG and greater diurnal cortisol AUCG levels compared to officers with the 4/4 genotype. Among those working more afternoon or night shifts, waking AUCI and AUCG were greater among officers with a 4/5 or 5/5 genotype compared to the 4/4 referents.
Cortisol secretion was modified among police officers with different PER3 VNTR clock gene variants.
PER3 VNTR; circadian; cortisol; shiftwork; police
Paclitaxel often induces persistent painful neuropathy as its most common treatment limiting side effect. Little is known concerning the underlying mechanisms. Given the prominent role of glial cells in many types of neuropathic pain, we investigated here the morphological and functional changes of spinal astrocytes and microglia in a rat model of paclitaxel-induced neuropathy. Immunohistochemistry, western blotting and real-time polymerase chain reaction (rt-PCR) were performed with samples from 109 rats up to 28 days after paclitaxel treatment. Paclitaxel (2mg/kg, i.p.) induced a rapid and persistent activation of spinal astrocytes assessed using glial fibrillary acidic protein (GFAP), but not apparent activation of microglia assessed using OX42, Iba-1 and phosphorylated p38. In the context of astocyte activation, there was a significant downregulation of glial glutamate transporters GLAST and GLT-1 in spinal dorsal horn. The activation of spinal astrocytes by paclitaxel was not associated with expression of pro-inflammatory cytokines including tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β) or interleukin-6 (IL-6) in spinal dorsal horn. Systemic treatment with minocycline (50mg/kg, i.p.) prevented activation of astrocytes and downregulation of glial glutamate transporters in spinal dorsal horn induced by paclitaxel. These data suggest the involvement of spinal astrocytes but not microglia in the pathogenesis of paclitaxel-induced neuropathy.
Paclitaxel; neuropathy; spinal cord; astrocyte; microglia; minocycline
The occurrence of asthma is weakly explained by known genetic variants. Epigenetic marks, DNA methylation (DNA-M) in particular, are considered to add to the explanation of asthma. However, no etiological model has yet been developed that integrates genetic variants and DNA-M. To explore a new model, we focused on one asthma candidate gene, the IL-4 receptor (IL4R). We hypothesized that genetic variants of IL4R in interaction with DNA-M at cytosine-phosphate-guanine (CpG) sites jointly alter the risk of asthma during adolescence. Blood samples were collected at age 18 years from 245 female cohort participants randomly selected for methylation analysis from a birth cohort (n = 1,456, Isle of Wight, UK). Genome-wide DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip.
Thirteen single nucleotide polymorphisms (SNPs) and twelve CpG sites of IL4R gene were analyzed. Based on linkage disequilibrium and association with asthma, eight SNPs and one CpG site were selected for further analyses. Of the twelve CpG sites in the IL4R gene, only methylation levels of cg09791102 showed an association with asthma at age 18 years (Wilcoxon test: P = 0.01). Log-linear models were used to estimate risk ratios (RRs) for asthma adjusting for uncorrelated SNPs within the IL4R gene and covariates. Testing for interaction between the eight SNPs and the methylation levels of cg09791102 on the risk for asthma at age 18 years, we identified the statistically significant interaction term of SNP rs3024685 × methylation levels of cg09791102 (P = 0.002; after adjusting for false discovery rate). A total of 84 participants had methylation levels ≤0.88, 112 participants between 0.89 and 0.90, and 35 between 0.91 and 0.92. For the SNP rs3024685 (‘CC’ vs. ‘TT’) at methylation levels of ≤0.85, 0.86, 0.90, 0.91, and 0.92, the RRs were 0.01, 0.04, 4.65, 14.76, 14.90, respectively (interaction effect, P = 0.0003).
Adjusting for multiple testing, our results suggest that DNA-M modulates the risk of asthma related to genetic variants in the IL4R gene. The strong interaction of one SNP and DNA-M is encouraging and provides a novel model of how a joint effect of genetic variants and DNA-M can explain occurrence of asthma.
Interleukin-4 receptor gene; DNA methylation; Genetic variants; Asthma; Epigenetics
Acetylcholine release at motor neuron synapses is long established, however recent discoveries indicate that synaptic transmission by motor neurons is more complex than previously thought. Using whole-cell patch clamp we show that spontaneous excitatory post-synaptic currents of rat motor neurons in primary ventral horn cultures are entirely glutamatergic, although the cells respond to exogenous acetylcholine. Motor neurons in culture express the vesicular glutamate transporter VGlut2, and culturing motor neurons for weeks while blocking glutamate receptors up-regulates glutamate signaling, without increasing cholinergic signaling. In spinal cord slices, motor neurons showed no decrease in spontaneous excitatory synaptic potentials after blocking acetylcholine receptors. Our results suggest that motor neuron synapses formed on other neurons are largely glutamatergic in culture and the spinal cord.
motor neuron; spinal cord; patch clamp; primary culture; slice recording
Purpose. To examine the associations among intake of refined grains, whole grains and dietary fiber and aggressiveness of prostate cancer in African Americans (AA, n = 930) and European Americans (EA, n = 993) in a population-based, case-only study (The North Carolina-Louisiana Prostate Cancer Project, PCaP). Methods. Prostate cancer aggressiveness was categorized as high, intermediate or low based on Gleason grade, PSA level and clinical stage. Dietary intake was assessed utilizing the NCI Diet History Questionnaire. Logistic regression (comparing high to intermediate/low aggressive cancers) and polytomous regression with adjustment for potential confounders were used to determine odds of high prostate cancer aggressiveness with intake of refined grains, whole grains and dietary fiber from all sources. Results. An inverse association with aggressive prostate cancer was observed in the 2nd and 3rd tertiles of total fiber intake (OR = 0.70; 95% CI, 0.50–0.97 and OR = 0.61; 95% CI, 0.40–0.93, resp.) as compared to the lowest tertile of intake. In the race-stratified analyses, inverse associations were observed in the 3rd tertile of total fiber intake for EA (OR = 0.44; 95% CI, 0.23–0.87) and the 2nd tertile of intake for AA (OR = 0.57; 95% CI, 0.35–0.95). Conclusions. Dietary fiber intake was inversely associated with aggressive prostate cancer among both AA and EA men.
Iodine deficiency and iodine excess are both associated with adverse health consequences. Iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. The results of our previous epidemiological study suggested that mild iodine excess might increase the prevalence of subclinical hypothyroidism. In the present study, female Wistar rats maintained on low-iodine grain were randomly assigned to three groups based on iodated water concentration: low iodine (LI, 1.2 μg/d), normal iodine (NI, 5–6 μg/d), and 3-fold high iodine (3HI, 15–16 μg/d). The present study investigated whether higher-than-normal iodine intake (3HI) by rats from before pregnancy until breastfeeding affects the postnatal (PN) neurodevelopment (PN7 and PN45) of their offspring during particularly sensitive periods in brain development.
After 12 weeks of treatment (before pregnancy), iodine concentrations in urine and thyroid tissue and circulating thyroxine of adult females correlated with iodine intake. Brain-derived neurotrophic factor (BDNF) expression in the hippocampi of pups on PN7 and PN45 was decreased in 3HI group compared to the NI controls (P < 0.05, all) On PN7 and PN45, the BDNF levels of the 3HI pups were 83.5% and 88.8%, respectively, that of the NI pups. In addition, the 3HI group had a higher neuroendocrine-specific protein A (NSP-A) level than the NI controls on PN7 (P < 0.05). NSP-A levels of the 3HI pups were 117.0% that of the NI pups. No significant difference was observed in the expressions of c-Fos or c-Jun in the hippocampal CA1 region of the 3HI group compared to the controls (P > 0.05). Results from the Morris water maze test revealed that pups of the 3HI group had mild learning and spatial memory deficits.
The neurodevelopmental and cognitive deficits of the 3HI pups were mild and temporary, likely related to the changes in hippocampal protein expressions of BDNF and NSP-A.
Iodine deficiency; Iodine excess; Thyroid hormone; Hippocampus; Neurodevelopment
Since sex hormone markers are metabolically linked, examining sex steroid hormones singly may account for inconsistent findings by age, race/ethnicity and body mass index (BMI) across studies. First, these markers were statistically combined into profiles to account for the metabolic relationship between markers. Then, the relationships between sex steroid hormone profiles and age, race/ethnicity and BMI were explored in multinomial logistic regression models.
The US Third National Health and Nutrition Examination Survey (NHANES III).
1538 Men, >17 years.
Primary outcome measure
Sex hormone profiles.
Cluster analysis was used to identify four statistically determined profiles with Blom-transformed T, E, sex hormone binding globulin (SHBG), and 3-α diol G. We used these four profiles with multinomial logistic regression models to examine differences by race/ethnicity, age and BMI. Mexican American men >50 years were associated with the profile that had lowest T, E and 3-α diol G levels compared to other profiles (p<0.05). Non-Hispanic Black, overweight (25–29.9 kg/m2) and obese (>30 kg/m2) men were most likely to be associated with the cluster with the lowest SHBG (p<0.05).
The associations of sex steroid hormone profiles by race/ethnicity are novel, while the findings by age and BMI groups are largely consistent with observations from single hormone studies. Future studies should validate these hormone profile groups and investigate these profiles in relation to chronic diseases and certain cancers.
Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification.
We sought to identify asthma susceptibility genes in children.
A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n=116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n=112) and normal controls (n=165). A genomic region containing the ATPAF1 gene was significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in eight independent study populations consisting of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in two consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatics and controls.
Asthma was associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene with two SNPs achieving significance at a genome-wide level (p=2.26×10−5 to 2.2×10−8). Asthma severity was also associated with SNPs and haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the four non-Hispanic populations. Haplotype associations were confirmed in the non-Hispanic populations (p=0.045 to 0.0009). ATPAF1 total RNA expression was significantly (p<0.01) higher in bronchial biopsies from asthmatics than controls.
Genetic variation in the ATPAF1 gene predisposes children of different ancestry to asthma.
asthma; ATPAF1; children; gene; genetic; genome-wide association; purinergic; respiratory; single nucleotide polymorphism; SNP
Disasters serve as shocks and precipitate unanticipated disturbances to the health care system. Public health surveillance is generally focused on monitoring latent health and environmental exposure effects, rather than health system performance in response to these local shocks. The following intervention study sought to determine the long-term effects of the 2005 chlorine spill in Graniteville, South Carolina on primary care access for vulnerable populations. We used an interrupted time-series approach to model monthly visits for Ambulatory Care Sensitive Conditions, an indicator of unmet primary care need, to quantify the impact of the disaster on unmet primary care need in Medicaid beneficiaries. The results showed Medicaid beneficiaries in the directly impacted service area experienced improved access to primary care in the 24 months post-disaster. We provide evidence that a health system serving the medically underserved can prove resilient and display improved adaptive capacity under adverse circumstances (i.e., technological disasters) to ensure access to primary care for vulnerable sub-groups. The results suggests a new application for ambulatory care sensitive conditions as a population-based metric to advance anecdotal evidence of secondary surge and evaluate pre- and post-health system surge capacity following a disaster.
technological disaster; vulnerable populations; access to care; ambulatory care sensitive conditions; secondary surge capacity; recovery; health system; forecast modeling
The role of breast milk on the risk of childhood asthma is in dispute. The aim of this prospective study is to determine the relationship of immune markers in maternal serum during gestation and breast milk to asthma-like symptoms (AS) in infancy.
Pregnant women were recruited in Columbia and Charleston, South Carolina. Blood (median: three weeks before delivery) and breast milk (three weeks after delivery) samples were collected. Concentrations of interferon (IFN)-γ, IFN gamma-induced protein 10 (IP-10 or CXCL10), CCL11, interleukin (IL) 1β, IL-4, IL-5, IL-6, CXCL8, IL-10, IL-12(p70), IL-13, transforming growth factor (TGF)-β1, and immunoglobulin (Ig) A in both maternal serum and milk whey were determined via immunoassays. Asthma-like symptoms (AS) of the infant were ascertained at 6 and 12 months, respectively. Generalized estimating equations assessed relative risks (RRs) of immune markers for repeated measurements of AS, considering intra-individual correlations and adjusting for confounders. To provide comparable risk estimates, quartiles of the immune markers were used, except for IL-5 in whey and IgA in serum, which were dichotomized.
Of 178 women, 161 provided blood and 115 breast milk samples. IL-12(p70), IL-4, IL-10, IL-1β, and CCL11 in serum and in whey were not further considered for the statistical analyses since the proportion of non-detectable values was high. Most immune markers in serum and milk whey were moderately or highly correlated; however, IgA was negatively correlated. Infants in the highest quartile of IL-13 in both serum and whey were at a higher risk of AS (RR = 3.02 and 4.18; respectively) compared to infants in the first quartile. High levels of IL-5 in serum and whey was also identified as a risk. In addition, increased secretory IgA and TGF-β1 in breast milk reduced the risks of AS.
Maternal serum and whey levels of IL-5 and IL-13 are risk markers for AS; whey IgA and TGF-β1 seem to be protective. Only focusing on breast milk portend that milk cytokines IL-5 and IL-13 have adverse effects. However, similar immune exposures during late gestation and via milk suggest that both may enhance AS among infants.
Breast milk; Maternal serum; Immune markers; Cytokines; Chemokines; Asthma-like symptoms; Children; Longitudinal study
Different water choices affect access to drinking water with different quality. Previous studies suggested social-economic status may affect the choice of domestic drinking water. The aim of this study is to investigate whether recent social economic changes in China affect residents’ drinking water choices.
We conducted a cross-sectional survey to investigate residents’ water consumption behaviour in 2011. Gender, age, education, personal income, housing condition, risk perception and personal preference of a certain type of water were selected as potential influential factors. Univariate and backward stepwise logistic regression analyses were performed to analyse the relation between these factors and different drinking water choices. Basic information was compared with that of a historical survey in the same place in 2001. Self-reported drinking-water-related diarrhoea was found correlated with different water choices and water hygiene treatment using chi-square test.
The percentage of tap water consumption remained relatively stable and a preferred choice, with 58.99% in 2001 and 58.25% in 2011. The percentage of bottled/barrelled water consumption was 36.86% in 2001 and decreased to 25.75% in 2011. That of household filtrated water was 4.15% in 2001 and increased to 16.00% in 2011. Logistic regression model showed strong correlation between one’s health belief and drinking water choices (P < 0.001). Age, personal income, education, housing condition, risk perception also played important roles (P < 0.05) in the models. Drinking-water-related diarrhoea was found in all types of water and improper water hygiene behaviours still existed among residents.
Personal health belief, housing condition, age, personal income, education, taste and if worm ever founded in tap water affected domestic drinking water choices in Shanghai.
Balkan endemic nephropathy (BEN) is a chronic kidney disease that affects persons living in the Balkans. Despite the unique geographical specificity of this disease, its etiology has remained unclear. Even if a positive family history of BEN has been identified, it is still uncertain how the disease develops in offspring. In this paper, we examine clinical mechanisms related to the onset of BEN in individuals who have a parental history of BEN to identify early detection of the disease and formulate interventions. We conducted a 5-year prospective study, using markers in years one and three to predict new cases of BEN in year five. New cases of BEN were defined based on three criteria: parental history of BEN, reduced kidney size, and reduced kidney function. Incident cases were divided into (1) probable, (2) definite, and (3) combined labeled total incidence. We evaluated parental history in relation to BEN and tested the potentially intervening effects of kidney length, kidney cortex width, β2-microglobulin, C-reactive protein, and creatinine clearance, using path analyses. The findings of the path analyses suggested that parental history of BEN had both direct and indirect effects. The direct effect was significant for all three modes of parental history (biparental, maternal, and paternal; odds ratios 71.5, 52.3, and 50.1, respectively). The indirect effects of maternal BEN acted via kidney length and creatinine clearance. Biparental BEN was mediated by (1) kidney length and creatinine clearance, and (2) creatinine clearance alone. Paternal BEN had three indirect effects: (1) through kidney length and creatinine clearance, (2) via kidney cortex width and creatinine clearance, and (3) via kidney cortex width only. In conclusion, a family history of BEN led to reduced kidney length and cortex width, and a decline in creatinine clearance, which in turn predicted the onset of BEN.
Balkan endemic nephropathy; incidence of BEN; parental history of BEN; kidney size; β2-microglobulin; creatinine clearance
Immune specific genes as well as genes regulating the formation of skin barrier are major determinants for eczema manifestation. There is a debate as to whether allergic sensitization and filaggrin gene (FLG) variants lead to eczema or FLG variants and eczema increase the risk of allergic sensitization. To investigate the time-order between eczema and allergic sensitization with respect to FLG variants, data from a large prospective study covering infancy to late adolescence were analyzed.
Repeated measurements of eczema and allergic sensitization (documented by skin prick tests) at ages 1, 2, 4, 10, and 18 years were ascertained in the Isle of Wight birth cohort (n = 1,456). Three transition periods were analyzed: age 1-or-2 to 4, 4 to 10, and 10 to 18 years. FLG variants were genotyped in 1,150 participants. Over the three transition periods, in temporal sequence analyses of initially eczema-free participants, the combined effect of FLG variants and allergic sensitization showed a 2.92-fold (95% CI: 1.47–5.77) increased risk ratio (RR) of eczema in subsequent examinations. This overall risk was more pronounced at a younger age (transition period 1-or-2 to 4, RR = 6.47, 95% CI: 1.96–21.33). In contrast, FLG variants in combination with eczema showed a weaker, but significant, risk ratio for subsequent allergic sensitization only up to 10 years of age.
Taking the time order into account, this prospective study demonstrates for the first time, that a combination of FLG variants and allergic sensitization increased the risk of eczema in subsequent years. Also FLG variants interacted with eczema and increased the risk of subsequent allergic sensitization, which, was limited to the younger age. Hence, early restoration of defective skin barrier could prevent allergic sensitization and subsequently reduce the risk of eczema development.
Skin prick testing (SPT) is fundamental to the practice of clinical allergy identifying relevant allergens and predicting the clinical expression of disease. Wheal sizes on SPT are used to identify atopic cases, and the cut-off value for a positive test is commonly set at 3 mm. However, the measured wheal sizes do not solely reflect the magnitude of skin reaction to allergens, but also skin reactivity (reflected in the size of histamine reaction) and other random or non-random factors. We sought to estimate wheal sizes exclusively due to skin response to allergens and propose gender-specific cutoff points of atopy.
We developed a Bayesian method to adjust observed wheal sizes by excluding histamine and other factor effects, based on which revised cutoff points are proposed for males and females, respectively. The method is then applied to and intensively evaluated using a study population aged 18, at a location on the Isle of Wight in the United Kingdom. To evaluate the proposed approach, two sample t-tests for population means and proportion tests are applied.
Four common aeroallergens, house dust mite (HDM), grass pollen, dog dander, and alternaria are considered in the study. Based on 3 mm cutoff, males tend to be more atopic than females (P-values are between 0.00087 and 0.062). After applying the proposed methods to adjust wheal sizes, our findings suggest that misclassifications of atopy occur more often in males. Revised allergen-specific cutoff values are proposed for each gender.
To reduce the gender discrepancy, we may have two potentially convenient solutions. One way is to apply allergen-specific and gender-specific cutoff values following the proposed method. Alternatively, we can revise the concentration of allergens in the SPT solutions but keep the cutoff values unchanged, which may be more convenient to clinicians.
SPT; atopy; Bayesian method; joint modeling; misclassification
African American men have among the highest prostate cancer incidence rates in the world yet rates among their African counterparts are unclear. In this paper, we compared reported rates among black men of Sub-Saharan African descent using data from the International Agency for Research on Cancer (IARC) and the National Cancer Institute Surveillance, Epidemiology, and End Results Program for 1973–2007. Although population-based data in Africa are quite limited, the available data from IARC showed that rates among blacks were highest in the East (10.7–38.1 per 100,000 man-years, age-adjusted world standard) and lowest in the West (4.7–19.8). These rates were considerably lower than those of 80.0–195.3 observed among African Americans. Rates in Africa increased over time (1987–2002) and have been comparable to those for distant stage in African Americans. These patterns are likely due to differences between African and African American men in medical care access, screening, registry quality, genetic diversity, and Westernization. Incidence rates in Africa will likely continue to rise with improving economies and increasing Westernization, warranting the need for more high-quality population-based registration to monitor cancer incidence in Africa.
BWI-1 (buckwheat trypsin inhibitor), a member of the potato inhibitor I family, suppresses the growth of T-acute lymphoblastic leukemia cells and induces apoptosis in human solid tumor cell lines. Here, we report the crystal structure of rBTI (recombinant buckwheat trypsin inhibitor), a recombinant protein of BWI-1, at 1.84 Å resolution and the structure of rBTI in complex with bovine trypsin at 2.26 Å resolution. A conformational change of Trp53 at the P8′ position in rBTI was observed upon its binding to trypsin, which is not seen in other members of the potato inhibitor I family reported previously. The role of the P8′ residue in the potato inhibitor I family was examined by measuring the association and dissociation rates of four rBTI mutants with different substitutions at the P2 and P8′ positions when binding to trypsin. One of the mutants, P44T, was found to be a much stronger inhibitor than wild-type rBTI, with a picomolar (pM) dissociation constant. Our results could provide valuable insights for designing a new rBTI-based antitumor drug in the future.