Mouse allergen, lung function, and atopy in Puerto Rican children

Objective

To examine the relation between mouse allergen exposure and asthma in Puerto Rican children.

Methods

Mus m 1, Der p 1, Bla g 2, and Fel d 1 allergens were measured in dust samples from homes of Puerto Rican children with (cases) and without (controls) asthma in Hartford, CT (n = 449) and San Juan (SJ), Puerto Rico (n = 678). Linear or logistic regression was used for the multivariate analysis of mouse allergen (Mus m 1) and lung function (FEV₁ and FEV₁/FVC) and allergy (total IgE and skin test reactivity (STR) to ≥1 allergen) measures.

Results

Homes in SJ had lower mouse allergen levels than those in Hartford. In multivariate analyses, mouse allergen was associated with higher FEV₁ in cases in Hartford (+70.6 ml, 95% confidence interval (CI) = 8.6–132.7 ml, P = 0.03) and SJ (+45.1 ml, 95% CI =  −0.5 to 90.6 ml, P = 0.05). In multivariate analyses of controls, mouse allergen was inversely associated with STR to ≥1 allergen in non-sensitized children (odds ratio [OR] for each log-unit increment in Mus m 1 = 0.7, 95% CI = 0.5–0.9, P<0.01). In a multivariate analysis including all children at both study sites, each log-increment in mouse allergen was positively associated with FEV₁ (+28.3 ml, 95% CI = 1.4–55.2 ml, P = 0.04) and inversely associated with STR to ≥1 allergen (OR for each log-unit increment in Mus m 1 = 0.8, 95% CI = 0.6–0.9, P<0.01).

Conclusions

Mouse allergen is associated with a higher FEV₁ and lower odds of STR to ≥1 allergen in Puerto Rican children. This may be explained by the allergen itself or correlated microbial exposures.     

Large asymmetric hypertrophy of rectus abdominis muscle in professional tennis players

Purpose

To determine the volume and degree of asymmetry of the musculus rectus abdominis (RA) in professional tennis players.

Methods

The volume of the RA was determined using magnetic resonance imaging (MRI) in 8 professional male tennis players and 6 non-active male control subjects.

Results

Tennis players had 58% greater RA volume than controls (P = 0.01), due to hypertrophy of both the dominant (34% greater volume, P = 0.02) and non-dominant (82% greater volume, P = 0.01) sides, after accounting for age, the length of the RA muscle and body mass index (BMI) as covariates. In tennis players, there was a marked asymmetry in the development of the RA, which volume was 35% greater in the non-dominant compared to the dominant side (P<0.001). In contrast, no side-to-side difference in RA volume was observed in the controls (P = 0.75). The degree of side-to-side asymmetry increased linearly from the first lumbar disc to the pubic symphysis (r = 0.97, P<0.001).

Conclusions

Professional tennis is associated with marked hypertrophy of the musculus rectus abdominis, which achieves a volume that is 58% greater than in non-active controls. Rectus abdominis hypertrophy is more marked in the non-dominant than in the dominant side, particularly in the more distal regions. Our study supports the concept that humans can differentially recruit both rectus abdominis but also the upper and lower regions of each muscle. It remains to be determined if this disequilibrium raises the risk of injury.     

Soccer attenuates the asymmetry of rectus abdominis muscle observed in non-athletes

Purpose

To determine the volume and degree of asymmetry of the rectus abdominis muscle (RA) in professional soccer players.

Methods

The volume of the RA was determined using magnetic resonance imaging (MRI) in 15 professional male soccer players and 6 non-active male control subjects.

Results

Soccer players had 26% greater RA volume than controls (P<0.05), due to hypertrophy of both the dominant (28% greater volume, P<0.05) and non-dominant (25% greater volume, P<0.01) sides, after adjusting for age, length of the RA muscle and body mass index (BMI) as covariates. Total volume of the dominant side was similar to the contralateral in soccer players (P = 0.42) and in controls (P = 0.75) (Dominant/non-dominant = 0.99, in both groups). Segmental analysis showed a progressive increase in the degree of side-to-side asymmetry from the first lumbar disc to the pubic symphysis in soccer players (r = 0.80, P<0.05) and in controls (r = 0.75, P<0.05). The slope of the relationship was lower in soccer players, although this trend was not statistically significant (P = 0.14).

Conclusions

Professional soccer is associated with marked hypertrophy of the rectus abdominis muscle, which achieves a volume that is 26% greater than in non-active controls. Soccer induces the hypertrophy of the non-dominant side in proximal regions and the dominant side in regions closer to pubic symphysis, which attenuates the pattern of asymmetry of rectus abdominis observed in non-active population. It remains to be determined whether the hypertrophy of rectus abdominis in soccer players modifies the risk of injury.     

African ancestry is associated with asthma risk in African Americans

Background

Asthma is a common complex condition with clear racial and ethnic differences in both prevalence and severity. Asthma consultation rates, mortality, and severe symptoms are greatly increased in African descent populations of developed countries. African ancestry has been associated with asthma, total serum IgE and lower pulmonary function in African-admixed populations. To replicate previous findings, here we aimed to examine whether African ancestry was associated with asthma susceptibility in African Americans. In addition, we examined for the first time whether African ancestry was associated with asthma exacerbations.

Methodology/Principal Findings

After filtering for self-reported ancestry and genotype data quality, samples from 1,117 self-reported African-American individuals from New York and Baltimore (394 cases, 481 controls), and Chicago (321 cases followed for asthma exacerbations) were analyzed. Genetic ancestry was estimated based on ancestry informative markers (AIMs) selected for being highly divergent among European and West African populations (95 AIMs for New York and Baltimore, and 66 independent AIMs for Chicago). Among case-control samples, the mean African ancestry was significantly higher in asthmatics than in non-asthmatics (82.0±14.0% vs. 77.8±18.1%, mean difference 4.2% [95% confidence interval (CI):2.0–6.4], p<0.0001). This association remained significant after adjusting for potential confounders (odds ratio: 4.55, 95% CI: 1.69–12.29, p = 0.003). African ancestry failed to show an association with asthma exacerbations (p = 0.965) using a model based on longitudinal data of the number of exacerbations followed over 1.5 years.

Conclusions/Significance

These data replicate previous findings indicating that African ancestry constitutes a risk factor for asthma and suggest that elevated asthma rates in African Americans can be partially attributed to African genetic ancestry.     

α-Adducin Gly460Trp gene mutation and essential hypertension in a Chinese population: a meta-analysis including 10,960 subjects

Background

The α-adducin Gly460Trp (G460W) gene polymorphism may be associated with susceptibility to essential hypertension (EH), but this relationship remains controversial. In an attempt to resolve this issue, we conducted a meta-analysis.

Methods

Twenty-three separated studies involving 5939 EH patients and 5021 controls were retrieved and analyzed. Four ethnicities were included: Han, Kazakh, Mongolian, and She. Eighteen studies with 5087 EH patients and 4183 controls were included in the Han subgroup. Three studies with 636 EH patients and 462 controls were included in the Kazakh subgroup. The Mongolian subgroup was represented by only one study with 100 EH patients and 50 controls; similarly, only one study with 116 EH patients and 326 controls was available for the She subgroup. The pooled and ethnic group odds ratios (ORs) along with the corresponding 95% confidence intervals (95% CI) were assessed using a random effects model.

Results

There was a significant association between the α-adducin G460W gene polymorphism and EH in the pooled Chinese population under both an allelic genetic model (OR: 1.12, 95% CI: 1.04–1.20, P = 0.002) and a recessive genetic model (OR: 1.40, 95% CI: 1.16–1.70, P = 0.0005). In contrast, no significant association between the α-adducin G460W gene polymorphism and EH was observed in the dominant genetic model (OR: 0.88, 95% CI: 0.72–1.09, P = 0.24). In stratified analysis by ethnicity, significantly increased risk was detected in the Han subgroup under an allelic genetic model (OR: 1.13, 95% CI: 1.04–1.23, P = 0.003) and a recessive genetic model (OR: 1.43, 95% CI: 1.17–1.75, P = 0.0006).

Conclusions

In a Chinese population of mixed ethnicity, the α-adducin G460W gene polymorphism was linked to EH susceptibility, most strongly in Han Chinese.     

Iliopsoas and gluteal muscles are asymmetric in tennis players but not in soccer players

Purpose

To determine the volume and degree of asymmetry of iliopsoas (IL) and gluteal muscles (GL) in tennis and soccer players.

Methods

IL and GL volumes were determined using magnetic resonance imaging (MRI) in male professional tennis (TP) and soccer players (SP), and in non-active control subjects (CG) (n = 8, 15 and 6, respectively).

Results

The dominant and non-dominant IL were hypertrophied in TP (24 and 36%, respectively, P<0.05) and SP (32 and 35%, respectively, P<0.05). In TP the asymmetric hypertrophy of IL (13% greater volume in the non-dominant than in the dominant IL, P<0.01) reversed the side-to-side relationship observed in CG (4% greater volume in the dominant than in the contralateral IL, P<0.01), whilst soccer players had similar volumes in both sides (P = 0.87). The degree of side-to-side asymmetry decreased linearly from the first lumbar disc to the pubic symphysis in TP (r = −0.97, P<0.001), SP (r = −0.85, P<0.01) and CG (r = −0.76, P<0.05). The slope of the relationship was lower in SP due to a greater hypertrophy of the proximal segments of the dominant IL. Soccer and CG had similar GL volumes in both sides (P = 0.11 and P = 0.19, for the dominant and contralateral GL, respectively). GL was asymmetrically hypertrophied in TP. The non-dominant GL volume was 20% greater in TP than in CG (P<0.05), whilst TP and CG had similar dominant GL volumes (P = 0.14).

Conclusions

Tennis elicits an asymmetric hypertrophy of IL and reverses the normal dominant-to-non-dominant balance observed in non-active controls, while soccer is associated to a symmetric hypertrophy of IL. Gluteal muscles are asymmetrically hypertrophied in TP, while SP display a similar size to that observed in controls. It remains to be determined whether the different patterns of IL and GL hypertrophy may influence the risk of injury.     

Hospitalisation with infection, asthma and allergy in Kawasaki disease patients and their families: genealogical analysis using linked population data

Background

Kawasaki disease results from an abnormal immunological response to one or more infectious triggers. We hypothesised that heritable differences in immune responses in Kawasaki disease-affected children and their families would result in different epidemiological patterns of other immune-related conditions. We investigated whether hospitalisation for infection and asthma/allergy were different in Kawasaki disease-affected children and their relatives.

Methods/Major Findings

We used Western Australian population-linked health data from live births (1970–2006) to compare patterns of hospital admissions in Kawasaki disease cases, age- and sex-matched controls, and their relatives. There were 295 Kawasaki disease cases and 598 age- and sex-matched controls, with 1,636 and 3,780 relatives, respectively. Compared to controls, cases were more likely to have been admitted at least once with an infection (cases, 150 admissions (50.8%) vs controls, 210 admissions (35.1%); odds ratio (OR) = 1.9, 95% confidence interval (CI) 1.4–2.6, P = 7.2×10⁻⁶), and with asthma/allergy (cases, 49 admissions (16.6%) vs controls, 42 admissions (7.0%); OR = 2.6, 95% CI 1.7–4.2, P = 1.3×10⁻⁵). Cases also had more admissions per person with infection (cases, median 2 admissions, 95% CI 1–5, vs controls, median 1 admission, 95% CI 1–4, P = 1.09×10⁻⁵). The risk of admission with infection was higher in the first degree relatives of Kawasaki disease cases compared to those of controls, but the differences were not significant.

Conclusion

Differences in the immune phenotype of children who develop Kawasaki disease may influence the severity of other immune-related conditions, with some similar patterns observed in relatives. These data suggest the influence of shared heritable factors in these families.     

Filaggrin gene defects are independent risk factors for atopic asthma in a Polish population: a study in ECAP cohort

Background

FLG null variants of which 2282del4 and R501X are the most frequent in Caucasians are established risk factors for atopic dermatitis (AD) with an effect probably mediated through impairment of epidermal barrier. Among subjects with AD FLG defects are also consistently associated with asthma and allergic rhinitis (AR) but it is less clear to what extent these associations are also present independently from skin disease. The aim of the present study was to evaluate the role of 2282del4 and R501X in predisposing to these allergic phenotypes in a Polish population.

Methodology

2282del4 and R501X were typed among 3,802 participants of the Epidemiology of Allergic Diseases in Poland (ECAP) survey, a cross-sectional population-based study using ECRHS II and ISAAC questionnaires, and ambulatory examination.

Principal Findings

The FLG null variants were associated with AD (OR = 2.01, CI: 1.20–3.36, P = 0.007), allergic rhinitis (in particular persistent form, OR = 1.69, CI:1.12–2.54, P = 0.011), and asthma (in particular atopic asthma, OR = 2.22, CI:1.24–3.96, P = 0.006). Association with atopic asthma (but not persistent allergic rhinitis) was also present in the absence of AD, (OR = 2.02, CI: 1.07–3.81, P = 0.027) as well as in the absence of AD and history of broadly defined inflammatory skin disease (OR = 2.30, CI: 1.07–4.93, P = 0.03). Association to atopic asthma would have not been found if diagnosis was made by questionnaire only (OR = 1.15, CI: 0.58–2.32, P = 0.8). We did not observe an association between FLG variants and allergic sensitizations (P = 0.8) or total IgE. (P = 0.6).

Conclusions/Significance

In a Polish population FLG 2282del4 and R501X carriage increases risk for development of AD and atopic asthma (also in the absence of AD or history thereof). This suggests that interventions aimed at restoring epidermal barrier may have a general role in asthma prophylaxis/treatment.     

Novel M tuberculosis antigen-specific T-cells are early markers of infection and disease progression

Background

Mycobacterium tuberculosis Region-of-Difference-1 gene products present opportunities for specific diagnosis of M. tuberculosis infection, yet immune responses to only two gene-products, Early Secretory Antigenic Target-6 (ESAT-6) and Culture Filtrate Protein-10 (CFP-10), have been comprehensively investigated.

Methods

T-cell responses to Rv3873, Rv3878 and Rv3879c were quantified by IFN-γ-enzyme-linked-immunospot (ELISpot) in 846 children with recent household tuberculosis exposure and correlated with kinetics of tuberculin skin test (TST) and ESAT-6/CFP-10-ELISpot conversion over six months and clinical outcome over two years.

Results

Responses to Rv3873, Rv3878, and Rv3879c were present in 20–25% of contacts at enrolment. Rv3873 and Rv3879c responses were associated with and preceded TST conversion (P = 0.02 and P = 0.04 respectively), identifying these antigens as early targets of cell-mediated immunity following M. tuberculosis exposure. Responses to Rv3873 were additionally associated with subsequent ESAT-6/CFP-10-ELISpot conversion (P = 0.04). Responses to Rv3873 and Rv3878 predicted progression to active disease (adjusted incidence rate ratio [95% CI] 3.06 [1.05,8.95; P = 0.04], and 3.32 [1.14,9.71; P = 0.03], respectively). Presence of a BCG-vaccination scar was associated with a 67% (P = 0.03) relative risk reduction for progression to active tuberculosis.

Conclusions

These RD1-derived antigens are early targets of cellular immunity following tuberculosis exposure and T-cells specific for these antigens predict progression to active tuberculosis suggesting diagnostic and prognostic utility.     

Vitamin D3 deficiency differentially affects functional and disease outcomes in the G93A mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by motor neuron death in the central nervous system. Vitamin D supplementation increases antioxidant activity, reduces inflammation and improves motor neuron survival. We have previously demonstrated that vitamin D₃ supplementation at 10× the adequate intake improves functional outcomes in a mouse model of ALS.

Objective

To determine whether vitamin D deficiency influences functional and disease outcomes in a mouse model of ALS.

Methods

At age 25 d, 102 G93A mice (56 M, 46 F) were divided into two vitamin D₃ groups: 1) adequate (AI; 1 IU D₃/g feed) and 2) deficient (DEF; 0.025 IU D₃/g feed). At age 113 d, tibialis anterior (TA), quadriceps (quads) and brain were harvested from 42 mice (22 M and 20 F), whereas the remaining 60 mice (34 M and 26 F) were followed to endpoint.

Results

During disease progression, DEF mice had 25% (P = 0.022) lower paw grip endurance AUC and 19% (P = 0.017) lower motor performance AUC vs. AI mice. Prior to disease onset (CS 2), DEF mice had 36% (P = 0.016) lower clinical score (CS) vs. AI mice. DEF mice reached CS 2 six days later vs. AI mice (P = 0.004), confirmed by a logrank test which revealed that DEF mice reached CS 2 at a 43% slower rate vs. AI mice (HR = 0.57; 95% CI: 0.38, 1.74; P = 0.002). Body weight-adjusted TA (AI: r = 0.662, P = 0.001; DEF: r = 0.622, P = 0.006) and quads (AI: r = 0.661, P = 0.001; DEF: r = 0.768; P<0.001) weights were strongly correlated with age at CS 2.

Conclusion

Vitamin D₃ deficiency improves early disease severity and delays disease onset, but reduces performance in functional outcomes following disease onset, in the high-copy G93A mouse.     

Detoxification center-based sampling missed a subgroup of higher risk drug users, a case from Guangdong, China

Background

Injection drug use remains among the most important HIV transmission risk in China. Representativeness of drug users sampled from detoxification centers is questionable. A respondent driven sampling survey was conducted to compare the results with those from the detoxification center in the same city.

Methods

In 2008, two independent surveys were conducted in Dongguan, China, one for community-based drug users using respondent driven sampling and the other for drug users in a compulsory detoxification center as routine sentinel surveillance. Demographic and behavioral information were collected using the same structured questionnaire. Intravenous blood samples were collected to measure antibodies to HIV-1, and syphilis.

Results

Compared to those 400 drug users recruited from the detoxification center, the 303 community-based drug users had higher HIV prevalence (14.7% versus 4.0%, P = 0.04), lower syphilis prevalence (4.7% versus 10.8%, P = 0.07), higher proportion of injection drug use (83.9% versus 60.2%, P = 0.01) and syringe sharing (47.8% versus 36.3%, P = 0.10), more likely to be separated (12.4% versus 3.8%, P = 0.01) and being migrants from Guangxi province (31.4% versus 18.0%, P = 0.09), more engaging in commercial sex (64.4% versus 52.5%, P = 0.04). HIV prevalence and rate of syringe sharing were consistently higher among drug users from Guangxi.

Conclusions

Detoxification center-based sampling missed a subgroup with higher HIV prevalence and higher rate of injection drug use. While detoxification center-based sampled can be used to monitor the trend of HIV prevalence and risk behaviors over time, periodic community-based sampling is still necessary to avoid possible systematic error in detoxification center-based samples.     

Prolactin secretion in healthy adults is determined by gender, age and body mass index

Background

Prolactin (PRL) secretion is quantifiable as mean, peak and nadir PRL concentrations, degree of irregularity (ApEn, approximate entropy) and spikiness (brief staccato-like fluctuations).

Hypothesis

Distinct PRL dynamics reflect relatively distinct (combinations of) subject variables, such as gender, age, and BMI.

Location

Clinical Research Unit.

Subjects

Seventy-four healthy adults aged 22–77 yr (41 women and 33 men), with BMI 18.3–39.4 kg/m².

Measures

Immunofluorometric PRL assay of 10-min samples collected for 24 hours.

Results

Mean 24-h PRL concentration correlated jointly with gender (P<0.0001) and BMI (P = 0.01), but not with age (overall R² = 0.308, P<0.0001). Nadir PRL concentration correlated with gender only (P = 0.017) and peak PRL with gender (P<0.001) and negatively with age (P<0.003), overall R² = 0.325, P<0.0001. Forward-selection multivariate regression of PRL deconvolution results demonstrated that basal (nonpulsatile) PRL secretion tended to be associated with BMI (R² = 0.058, P = 0.03), pulsatile secretion with gender (R² = 0.152, P = 0.003), and total secretion with gender and BMI (R² = 0.204, P<0.0001). Pulse mass was associated with gender (P = 0.001) and with a negative tendency to age (P = 0.038). In male subjects older than 50 yr (but not in women) approximate entropy was increased (0.942±0.301 vs. 1.258±0.267, P = 0.007) compared with younger men, as well as spikiness (0.363±0.122 vs. 0463±2.12, P = 0.031). Cosinor analysis disclosed higher mesor and amplitude in females than in men, but the acrophase was gender-independent. The acrophase was determined by age and BMI (R² = 0.186, P = 0.001).

Conclusion

In healthy adults, selective combinations of gender, age, and BMI specify distinct PRL dynamics, thus requiring balanced representation of these variables in comparative PRL studies.     

An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension

Background

Numerous individually underpowered association studies have been conducted on endothelial nitric oxide synthase (eNOS) genetic variants across different ethnic populations, however, the results are often irreproducible. We therefore aimed to meta-analyze three eNOS widely-evaluated polymorphisms, G894T (rs1799983) in exon 7, 4b/a in intron 4, and T−786C (rs2070744) in promoter region, in association with hypertension from both English and Chinese publications, while addressing between-study heterogeneity and publication bias.

Methods

Data were analyzed using Stata software (version 11.0), and random-effects model was applied irrespective of between-study heterogeneity, which was evaluated by subgroup and meta-regression analyses. Publication bias was weighed using the Egger''s test and funnel plot.

Results

There were total 19284/26003 cases/controls for G894T, and 6890/6858 for 4b/a, and 5346/6392 for T−786C polymorphism. Overall comparison of allele 894T with 894G in all study populations yielded a 16% increased risk for hypertension (odds ratio [OR] = 1.16; 95% confidence interval [95% CI]: 1.07–1.27; P = 0.001), and particularly a 32% increased risk (95% CI: 1.16–1.52; P<0.0005) in Asians and a 40% increased risk (95% CI: 1.19–1.65; P<0.0005) in Chinese. Further subgroup analyses suggested that published languages accounted for the heterogeneity for G894T polymorphism. The overall OR of allele 4a versus 4b was 1.29 (95% CI: 1.13–1.46; P<0.0005) in all study populations, and this estimate was potentiated in Asians (OR = 1.42; 95% CI: 1.16–1.72; P<0.0005). For T−786C, ethnicity-stratified analyses suggested a significantly increased risk for −786C allele (OR = 1.25; 95% CI: 1.06–1.47; P = 0.007) and −786CC genotype (OR = 1.69; 95% CI: 1.20–2.38; P = 0.003) in Whites. As an aside, the aforementioned risk estimates reached significance after Bonferroni correction. Finally, meta-regression analysis on other study-level covariates failed to provide any significance for all polymorphisms.

Conclusion

We, via a comprehensive meta-analysis, ascertained the role of eNOS G894T and 4b/a polymorphisms on hypertension in Asians, and T−786C polymorphism in Whites.     

The -675 4G/5G polymorphism in plasminogen activator inhibitor-1 gene is associated with risk of asthma: a meta-analysis

Background

A number of studies assessed the association of −675 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor (PAI)-1 gene with asthma in different populations. However, most studies reported inconclusive results. A meta-analysis was conducted to investigate the association between polymorphism in the PAI-1 gene and asthma susceptibility.

Methods

Databases including Pubmed, EMBASE, HuGE Literature Finder, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the dominant model, recessive model, codominant model, and additive model.

Results

Eight studies involving 1817 cases and 2327 controls were included. Overall, significant association between 4G/5G polymorphism and asthma susceptibility was observed for 4G4G+4G5G vs. 5G5G (OR = 1.56, 95% CI 1.12–2.18, P = 0.008), 4G/4G vs. 4G/5G+5G/5G (OR = 1.38, 95% CI 1.06–1.80, P = 0.02), 4G/4G vs. 5G/5G (OR = 1.80, 95% CI 1.17–2.76, P = 0.007), 4G/5G vs. 5G/5G (OR = 1.40, 95% CI 1.07–1.84, P = 0.02), and 4G vs. 5G (OR = 1.35, 95% CI 1.08–1.68, P = 0.008).

Conclusions

This meta-analysis suggested that the −675 4G/5G polymorphism of PAI-1 gene was a risk factor of asthma.     

Profiling of VEGFs and VEGFRs as prognostic factors in soft tissue sarcoma: VEGFR-3 is an independent predictor of poor prognosis

Background

In non-gastrointestinal stromal tumor soft tissue sarcoma (non-GIST STS) optimal treatment is surgery with wide resection margins. Vascular endothelial growth factors (VEGFs) and receptors (VEGFRs) are known to be key players in the initiation of angiogenesis and lymphangiogenesis. This study investigates the prognostic impact of VEGFs and VEGFRs in non-GIST STS with wide and non-wide resection margins.

Methods

Tumor samples from 249 patients with non-GIST STS were obtained and tissue microarrays were constructed for each specimen. Immunohistochemistry was used to evaluate the expressions of VEGF-A, -C and -D and VEGFR-1, -2 and -3.

Results

In the univariate analyses, VEGF-A (P = 0.040) in the total material, and VEGF-A (P = 0.018), VEGF-C (P = 0.025) and VEGFR-3 (P = 0.027) in the subgroup with wide resection margins, were significant negative prognostic indicators of disease-specific survival (DSS). In the multivariate analysis, high expression of VEGFR-3 (P = 0.042, HR = 1.907, 95% CI 1.024-3.549) was an independent significant negative prognostic marker for DSS among patients with wide resection margins.

Conclusion

VEGFR-3 is a strong and independent negative prognostic marker for non-GIST STSs with wide resection margins.     

Bone related health status in adolescent cyclists

Purpose

To describe bone status and analyse bone mass in adolescent cyclists.

Methods

Male road cyclists (n = 22) who had been training for a minimum of 2 years and a maximum of 7 years with a volume of 10 h/w, were compared to age-matched controls (n = 22) involved in recreational sports activities. Subjects were divided in 2 groups based on age: adolescents under 17 yrs (cyclists, n = 11; controls, n = 13) and over 17 yrs (cyclists, n = 11; controls, n = 9). Peak oxygen uptake (VO₂max) was measured on a cycloergometer. Whole body, lumbar spine, and hip bone mineral content (BMC), density (BMD) and bone area were assessed using dual x-ray absorptiometry (DXA). Volumetric BMD (vBMD) and bone mineral apparent density (BMAD) were also estimated.

Results

The BMC of cyclists was lower for the whole body, pelvis, femoral neck and legs; BMD for the pelvis, hip, legs and whole body and legs bone area was lower but higher in the hip area (all, P≤0.05) after adjusting by lean mass and height. The BMC of young cyclists was 10% lower in the leg and 8% higher in the hip area than young controls (P≤0.05). The BMC of cyclists over 17 yrs was 26.5%, 15.8% and 14.4% lower BMC at the pelvis, femoral neck and legs respectively while the BMD was 8.9% to 24.5% lower for the whole body, pelvis, total hip, trochanter, intertrochanter, femoral neck and legs and 17.1% lower the vBMD at the femoral neck (all P≤0.05). Grouped by age interaction was found in both pelvis and hip BMC and BMD and in femoral neck vBMD (all P≤0.05).

Conclusion

Cycling performed throughout adolescence may negatively affect bone health, then compromising the acquisition of peak bone mass.     

Wheeze in preschool age is associated with pulmonary bacterial infection and resolves after antibiotic therapy

Background

Neonates with airways colonized by Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis are at increased risk for recurrent wheeze which may resemble asthma early in life. It is not clear whether chronic colonization by these pathogens is causative for severe persistent wheeze in some preschool children and whether these children might benefit from antibiotic treatment. We assessed the relevance of bacterial colonization and chronic airway infection in preschool children with severe persistent wheezing and evaluated the outcome of long-time antibiotic treatment on the clinical course in such children.

Methodology/Principal Findings

Preschool children (n = 42) with severe persistent wheeze but no symptoms of acute pulmonary infection were investigated by bronchoscopy and bronchoalveolar lavage (BAL). Differential cell counts and microbiological and virological analyses were performed on BAL samples. Patients diagnosed with bacterial infection were treated with antibiotics for 2–16 weeks (n = 29). A modified ISAAC questionnaire was used for follow-up assessment of children at least 6 months after bronchoscopy. Of the 42 children with severe wheezing, 34 (81%) showed a neutrophilic inflammation and 20 (59%) of this subgroup had elevated bacterial counts (≥10⁴ colony forming units per milliliter) suggesting infection. Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis were the most frequently isolated species. After treatment with appropriate antibiotics 92% of patients showed a marked improvement of symptoms upon follow-up examination.

Conclusions/Significance

Chronic bacterial infections are relevant in a subgroup of preschool children with persistent wheezing and such children benefit significantly from antibiotic therapy.     

Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain

Background

Intravascular hemolysis in sickle cell anemia could contribute to complications associated with nitric oxide deficiency, advancing age, and increased mortality. We have previously reported that intense hemolysis is associated with increased risk of vascular complications in a small cohort of adults with sickle cell disease. These observations have not been validated in other populations.

Methods

The distribution of serum lactic dehydrogenase (LDH) values was used as a surrogate measure of intravascular hemolysis in a contemporaneous patient group and an historical adult population from the Cooperative Study of Sickle Cell Disease (CSSCD), all with sickle cell anemia. Chronic hyper-hemolysis was defined by the top LDH quartile and was compared to the lowest LDH quartile.

Results

Hyper-hemolysis subjects had higher systolic blood pressure, higher prevalence of leg ulcers (OR 3.27, 95% CI 1.92-5.53, P<0.0001), priapism (OR 2.62, 95% CI 1.13-6.90, P = 0.03) and pulmonary hypertension (OR 4.32, 95% CI 2.12-8.60, P<0.0001), while osteonecrosis (OR 0.32, 95% CI 0.19-0.54, P<0.0001) and pain (OR 0.23, 95% CI 0.09-0.55, P = 0.0004) were less prevalent. Hyper-hemolysis was influenced by fetal hemoglobin and α thalassemia, and was a risk factor for early death in the CSSCD population (Hazard Ratio = 1.97, P = 0.02).

Conclusions

Steady state LDH measurements can identify a chronic hyper-hemolysis phenotype which includes less frequent vasooclusive pain and earlier mortality. Clinicians should consider sickle cell specific therapies for these patients, as is done for those with more frequent acute pain. The findings also suggest that an important class of disease modifiers in sickle cell anemia affect the rate of hemolysis.     

Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival

Introduction

Hypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. HIFs are regulated by four hydroxylases; Prolyl hydroxylase (PHD)-1,-2,-3 and factor inhibiting HIF (FIH). We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC.

Methods

Tumor tissue samples from 335 resected stages I to IIIA NSCLC patients was obtained and tissue microarrays (TMAs) were constructed. Hydroxylase expression was evaluated by immunohistochemistry.

Principal Findings

There was scorable expression for all HIF hydroxylases in tumor cells, but not in stroma. In univariate analyses, high tumor cell expression of all the HIF hydroxylases were unfavorable prognosticators for disease-specific survival (DSS); PHD1 (P = 0.023), PHD2 (P = 0.013), PHD3 (P = 0.018) and FIH (P = 0.033). In the multivariate analyses we found high tumor cell expression of PHD2 (HR = 2.03, CI 95% 1.20–3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01–2.10, P = 0.047) to be significant independent prognosticators for DSS. Besides, there was an additive prognostic effect by the increasing number of highly expressed HIF hydroxylases. Provided none high expression HIF hydroxylases, the 5-year survival was 80% vs. 23% if all four were highly expressed (HR = 6.48, CI 95% 2.23–18.8, P = 0.001).

Conclusions

HIF hydroxylases are, in general, poor prognosticators for NSCLC survival. PHD1 and PHD2 are independent negative prognostic factors in NSCLC. Moreover, there is an additive poor prognostic impact by an increasing number of highly expressed HIF hydroxylases.     

The burden of invasive bacterial infections in Pemba, Zanzibar

Background

We conducted a surveillance study to determine the leading causes of bloodstream infection in febrile patients seeking treatment at three district hospitals in Pemba Island, Zanzibar, Tanzania, an area with low malaria transmission.

Methods

All patients above two months of age presenting to hospital with fever were screened, and blood was collected for microbiologic culture and malaria testing. Bacterial sepsis and malaria crude incidence rates were calculated for a one-year period and were adjusted for study participation and diagnostic sensitivity of blood culture.

Results

Blood culture was performed on 2,209 patients. Among them, 166 (8%) samples yielded bacterial growth; 87 (4%) were considered as likely contaminants; and 79 (4%) as pathogenic bacteria. The most frequent pathogenic bacteria isolated were Salmonella Typhi (n = 46; 58%), followed by Streptococcus pneumoniae (n = 12; 15%). The crude bacteremia rate was 6/100,000 but when adjusted for potentially missed cases the rate may be as high as 163/100,000. Crude and adjusted rates for S. Typhi infections and malaria were 4 and 110/100,000 and 4 and 47/100,000, respectively. Twenty three (51%), 22 (49%) and 22 (49%) of the S.Typhi isolates were found to be resistant toward ampicillin, chloramphenicol and cotrimoxazole, respectively. Multidrug resistance (MDR) against the three antimicrobials was detected in 42% of the isolates.

Conclusions

In the presence of very low malaria incidence we found high rates of S. Typhi and S. pneumoniae infections on Pemba Island, Zanzibar. Preventive measures such as vaccination could reduce the febrile disease burden.