Factors affecting human IgE and IgG responses to allergen-like Schistosoma mansoni antigens: Molecular structure and patterns of in vivo exposure

BACKGROUND: The human IgE response is associated with allergy and with host defence against parasitic worms. A response to Sm22.6, the dominant IgE antigen in adult Schistosoma mansoni worms, correlates with resistance to re-infection after treatment. Sm22.6 is one of a family of EF-hand containing parasite proteins with sequence similarity to dynein light chain (DLC) and with major non-parasite allergens. Here we compare human IgE and IgG responses to other family members, Sm20.8 and Sm21.7, as well as to SmDLC1, relating these to antigen structure and expression in parasite life stages. METHODS: Recombinant antigens were used in ELISA to measure antibody isotype responses in 177 cases from an endemic area, before and 7 weeks after treatment. Parasite antigen expression was assessed by RT-PCR and Western blotting. RESULTS: Levels of antibodies to Sm22.6 and Sm20.8 (but not to Sm21.7 or SmDLC1) showed posttreatment increases in all but young children. Many produced IgE to Sm22.6 and Sm20.8 (2 EF-hands), few to Sm21.7 (1 EF-hand) or SmDLC1 (no EF-hands). Sm21.7 was expressed in cercariae, adults and eggs, Sm22.6 and Sm20.8 were concentrated in the adult. CONCLUSIONS: These studies suggest that IgE antigens Sm22.6 and Sm20.8 are only released to boost antibodies when adult worms die, whilst Sm21.7 and SmDLC1 are released constantly from eggs dying in host tissue. IgE responses to these allergen-like molecules may be influenced by patterns of exposure and the number of EF-hand motifs.     

Short-term street soccer improves fitness and cardiovascular health status of homeless men

This study examined the effect of 12 weeks of small-sided street soccer (2.2 ± 0.7 sessions/week) and fitness center training (0.5 ± 0.2 sessions/week) on physical fitness and cardiovascular health profile for homeless men. Exercise capacity, maximal oxygen uptake (VO(2max)), body composition (DXA scans), blood pressure (BP), and blood lipid profile were determined before and after the intervention period for 22 soccer-group subjects (SG) and 10 waiting list controls (CO). In addition, time-motion analyses, HR measurements, and pedometer recordings were performed during street soccer training and daily-life activities. During a 60 min 4 versus 4 street soccer session 182 ± 62 intense running bouts were performed; mean HR was 82 ± 4% HR(max) and HR was >90% HR(max) for 21 ± 12% (±SD) of total time. On a day without training the participants performed 10,733 ± 4,341 steps and HR was >80% HR(max) for 2.4 ± 4.3 min. In SG, VO(2max) was elevated (p < 0.05) from 36.7 ± 7.6 to 40.6 ± 8.6 ml/min/kg after 12 weeks and incremental cycle test performance was improved (p < 0.05) by 81 s (95% CI: 47-128 s). After 12 weeks, fat percentage (19.4 ± 8.5 to 17.5 ± 8.6%) and LDL cholesterol (3.2 ± 1.1 to 2.8 ± 0.8 mmol L(-1)) were lowered (p < 0.05) in SG. The observed changes in SG were different (p < 0.05) from CO and no intra-group changes occurred for CO (p > 0.05). BP was unaltered after 12 weeks (p > 0.05), but diastolic BP was lowered for all SG subjects with pre-values >75 mmHg (83 ± 6 to 76 ± 6 mmHg, n = 8, p < 0.05). In conclusion, the exercise intensity is high during street soccer and regular street soccer training can be used as an effective activity to promote physical fitness and cardiovascular health status for homeless men.     

The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases

We describe a revised and expanded database on human intermediate filament proteins, a major component of the eukaryotic cytoskeleton. The family of 70 intermediate filament genes (including those encoding keratins, desmins, and lamins) is now known to be associated with a wide range of diverse diseases, at least 72 distinct human pathologies, including skin blistering, muscular dystrophy, cardiomyopathy, premature aging syndromes, neurodegenerative disorders, and cataract. To date, the database catalogs 1,274 manually-curated pathogenic sequence variants and 170 allelic variants in intermediate filament genes from over 459 peer-reviewed research articles. Unrelated cases were collected from all of the six sequence homology groups and the sequence variations were described at cDNA and protein levels with links to the related diseases and reference articles. The mutations and polymorphisms are presented in parallel with data on protein structure, gene, and chromosomal location and basic information on associated diseases. Detailed statistics relating to the variants records in the database are displayed by homology group, mutation type, affected domain, associated diseases, and nucleic and amino acid substitutions. Multiple sequence alignment algorithms can be run from queries to determine DNA or protein sequence conservation. Literature sources can be interrogated within the database and external links are provided to public databases. The database is freely and publicly accessible online at www.interfil.org (last accessed 13 September 2007). Users can query the database by various keywords and the search results can be downloaded. It is anticipated that the Human Intermediate Filament Database (HIFD) will provide a useful resource to study human genome variations for basic scientists, clinicians, and students alike.     

Development of gut microbiota in infants not exposed to medical interventions

Knowledge of the composition of a normal healthy gut microbiota during infancy is important for understanding the role of gut microbiota in disease. A limitation of previous studies is that they are based on infants who have been subject to factors, which can have a profound disruptive effect on the natural colonization process. We describe the colonization process, during the first 4 months after birth, in 85 infants who have experienced no major medical or dietary interventions. They were all vaginally delivered, healthy, term infants, who were not exposed to antibiotics, exclusively breastfed during their first month of life and at least partially breastfed up to 4 months. Selected microbial groups were identified by targeting small subunit microbial ribosomal RNA genes. In contrast to more recent studies, but in agreement with older studies, almost all our infants harbored γ-Proteobacteria and Bifidobacterium. Yet undefined non-cultivable species belonging to Bacteroides, as well as microbes identified as Lachnospiraceae 2, were common. Strong associations were observed between some specific constituents of microbiota at day 4 and the concentration of specific microbial groups at day 120, indicating that early gut microbiota may influence later microbiota. Novel information of the undisturbed composition of early gut microbiota in babies is presented.     

Evaluating TIMP-1, Ki67, and HER2 as markers for non-sentinel node metastases in breast cancer patients with micrometastases to the sentinel node

The aim was to investigate whether the biochemical prognostic markers TIMP-1, Ki67, and HER2 could predict metastatic spread to non-sentinel nodes (NSN) in breast cancer patients with micrometastases to sentinel node (SN). We included all breast cancer patients with micrometastases to SN operated between 2001 and 2007 at the Department of Breast Surgery, Herlev Hospital. The study was designed as a matched case-control study with 25 cases with micrometastases to SN and, in addition, metastatic spread to NSN and 50 matched controls with micrometastases to SN, but without NSN metastases. Patient and tumor characteristics were retrieved from the Danish Breast Cancer Cooperative Group database. Immunohistochemical analyses of TIMP-1 and Ki67 and measurements of HER2 on formalin-fixed paraffin-embedded tumor tissue were performed. No significant differences in the immunoreactivity of TIMP-1 and Ki67 were found between patients with and without NSN metastases. Six of seven HER2 positive patients did not have NSN metastases, but the results did not reach statistical significance. Despite being prognostic markers in breast cancer, TIMP-1 and Ki67 could not predict NSN metastases in women with micrometastatic disease to SN. Larger studies are needed to further validate HER2 as a marker for NSN metastases in these patients.     

Associations between physical and mental health problems and sexual dysfunctions in sexually active Danes

IntroductionStudies have shown a high prevalence of sexual dysfunctions among individuals with a variety of health problems.AimTo obtain a population‐based assessment of these matters, we studied associations between indicators of physical and mental health problems and sexual dysfunctions in Denmark.MethodsWe used questionnaire data from 4,415 sexually active men (mean age 48 years) and women (mean age 45 years) who participated in a nationally representative survey in 2005. Cross‐sectional associations of overall health and physical and mental health problems with sexual dysfunctions in the last year were estimated by logistic regression‐derived, confounder‐adjusted odds ratios (OR_adj).Main Outcome MeasuresWe calculated OR_adj with 95% confidence intervals (CI) for erectile dysfunction, anorgasmia, premature ejaculation, and dyspareunia in men, for lubrication insufficiency, anorgasmia, dyspareunia, and vaginismus in women, and for sexual dysfunction and sexual difficulties overall in both sexes.ResultsSexual dysfunction was significantly more common among participants with poor self‐rated health (OR_adj 1.86, 95% CI 1.05‐3.33 in men, OR_adj 1.91, 1.08–3.37 in women). Physical health problems were significantly associated with male sexual dysfunctions (OR_adj 1.75, 1.18–2.61), whereas mental health problems were significantly associated with female sexual dysfunctions (OR_adj 2.59, 1.60–4.22).ConclusionAmong sexually active Danes, poor self‐reported overall health is associated with increased rates of sexual dysfunction in both sexes, with physical health problems mainly affecting men's sex lives, and mental health problems being strongly associated with female sexual dysfunction. Christensen BS, Grønbæk M, Osler M, Pedersen BV, Graugaard C, and Frisch M. Associations between physical and mental health problems and sexual dysfunctions in sexually active Danes. J Sex Med 2011;8:1890–1902.     

Predictive value of combined analysis of pro‐NPY and ERG in localized prostate cancer

This study aimed to investigate if combined analysis of pro‐Neuropeptide Y (NPY) and ERG expression in tumor tissue are associated with biochemical failure (BF), castration‐based treatment, castration‐resistant prostate cancer (CRPC), and prostate cancer (PCa)‐specific death for men undergoing radical prostatectomy (RP) for PCa. This study included 315 patients, who underwent RP from 2002 to 2005. Both pro‐NPY and ERG expression were analyzed using immunohistochemistry and were scored as low or high and negative or positive, respectively. Risk of BF, castration‐based treatment, CRPC, and PCa‐specific death were analyzed with multiple cause‐specific Cox regression analyses and stratified cumulative incidences using competing risk assessment. Median follow‐up was 13.0 years (95% CI: 12.7–13.2). In total, 85.7% were pro‐NPY high and 14.3% were pro‐NPY low. The combined analyses of pro‐NPY and ERG expression was not associated with risk of BF (p = 0.7), castration‐based treatment (p = 0.8), CRPC (p = 0.4) or PCa‐specific death (p = 0.5). In the multiple cause‐specific Cox regression analysis, pro‐NPY high and ERG positivity was not associated with BF (HR: 1.02; 95% CI 0.6–1.7; p = 0.94). In conclusion the combination of pro‐NPY and ERG expression did not show association with risk of BF, castration‐based treatment, CRPC, and PCa‐specific death following RP.     

A mutation update on the LDS‐associated genes TGFB2/3 and SMAD2/3

The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor‐β (TGF‐β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF‐β signaling. More recently, TGF‐β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF‐β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF‐β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.     

Reliability of histological malignancy grade,ER and HER2 status on core needle biopsy vs surgical specimen in breast cancer

Early determination of malignancy grade and biomarkers in primary breast cancer is important when planning the treatment with neoadjuvant therapy and breast‐conserving surgery. The aim of this study was to assess the reliability of malignancy grade on core needle biopsies, and to compare the concordance of ER and HER2 status on core needle biopsies vs surgical specimens. Eighty‐nine patients with invasive ductal or lobular carcinoma were included. Malignancy grade was upgraded by one degree in 23.0%. The mitotic count had most impact on the malignancy grade, and may be underestimated on core needle biopsies compared with surgical specimens. ER status was concordant in core needle biopsies and surgical specimens in 98.0%, but should be repeated when doubtfully negative. HER2 status was concordant in 84.0% prior to FISH‐HER2. Including FISH‐HER2 data, the core needle biopsies showed a final total concordance of 95.4%. In conclusion, ER and HER2 are useful markers in core needle biopsies, providing a reliable base for preoperative decisions in neoadjuvant chemotherapy, and may be omitted on surgical specimens with certain precautions and exceptions. Determination of malignancy grade should be repeated on surgical specimens, and one should be aware of underestimation on core needle biopsies.