Soluble HLA-G in rheumatoid arthritis

We investigated potential correlations between soluble HLA-G (sHLA-G) and soluble HLA class I (sHLA-I) levels, respectively, and parameters of disease activity or genetic factors determined by HLA-DRB1 and HLA-DQB1 in patients with rheumatoid arthritis (RA). SHLA-G plasma concentrations from 106 RA patients (mean age 59.8 years, 80 women) were assessed by a sensitive enzyme-linked immunosorbent assay format. The mean sHLA-G levels were lower and sHLA-I levels higher in the RA patients than in healthy controls. Correlation coefficients of 0.248 to 0.344 (p < 0.01) between sHLA-G and rheumatoid factor, CRP, and EULAR joint swelling score were found. Patients with disease-associated HLA epitopes had higher sHLA-G levels than those without. Significantly lower sHLA-G was observed in groups of patients having HLA-DRB1*03 or HLA-DQB1*02 compared to groups without these genotypes. In contrast, HLA-DQB1*03 or disease-associated epitopes combined with HLA-DQB1*03 were associated with higher sHLA-G levels, whereas the inverse was observed in the combined presence of HLA-DRB1*03 and HLA-DQB1*02. SHLA-G as a percentage of sHLA-I was lower in patients positive for HLA-DQB1*02 and higher in patients positive for HLA-DQB1*03 and in its combined presence with disease-associated epitopes or with HLA-DRB1*07. As especially sHLA-G strongly inhibits T and natural killer (NK) cell functions, low sHLA-G suggests that T and NK cell activities are not efficiently restricted by sHLA-G molecules in rheumatoid arthritis. The sHLA-G levels, however, increase in correlation with parameters of disease activity and appear to be affected by the presence of disease-predisposing epitopes and other HLA-DRB1, DQB1 genotypes.     

Genotype-Specific Clearance of Genital Human Papillomavirus (HPV) Infections among Mothers in the Finnish Family HPV Study

The majority of cervical human papillomavirus (HPV) infections in young women are transient, but whether the clearance differs among different HPV genotypes and the different factors predicting genotype-specific clearance are partly unknown. In the Finnish Family HPV Study, 131 of 252 women (mean age, 25.5 years) cleared their infection during the prospective follow-up of 6 years (median, 62.4 months; range, 1.6 to 94.5 months). Cervical scrapings collected at each visit were tested for 24 low-risk and high-risk (HR) HPV types with multiplex HPV genotyping. Poison regression (panel data) was used to estimate predictors for the clearance of species 7 and 9 HPV genotypes. Of all HPV genotypes detected in these women, multiple-type and HPV type 16 (HPV16) infections showed clearance least frequently (46.1% and 50.5%, respectively). The actuarial and crude mean times to first clearance were variable among different genotypes. The actuarial clearance rate (events/person-time at risk) was highest for HPV16 and multiple-type infections, while HPV66 and -82 had the highest crude clearance rate. Independent predictors increasing type-specific clearance of species 7/9 HPV genotypes were older age (incidence rate ratio [IRR] = 1.1; 95% confidence interval [95% CI], 1.03 to 1.18; P = 0.002) and baseline oral HR HPV DNA-negative status (IRR = 2.94; 95% CI, 1.03 to 8.36; P = 0.042), while a higher number of sexual partners during the follow-up decreased the probability of clearance (IIR = 0.35; 95% CI, 0.15 to 0.83; P = 0.018). To conclude, HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance.Genital human papillomavirus (HPV) infections are transient in most cases (3, 7). Most studies on HPV clearance have addressed high-risk (HR) HPV types collectively and/or have compared clearance between HR and low-risk (LR) HPV types (3, 4, 12, 13, 17, 18, 21, 23, 24). Earlier data suggest that HR HPV infections usually clear more slowly than LR HPV infections (4, 25) and that the likelihood of an infection not clearing increases in parallel with its duration (7, 13).It was not until recently that data on HPV clearance at the genotype level were available (5, 9, 19, 25). The results indicate that infection with HPV type 16 (HPV16) has the lowest tendency for clearance. Accurate data on actual and crude clearance times and clearance rates (CRs) for individual genotypes are needed to understand the natural history of HPV infections.The present study is one of the first to assess the frequency of HPV type-specific clearance as well as the actuarial and crude clearance times and clearance rates for the 24 most common LR and HR HPV genotypes. The study was performed among newly delivered mothers who were followed up for 6 years in the Finnish Family HPV Study. In addition, predictors of species 7/9 HPV genotype clearance were analyzed in a panel Poisson regression model.     

Innate immunity and neuroinflammation in the CNS: The role of microglia in Toll‐like receptor‐mediated neuronal injury

Microglia are key players of the immune response in the central nervous system (CNS) and, being the resident innate immune cells, they are responsible for the early control of infections and for the recruitment of cells of the adaptive immune system required for pathogen clearance. The innate and adaptive immune responses triggered by microglia include the release of proinflammatory mediators. Although an efficient immune response is required for the defense against invading pathogens, an inflammatory response in the CNS may also lead to tissue injury and neurodegeneration. Engagement of Toll‐like receptors (TLRs), a major family of pattern recognition receptors that mediate innate immunity but also link with the adaptive immune response, provides an important mechanism by which microglia are able to sense both pathogen‐ and host‐derived ligands within the CNS. Although there is an increasing body of evidence that TLR signaling mediates beneficial effects in the CNS, it has become clear that TLR‐induced activation of microglia and the release of proinflammatory molecules are responsible for neurotoxic processes in the course of various CNS diseases. Thus, the functional outcome of TLR‐induced activation of microglia in the CNS depends on a subtle balance between protective and harmful effects. This review focuses on the neurodegenerative effects of TLR signaling in the CNS. © 2009 Wiley‐Liss, Inc.     

Heterogeneous effects of distinct tocopherol analogues on NO release, cell volume, and cell death in microglial cells

Tocopherols (vitamin E) are potent antioxidants as well as modulators of enzymes involved in signal transduction, like nitric oxide synthase (NOS). In primary murine microglial cells and in the microglial cell line BV-2, alpha-, gamma-, and delta-tocopherol and alpha-tocopherol acid succinate, respectively, promote nitric oxide (NO) release. The NOS inhibitors aminoguanidine and N(G)-methyl-L-arginine (L-NMMA) suppressed alpha- and gamma-tocopherol-induced NO release, but had no significant effect on delta-tocopherol- and alpha-tocopherol acid succinate-induced NO release. In BV-2 cells, but not in primary microglial cells, gamma- and delta-tocopherol and alpha-tocopherol acid succinate, respectively, led to cell death, characterized by exposition of phosphatidylserine on the cell surface, chromatin condensation, changes in cell volume, and formation of blebs on the cell surface. Aminoguanidine, L-NMMA, and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) enhanced apoptosis in gamma-tocopherol-exposed cells and suppressed apoptosis in delta-tocopherol-treated cells, but had no effect on cells supplemented with alpha-tocopherol acid succinate. The NO donors sodium nitroprusside and 2-(N,N-diethylamino)-diazenolate 2-oxide enhanced apoptosis in gamma- or delta-tocopherol-treated cells, but rescued cells from alpha-tocopherol acid succinate-induced cell death.     

Social functioning and survival: A 10-year follow-up study

Although otherwise extensively researched, one aspect of social functioning in older people that has received less attention is its association with staying at home for as long as possible. This 10-year follow-up examines factors of social functioning that support older people's independent living in their own homes and that reduce the risk of mortality. The data were collected in 1991 by a postal questionnaire that was sent to all residents of Turku, Finland, born in 1920. A physical examination was also conducted. Ten years later, in 2001, the mortality rate of this population was determined. The data were examined statistically. Female gender reduced the risk of mortality. In addition, daily outdoor activities, and not needing help (from different sources) were associated with a reduced risk of mortality. No need for help and a more positive attitude towards life reduced the risk of mortality of women. There were found only non-significant trends for men. Having plans for the future also reduced the risk of mortality. The findings of this study offer useful clues for planning the services provided by home health care personnel. In planning these services it is important that home health care workers take into account the differences between women and men customers: men may need and want different things from the home health care service than women do.     

Human papillomavirus DNA is found in the vas deferens

The role of the male reproductive tract as a reservoir for human papillomavirus (HPV) infection is poorly understood. To analyze the presence of HPV DNA, 27 samples, comprising postvasectomy semen samples and pre- and postejaculation urine samples, were obtained from 18 men recalled for follow-up. HPV DNA was analyzed by nested polymerase chain reaction, confirmed with Southern blot hybridization, cloned, and sequenced. Multiple HPV types were found in different DNA samples of the same men. Five (18.5%) of 27 vas deferens samples contained HPV type 6, 11, or 16. Five (27.8%) of 18 seminal plasma samples (secretions without semen cells) were HPV DNA positive. None of the men had both vas deferens and semen plasma samples HPV positive. Several HPV types can be detected in the male reproductive tract at the same time. This is the first report to show HPV DNA in the vas deferens.     

The androgenic sex hormone profile is an essential feature of metabolic syndrome in premenopausal women: a controlled community-based study

OBJECTIVE: To evaluate sex hormones in premenopausal white women with metabolic syndrome (MBS). DESIGN: Cross-sectional controlled community-based study. SETTING: Pieks?m?ki District Health Center, Pieks?m?ki, Finland. PATIENT(S): Five hundred forty-three women, aged 34 to 54 years, were screened according to National Cholesterol Education Program criteria: waist >88 cm, hypertension >/=130/>/=85 mm Hg, hypertriglyceridemia >/=1.7 mmol/L, high-density lipoprotein (HDL)-cholesterol <1.3 mmol/L, and fasting glucose >/=6.1 mmol/L. Sixty-three women fulfilled at least three of the above-mentioned criteria and were enrolled. Eighty-eight age-matched women without MBS served as controls. INTERVENTION(S): None. MAIN OUTCOME MEASURES: Sex steroid levels in relation to insulin sensitivity and body composition. RESULT(S): A markedly lower insulin sensitivity index and higher free androgen index were detected in the women with MBS than in the controls. Abdominal obesity and increased diastolic blood pressure were significantly associated with high free androgen index in multiple regression analysis. CONCLUSION(S): A hyperandrogenic hormone profile appeared to be a typical feature of premenopausal female MBS even without polycystic ovary syndrome (PCOS).     

Post-molar trophoblastic disease following coexisting molar pregnancy and living fetus subsequent to clomiphene citrate therapy

A case of the combination of a complete hydatidiform mole and a coexisting, living fetus arising from a twin pregnancy, subsequent to clomiphene citrate therapy for ovulation induction, is presented. The diagnostic problems of this combination as well as the incidence of molar pregnancy following the use of ovulation inducers are discussed.     

Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness.

PURPOSE: Hypoxia in tumors is associated with poor prognosis and resistance to treatment. The outcome of hypoxia is largely regulated by the hypoxia-inducible factors (HIF-1alpha and HIF-2alpha). HIFs in turn are negatively regulated by a family of prolyl hydroxylases (PHD1-3). The PHD2 isoform is the main down-regulator of HIFs in normoxia and mild hypoxia. This study was designed to analyze the correlation of the expression and subcellular localization of PHD2 with the pathologic features of human carcinomas and HIF-1alpha expression. EXPERIMENTAL DESIGN: The expression of PHD2 was studied from paraffin-embedded normal tissue (n = 21) and head and neck squamous cell carcinoma (HNSCC; n = 44) by immunohistochemistry. Further studies included PHD2 mRNA detection and HIF-1alpha immunohistochemistry from HNSCC specimens as well as PHD2 immunocytochemistry from HNSCC-derived cell lines. RESULTS: In noncancerous tissue, PHD2 is robustly expressed by endothelial cells. In epithelium, the basal proliferating layer also shows strong expression, whereas the more differentiated epithelium shows little or no PHD2 expression. In HNSCC, PHD2 shows strongly elevated expression both at the mRNA and protein level. Moreover, PHD2 expression increases in less differentiated phenotypes and partially relocalizes from the cytoplasm into the nucleus. Endogenously high nuclear PHD2 is seen in a subset of HNSCC-derived cell lines. Finally, although most of the tumor regions with high PHD2 expression show down-regulated HIF-1alpha, regions with simultaneous HIF-1alpha and PHD2 expression could be detected. CONCLUSIONS: Our results show that increased levels and nuclear translocation of the cellular oxygen sensor, PHD2, are associated with less differentiated and strongly proliferating tumors. Furthermore, they imply that even the elevated PHD2 levels are not sufficient to down-regulate HIF-1alpha in some tumors.     

Expression of integrin α9 subunit and tenascin in oral leukoplakia, lichen planus, and squamous cell carcinoma

OBJECTIVES: Integrin alpha9 subunit is a member of beta1 integrin family and binds tenascin (TN). It is expressed by stratified squamous epithelium and may be associated with cell differentiation and growth. We studied if the expression of alpha9 integrin and TN is altered in leukoplakia, lichen planus, and squamous cell carcinoma (SCC).METHODS: Frozen sections of tissue samples obtained from normal human keratinized (16 subjects) and non-keratinized (three subjects) oral mucosa, oral leukopakias with dysplasia (19 subjects), reticular type lichen planus (nine subjects), or oral mucosal SCC (23 subjects) were stained immunohistochemically with antibodies against alpha9 integrin and TN.RESULTS: In contrast to its most prominent localization at the cell membranes of the basal epithelial cells in the normal mucosa, alpha9 integrin was localized in a more diffuse pattern with focal loss of expression at the epithelial cell membranes in leukoplakic dysplasia, lichen planus, and SCC. In some areas of SCC, alpha9 integrin localized throughout all cell layers of the tumor epithelium. In most areas, alpha9 integrin colocalized with TN but in heavily inflamed areas there was focal loss of TN and alpha9 integrin at the basement membrane zone. CONCLUSIONS: The findings show that alpha9 integrin expression is altered in leukoplakic dysplasia, lichen planus, and SCC.