Factors associated with general and health-related quality of life in menopausal transition among women from Serbia

ABSTRACT

This study assessed factors associated with quality of life (QOL) among Serbian peri- and postmenopausal women using two menopause-specific scales. This cross-sectional study included 500 women aged 40–65 years who had a gynecologic check-up in one of two Community Health Centers in Belgrade during February 2014 to January 2015. Women completed: a questionnaire about socio-demographics, habits, and health status; a menopause-specific questionnaire, Utian’s Quality of Life Scale (UQOL); and a Women’s Health Questionnaire (WHQ) and Beck’s Depression Inventory (BDI). Higher education was associated with better occupational UQOL and memory/concentration, but with lower emotional UQOL and more anxiety/fears. City center residency was associated with better occupational and sexual UQOL. Being employed was associated with better occupational UQOL and lower anxiety/fears. Higher income was associated with better emotional UQOL. Not having uterine prolapse, insomnia, or tachycardia was associated with better occupational UQOL and fewer sleep problems. Higher parity was associated with better sexual UQOL. Having regular recreation was associated with better health and sexual UQOL but with more frequent vasomotor symptoms. Leaner women felt more attractive. QOL during the menopausal transition does not entail only somatic symptoms and therefore requires a more comprehensive approach that includes psychosocial underpinnings.     

Organochlorine pesticides exposure in female adolescents: potential impact on sexual hormones and interleukin-1 levels

The objective of this study was to assess the potential impact of organochlorine pesticides (OCPs) on IL-1 axis in exposed female adolescents through an observational cross-sectional study. The study was conducted in Sary-Agach District (OCPs exposed girls) and Sairam District (OCPs unexposed controls), South Kazakhstan. The study included 524 female adolescents aged 10–17 years (OCPs exposed, n?=?253; OCPs unexposed, n?=?271). The main outcome was assessment of OCPs blood levels (correlating to pubertal development and sexual hormonal status) and IL-1 levels. The delayed sexual development and the hormonal profile in OCPs exposed female adolescents correlated to the blood levels of OCPs. Interestingly, serum IL-1α and IL-1β in girls living in contaminated areas correlated to OCPs blood levels as well. Both OCPs and IL-1 blood levels in exposed female adolescents resulted to be increased, but further research is required to establish if that might represent an additional factor contributing to puberty disorders and/or reproductive health issues.     

Elevated Intact Proinsulin Levels During an Oral Glucose Challenge Indicate Progressive ?-Cell Dysfunction and May Be Predictive for Development of Type 2 Diabetes

Background:Elevated fasting intact proinsulin is a biomarker of late-stage ß-cell-dysfunction associated with clinically relevant insulin resistance. In this pilot investigation, we explored the potential value of measuring intact proinsulin as a functional predictor of ß-cell exhaustion during an oral glucose tolerance test (OGTT).Methods:The study was performed with 31 participants, 11 of whom were healthy subjects (7 female, age: 59 ± 20 years), 10 had impaired glucose tolerance (IGT, 6 female, 62 ± 10 years), and 10 had known type 2 diabetes (T2DM, 5 female, 53 ± 11 years, HbA1c: 7.0 ± 0.6%, disease duration: 8 ± 5 years). During OGTT, blood was drawn after 0 hours, 1 hour, and 2 hours for determination of glucose and intact proinsulin. Five years later, patients were again contacted to assess their diabetes status and the association to the previous OGTT results was analyzed.Results:The OGTT (0 hours/1 hour/2 hours) results were as follows: healthy subjects: glucose: 94 ± 8 mg/dL/140 ± 29 mg/dL/90 ± 24 mg/dL, intact proinsulin: 3 ± 2 pmol/L/10 ± 7 pmol/L/10 ± 5 pmol/L); IGT: glucose: 102 ± 9 mg/dL/158 ± 57 mg/dL/149 ± 34 mg/dL, intact proinsulin: 7 ± 4 pmol/L/23 ± 8 pmol/L/28 ± 6 pmol/L; T2DM: glucose: 121 ± 20 mg/dL/230 ± 51 mg/dL/213 ± 34 mg/dL; intact proinsulin: 7 ± 7 pmol/L/26 ± 9 pmol/L/27 ± 10 pmol/L). Five years later, all of the IGT and 2 of the healthy subjects had developed T2DM and one had devloped IGT. All of them had elevated 2-hour proinsulin values in the initial OGTT, while patients with normal intact proinsulin results did not develop diabetes.Conclusions:Elevated 2-hour intact proinsulin levels during OGTT were predictive for later type 2 diabetes development. Further studies need to confirm our findings in larger populations.     

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.Metastatic melanoma is a highly aggressive cancer with a fast increasing incidence worldwide. Unless diagnosed early and surgically resected, the disease becomes metastatic and life threatening. Both chemotherapy and irradiation are ineffective. Novel therapies that target oncogenic drivers have brought some improvements, but tumor cells escape regularly (1). Melanoma is a prototypical immunogenic tumor, as shown by the occurrence of spontaneous CD8 T-cell responses that drive tumor regressions and by the identification of CD8 T cells that recognize melanoma antigens (2, 3). Although many immunotherapeutic strategies have been developed to induce such responses, clinical efficacies have been poor. More recently, “checkpoint blockade” therapies that target T-cell–inhibitory pathways mediated by CTLA4 (4) and PD1 (5) have yielded encouraging clinical results and demonstrated that spontaneous CD8 T-cell responses in tumors can be boosted to treat melanoma.The mechanisms that drive spontaneous antitumor immune responses are poorly understood. Type I IFNs (IFN-α and IFN-β) may play a role as the expression type I IFN-related genes in primary melanoma has been associated with spontaneous tumor regressions (6) and correlated to the tumor infiltration by specific CD8+ T cells (6, 7). Furthermore, the lack of type I IFN signaling or IFN-β expression inhibited the generation of tumor-specific CD8 T cells and accelerated tumor growth in a murine melanoma model (7–9).Type I IFNs are typically induced upon recognition of nucleic acids in intracellular compartments. Several cytosolic DNA receptors have been identified and include DNA-dependent activator of IFN-regulatory factors (DAI) (10), gamma-interferon-inducible protein-16 (IFI16) (11), and the helicase DEAD (Asp-Glu-Ala-Asp) box protein 41 (DDX41) (12). These cytosolic receptors trigger IFN-β production via a signaling cascade that involves the master adaptor molecule stimulator of IFN genes (STING), which binds to tank-binding kinase 1 (TBK1) and induces phosphorylation of the interferon regulatory factor 3 (IRF3) (13). STING associates weakly to dsDNA (14) but strongly binds the endogenous cyclic dinucleotide GMP-AMP (cGAMP) synthesized by the cGMP-AMP synthase (cGAS) (15, 16).Recently, spontaneous STING activation was found to be required for the spontaneous induction of antitumor immunity (17). Activation of STING occurred via tumor DNA-dependent cGAS activation and generation of endogenous cGAMP (17, 18). However, the cellular mechanism underlying this response and whether this mechanism could be exploited to generate more efficient antitumor immune responses is currently unknown.Here, we show that intratumoral injection of exogenous cGAMP enhanced STING activation and strongly promoted the generation of antitumor CD8 T-cell responses leading to efficient growth control of injected and contralateral tumors. This response was dependent on IFN-β produced by tumor endothelial cells. In fact, endothelial cells were found to be the principal producers of type I IFN in response to both spontaneous and enforced STING activation, suggesting a role of the tumor vasculature in the initiation of antitumor immunity.     

New protic ionic liquids for fungi and bacteria removal from paper heritage artefacts

In this work, new protic ionic liquids (PILs) with 1-ammonium-2-propanol cation and nine different anions: formate (For), acetate (Ac), lactate (Lac), trifluoroacetate (TFA), chloroacetate (ClA), trichloroacetate (TClA), 3-chloropropionate (3-ClP), 4-chlorobutyrate (4-ClB) and mandelate (Man) were prepared in order to study their antimicrobial activity and possible application for fungi and bacteria removal from deteriorated paper heritage. Ten filamentous fungal strains isolated from specific pigmented area of the damaged books: Trichoderma sp., Cladosporium sp., Penicillium sp.⁽¹⁻³⁾, Penicillium citrinum, Aspergillus sp.^(1,2), Aspergillus flavus, Fusarium graminearum, eight Gram positive and Gram negative ATCC bacterial strains: B. subtilis⁽⁶⁶³³⁾, S. aureus⁽⁶⁵³⁸⁾, E. faecalis^(19433), K. rhizophila⁽⁹³⁴¹⁾, E. coli^(11229), S. enteritidis^(13076), P. mirabilis^(12453), P. aeruginosa^(15692) and two yeast Candida strains: Candida albicans^{(ATCC 10231)} and Candida albicans^(L) were used in this study. The results indicated that antimicrobial activity of selected ionic liquids is significantly affected by the size and specific functional groups in the anion structure. These facts opened the possibility for molecular design of new ionic liquids with strong inhibition properties against the specific bacterial, mould and yeast strains. The significant antimicrobial properties observed in this research suggest that studied PILs may have potential applications in the paper art and artefact cleaning and conservation replacing thus, conventional solvents and organic substances that are toxic for humans and environment.

New protic ionic liquids with 1-ammonium-2-propanol cation and nine different anions were prepared in order to study their antimicrobial activity and possible application for fungi and bacteria removal from deteriorated paper heritage.