Assessment of Obstructive Sleep Apnea and its Severity during Wakefulness

In this article, a novel technique for assessment of obstructive sleep apnea (OSA) during wakefulness is proposed; the technique is based on tracheal breath sound analysis of normal breathing in upright sitting and supine body positions. We recorded tracheal breath sounds of 17 non-apneic individuals and 35 people with various degrees of severity of OSA in supine and upright sitting positions during both nose and mouth breathing at medium flow rate. We calculated the power spectrum, Kurtosis, and Katz fractal dimensions of the recorded signals and used the one-way analysis of variance to select the features, which were statistically significant between the groups. Then, the maximum relevancy minimum redundancy method was used to reduce the number of characteristic features to two. Using the best two selected features, we classified the participant into severe OSA and non-OSA groups as well as non-OSA or mild vs. moderate and severe OSA groups; the results showed more than 91 and 83% accuracy; 85 and 81% specificity; 92 and 95% sensitivity, for the two types of classification, respectively. The results are encouraging for identifying people with OSA and also prediction of OSA severity. Once verified on a larger population, the proposed method offers a simple and non-invasive screening tool for prediction of OSA during wakefulness.     

Determinants of quality of life in Greek middle-age women: a population survey

Objectives

The aim of the present study was to evaluate how sociodemographic parameters, lifestyle indicators and intensity of climacteric symptoms affect the quality of life (QOL) of Greek community dwelling middle-aged women.

Study design

This population survey included 1140 middle-aged women aged 45–65 who represented 1% of the whole female population of this age group in Greece, stratified by residential area.

Main outcome measures

Participants were asked to complete a questionnaire concerning sociodemographic and anthropometric parameters, medical history, the Utian quality of life (QOL) scale and the Greene climacteric scale rating menopausal symptoms.

Results

In the univariate analysis, normal body mass index, married status, higher education, employment, good financial status, physical exercise and a high calcium diet were associated with higher total QOL scores (p-value < 0.001). Multivariate regression analysis showed that higher total QOL scores were predicted by being married (separated/divorced/widowed: beta = −3.17, p-value = 0.008), by physical exercise (beta = 4.84 and beta = 4.57 for 1–3 h and >3 h per week respectively, p-value < 0.001) and by a good financial status (beta = 7.05, p-value < 0.001), while a higher score in the Greene scale resulted in lower total QOL scores (beta = −0.77, p-value < 0.001). Women with a better QOL were more health conscious and more probable to have utilized the public health preventive resources.

Conclusions

Menopause as a life event has no effect on the QOL of Greek middle-aged women. On the contrary, the presence and intensity of climacteric symptoms have a negative impact on all aspects of QOL. Marital and financial status, as well as physical exercise, are also significant predictors of QOL.     

Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: The effect of minocycline

Comorbidity of cognitive and stress disorders is a common clinical sequel of traumatic brain injury (TBI) that is essentially determined by the site and severity of the insult, but also by the extent of the ensuing neuroinflammatory response. The present study sought to examine the late effects of closed-head TBI on memory function and anxiety in mice, in order to further examine the potential efficacy of an acute anti-inflammatory treatment with minocycline. The mouse model of closed-head injury by mechanical percussion was applied on anesthetized Swiss mice. The treatment protocol included three injections of minocycline (i.p.) at 5 min (90 mg/kg), 3 h and 9 h (45 mg/kg) post-TBI. The Novel Object Recognition Test as well as the Elevated Plus Maze (EPM) and Elevated Zero Maze (EZM) tasks were employed to assess post-TBI memory and anxiety respectively. Our results revealed a recognition memory deficit that was significant up to at least 13 weeks post-TBI. However, neither EPM nor EZM revealed any alteration in post-TBI anxiety levels albeit some mild disinhibition. Most importantly, minocycline was able to attenuate the memory impairment in an effective and lasting manner, highlighting its therapeutic potential in TBI.     

Mutations in CYP1B1 cause primary congenital glaucoma by reduction of either activity or abundance of the enzyme

Primary congenital glaucoma (PCG) is an autosomal recessive disorder caused predominantly by mutations in the CYP1B1 gene. A total of five frequent single nucleotide polymorphisms (SNPs) have been identified in the coding sequence of CYP1B1: rs10012C>G (p.R48G), rs1056827G>T (p.A119S), rs1056836C>G (p.V432L), rs1056837C>T (p.D449D), and rs1800440A>G (p.N453S). We performed a functional characterization of four common CYP1B1 variants presenting different coding SNP haplotypes (RAVDN, GSLDN, RALDS, and RALDN) and five CYP1B1 mutations reported for PCG patients: c.182G>A (p.G61E), c.608A>G (p.N203S), c.1033_1035del (p.L343del), c.241 T>A (p.Y81N), and c.685G>A (p.E229 K). Each mutation was embedded in its corresponding background SNP haplotype. The common variants revealed variation in enzymatic activity; among them, RAVDN showed the highest activity. Mutants p.G61E, p.N203S, and p.L343del each revealed a residual activity (<10%) of their respective haplotype. The microsomal CYP1B1 abundance relative to total protein also showed variation in common variants and a significant reduction in p.L343del, p.Y81N, and p.E229 K. The free energy of folding (DeltaDeltaG) values suggest that the lower stability of the mutants is one key property leading to the experimentally observed lower protein abundance. Our new measure of relative enzymatic activity (U/mg total protein), which combines activity and abundance values, was significantly lower for all five mutations compared to the corresponding background haplotype. We classified p.Y81N and p.E229 K not as mutations but as hypomorphic alleles, since their relative activity values are intermediate between bona fide mutations and the common variant with the lowest activity (RALDS). We propose that CYP1B1 mutations can act by either reducing enzymatic activity (p.G61E and p.N203S), reducing the abundance of the enzyme (p.Y81N and p.E229 K), or both (p.L343del).     

Transforming growth factor beta cooperates with persephin for dopaminergic phenotype induction

The aim of the present study was to investigate the putative cooperative effects of transforming growth factor beta (TGF-beta) and glial cell line-derived neurotrophic factor (GDNF) family ligands in the differentiation of midbrain progenitors toward a dopaminergic phenotype. Therefore, a mouse midbrain embryonic day (E) 12 neurospheres culture was used as an experimental model. We show that neurturin and persephin (PSPN), but not GDNF, are capable of transient induction of dopaminergic neurons in vitro. This process, however, requires the presence of endogenous TGF-beta. In contrast, after 8 days in vitro GDNF rescued the TGF-beta neutralization-dependent loss of the TH-positive cells. In vivo, at E14.5, no apparent phenotype concerning dopaminergic neurons was observed in Tgf-beta2(-/-)/gdnf(-/-) double mutant mice. In vitro, combined TGF-beta/PSPN treatment achieved a yield of approximately 20% TH-positive cells that were less vulnerable against 1-methyl-4-phenyl pyridinium ion toxicity. The underlying TGF-beta/PSPN differentiation signaling is receptor-mediated, involving p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. These results indicate that phenotype induction and survival of fully differentiated neurons are accomplished through distinct pathways and individual factor requirement. TGF-beta is required for the induction of dopaminergic neurons, whereas GDNF is required for regulating and/or maintaining a differentiated neuronal phenotype. Moreover, this study suggests that the combination of TGF-beta with PSPN is a potent inductive cocktail for the generation of dopaminergic neurons that should be considered in tissue engineering and cell replacement therapies for Parkinson's disease.     

Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling

Tzelepi V, Karlou M, Wen S, Hoang A, Logothetis C, Troncoso P & Efstathiou E
(2011) Histopathology 58, 1037–1047
Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling Aims: The hedgehog (Hh) signalling pathway has been implicated in the pathogenesis and aggressiveness of prostate cancer through epithelial–mesenchymal interactions. The aim of this study was to elucidate the cell‐type partitioned expression of the Hh pathway biomarkers in the non‐neoplastic and tumour microenvironments and to correlate it with the grade and stage of prostate cancer. Methods and results: Expression of the Hh pathway components (Shh, Smo, Ptch, Gli1) in the microenvironment of non‐neoplastic peripheral zone (n = 119), hormone‐naive primary prostate carcinoma (n = 141) and castrate‐resistant bone marrow metastases (n = 53) was analysed using immunohistochemistry in tissue microarrays and bone marrow sections. Results showed that epithelial Shh, Smo and Ptch expression was up‐regulated, whereas stromal Smo, Ptch, and Gli1 expression was down‐regulated in prostate carcinomas compared to non‐neoplastic peripheral zone tissue. Ptch expression was modulated further in high‐grade and high‐stage primary tumours and in bone marrow metastases. Hh signalling correlated with ki67 and vascular endothelial growth factor (VEGF) but not with CD31 expression. Conclusion: Our results highlight the importance of Hh‐mediated epithelial–mesenchymal interactions in the non‐neoplastic prostate and imply that shifting the balance from paracrine towards autocrine signalling is important in the pathogenesis and progression of prostate carcinoma.     

Lack of TNF-α-induced MMP-9 production and abnormal E-cadherin redistribution associated with compromised fusion in MCP-1-null macrophages

Homotypic cell fusion occurs in several cell types including macrophages in the formation of foreign body giant cells. Previously, monocyte chemoattractant protein-1 (MCP-1) was demonstrated to be required for foreign body giant cell formation in the foreign body response. The present study investigated the fusion defect in MCP-1-null macrophages by implanting biomaterials intraperitoneally in wild-type and MCP-1-null mice and monitoring the macrophage response at 12 hours to 4 weeks. MCP-1-null mice exhibited reduced accumulation and fusion of macrophages on implants, which was associated with attenuation of the foreign body response. Consistent with previous in vitro findings, the level of matrix metalloproteinase-9 (MMP-9) was reduced in MCP-1-null macrophages adherent to implants. In contrast, CCR2 expression was unaffected. In vitro studies revealed reduced tumor necrosis factor-α (TNF-α) production and abnormal subcellular redistribution of E-cadherin and β-catenin during fusion in MCP-1-null macrophages. Exogenous TNF-α caused an increase in the production of MMP-9 and rescued the fusion defect. Addition of GM6001 (MMP inhibitor) or NSC23766 (Rac1 inhibitor) indicated two distinct induction pathways, one for E-cadherin/β-catenin and one for MCP-1, TNF-α, and MMP-9. Considered together, these observations demonstrate that induction of E-cadherin/β-catenin is not sufficient for fusion in the absence of MCP-1 or the downstream mediators TNF-α and MMP-9. Moreover, attenuation of the foreign body response in intraperitoneal implants in MCP-1-null mice demonstrates that the process depends on tissue-specific factors.     

Association of sleep duration and quality with immunological response after vaccination against severe acute respiratory syndrome coronavirus-2 infection

Growing evidence suggests that sleep could affect the immunological response after vaccination. The aim of this prospective study was to investigate possible associations between regular sleep disruption and immunity response after vaccination against coronavirus disease 2019 (COVID-19). In total, 592 healthcare workers, with no previous history of COVID-19, from eight major Greek hospitals were enrolled in this study. All subjects underwent two Pfizer–BioNTech messenger ribonucleic acid (mRNA) COVID-19 vaccine BNT162b2 inoculations with an interval of 21 days between the doses. Furthermore, a questionnaire was completed 2 days after each vaccination and clinical characteristics, demographics, sleep duration, and habits were recorded. Blood samples were collected and anti-spike immunoglobulin G antibodies were measured at 20 ± 1 days after the first dose and 21 ± 2 days after the second dose. A total of 544 subjects (30% males), with median (interquartile range [IQR]) age of 46 (38–54) years and body mass index of 24·84 (22.6–28.51) kg/m² were eligible for the study. The median (IQR) habitual duration of sleep was 6 (6–7) h/night. In all, 283 participants (52%) had a short daytime nap. In 214 (39.3%) participants the Pittsburgh Sleep Quality Index score was >5, with a higher percentage in women (74·3%, p < 0.05). Antibody levels were associated with age (r = −0.178, p < 0.001), poor sleep quality (r = −0.094, p < 0.05), insomnia (r = −0.098, p < 0.05), and nap frequency per week (r = −0.098, p < 0.05), but after adjusting for confounders, only insomnia, gender, and age were independent determinants of antibody levels. It is important to emphasise that insomnia is associated with lower antibody levels against COVID-19 after vaccination.     

Cellular FLIP long isoform transgenic mice overcome inherent Th2-biased immune responses to efficiently resolve Leishmania major infection

c-FLIP(L) expression in T cells is required for mounting effective T cell responses and can also be critical for effector T cell differentiation, as has recently been shown by a number of in vivo studies in conditional knockout and transgenic mouse systems. Available data supports therefore a novel immunomodulatory role of this anti-apoptotic protein besides its traditionally proposed function in homeostatic maintenance of T cell populations. In this study, the responses to infection with Leishmania major of mice over-expressing FLIP(L) specifically in the T cell compartment (TgFLIP(L)) are assessed. Although previous studies have shown that FLIP(L) drives T cells towards a T(h)2 differentiation programme in various autoimmune and allergic paradigms, in this study, we show that TgFLIP(L) are able to overcome this T(h)2 bias in a dermal L. major infection model to mount a robust T(h)1 response to pathogen and effectively clear infection. Our results suggest that vaccination protocols designed to enhance FLIP(L) expression in T cells may be useful for the treatment of autoimmune diseases like multiple sclerosis, without necessarily compromising immune responses towards infectious agents.