Characterization of sleep spindles using higher order statistics and spectra

Cataloged from PDF version of article.This work characterizes the dynamics of sleep spindles, observed in electroencephalogram (EEG) recorded from humans during sleep, using both time and frequency domain methods which depend on higher order statistics and spectra. The time domain method combines the use of second- and third-order correlations to reveal information on the stationarity of periodic spindle rhythms to detect transitions between multiple activities. The frequency domain method, based on normalized spectrum and bispectrum, describes frequency interactions associated with nonlinearities occuring in the observed EEG

Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34<sup>+</sup>38<sup>lo</sup>) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells <i>in vitro</i>. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34<sup>+</sup> cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease

Role of lipooligosaccharide in the attachment of Moraxella catarrhalis to human pharyngeal epithelial cells

The goal of this study was to determine the role of lipooligosaccharide in the attachment of Moraxella catarrhalis to human pharyngeal epithelial cells. Strain 2951 and its Pk mutant strain 2951 galE were used in this study. This study suggests that the Pk epitope of LOS is not an adhesin for M. catarrhalis, but plays a crucial role by its surface charge in the initial stage of attachment

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Unusual presentation of eosinophilic fasciitis: two case reports and a review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Eosinophilic fasciitis is an uncommon disorder with unknown etiology and a poorly understood pathogenesis. We present the cases of two patients with eosinophilic fasciitis with unusual presentation, and describe the clinical characteristics and laboratory findings related to them.</p> <p>Case presentation</p> <p>The first case involves a 29-year-old Turkish man admitted with pain, edema and induration of his right-upper and left-lower limbs. Unilateral edema and stiffness with prominent pretibial edema was noted upon physical examination. A high eosinophil count was found on the peripheral smear. The second case involves a 63-year-old Turkish man who had pain, edema, erythema, and itching on his upper and lower extremities, which developed after strenuous physical activity. He had cervical lymphadenopathy and polyarthritis upon physical examination, and rheumatoid factor and antinuclear antibody upon laboratory examination.</p> <p>Conclusion</p> <p>Eosinophilic fasciitis can present with various symptoms. When patients exhibit eosinophilia, arthralgia and myalgia, eosinophilic fasciitis should be considered as a possible diagnosis.</p

Evaluation of the metabolism properties of choline kinase alpha in neoplasms of the parathyroid glands. A pilot study

BACKGROUND: Primary hyperparathyroidism (PHPT) is a widespread endocrine disease characterized by excessive production of parathyroid hormone (PTH) due to parathyroid gland hyperplasia (PGH) or tumor lesions (adenoma or cancer of the parathyroid gland (PG) in 80% and 1&ndash;5% of cases respectively). Choline kinase &alpha;&ndash;alpha (XK&alpha;) overexpression is described in tumors of different localization, but there is no data on its expression in PG tumors. AIMS: To study the character of XK&alpha; expression in PG neoplasms and its relationship with clinical, laboratory, and visualization characteristics (positron emission tomography combined with computed tomography (PET/CT) with 18F&ndash;fluorocholine (18F&ndash;FC)). MATERIALS AND METHODS: The material for the study was based on tissue samples from 10 patients of 34&ndash;70 years old (Me = 61.5; [48; 66]), with a laboratory&ndash;confirmed diagnosis of PHT. An immunohistochemical study (IHC) was carried out on materials from 2 patients with hyperplasia of the main cells, from 5 patients with adenoma of PG, from 1 patient with atypical adenoma and 1 with carcinoma of PG; in 1 case the metastasis of cancer of the neck with lymph node was examined. RESULTS: The expression of XK&alpha; is spotted in all types of PG cells (chief cells: active and inactive forms), transitional forms between the chief cells and oxyphil; oxyphil cells, but it was most intense in active chief cells. The expression of XK&alpha; was observed in neoplasms of PG of various degrees of malignancy. In the most numerous group of PG formations with a favorable prognosis (11 samples from 7 patients), no statistically significant correlation (p&gt; 0.05) was obtained between the intensity expression of the XK&alpha;, of the PTH and the proliferative activity index Ki&ndash;67, the level of radiopharmaceutical accumulation in PET/CT with 18F&ndash;FC (SUVmax) and laboratory data (PTH, Ca, Ca++). CONCLUSIONS: In the majority of investigated cases, moderate and intensive expression of the XK&alpha; was detected in PG cells. A small amount of studied cases does not allow us to identify the connection between the intensity of XK&alpha; expression and the malignant potential for the formation of PG

Türkiye’de bulunan yoğun bakımlarda sabun, kağıt havlu ve alkol bazlı el dezenfektanı yeterli mi?: Phokai çalışması sonuçları

Introduction: Hand hygiene is one of the most effective infection control measures to prevent the spread of healthcare-associated infections (HCAI). Water, soap, paper towel and hand disinfectant must be available and adequate in terms of effective hand hygiene. The adequacy of hand hygiene products or keeping water-soap and paper towel is still a problem for many developing countries like Turkey. In this multicenter study, we analyzed the adequacy in number and availability of hand hygiene products.Materials and Methods: This study was performed in all intensive care units (ICUs) of 41 hospitals (27 tertiary-care educational, 10 state and four private hospitals) from 22 cities located in seven geographical regions of Turkey. We analyzed water, soap, paper towel and alcohol-based hand disinfectant adequacy on four different days, two of which were in summer during the vacation time (August, 27th and 31st 2016) and two in autumn (October, 12th and 15th 2016).Results: The total number of ICUs and intensive care beds in 41 participating centers were 214 and 2357, respectively. Overall, there was no soap in 3-11% of sinks and no paper towel in 10-18% of sinks while there was no alcohol-based hand disinfectant in 1-4.7% of hand disinfectant units on the observation days. When we compared the number of sinks with soap and/or paper towel on weekdays vs. weekends, there was no significant difference in summer. However, on autumn weekdays, the number of sinks with soap and paper towel was significantly lower on weekend days (p<0.0001, p<0.0001) while the number of hand disinfectant units with alcohol-based disinfectant was significantly higher (p<0.0001).Conclusion: There should be adequate and accessible hand hygiene materials for effective hand hygiene. In this study, we found that soap and paper towels were inadequate on the observation days in 3-11% and 10-18% of units, respectively. Attention should be paid on soap and paper towel supply at weekends as well

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1

The wogonin-containing herb Scutellaria baicalensis has successfully been used for curing various diseases in traditional Chinese medicine. Wogonin has been shown to induce apoptosis in different cancer cells and to suppress growth of human cancer xenografts in vivo. However, its direct targets remain unknown. In this study, we demonstrate for the first time that wogonin and structurally related natural flavones, for example, apigenin, chrysin and luteolin, are inhibitors of cyclin-dependent kinase 9 (CDK9) and block phosphorylation of the carboxy-terminal domain of RNA polymerase II at Ser2. This effect leads to reduced RNA synthesis and subsequently rapid downregulation of the short-lived anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) resulting in apoptosis induction in cancer cells. We show that genetic inhibition of Mcl-1 or CDK9 expression by siRNA is sufficient to mimic flavone-induced apoptosis. Pull-down and in silico docking studies demonstrate that wogonin directly binds to CDK9, presumably to the ATP-binding pocket. In contrast, wogonin does not inhibit CDK2, CDK4 and CDK6 at doses that inhibit CDK9 activity. Furthermore, we show that wogonin preferentially inhibits CDK9 in malignant compared with normal lymphocytes. Thus, our study reveals a new mechanism of anti-cancer action of natural flavones and supports CDK9 as a therapeutic target in oncology

Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer

Myeloid cell leukaemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family that is elevated in a variety of tumour types including breast cancer. In breast tumours, increased Mcl-1 expression correlates with high tumour grade and poor patient survival. We have previously demonstrated that Her-2 levels correspond to increased Mcl-1 expression in breast tumours. Epidermal growth factor (EGF) receptor signalling is frequently deregulated in breast cancer and leads to increased proliferation and survival. Herein, we determined the critical downstream signals responsible for the EGF mediated increase of Mcl-1 and their role in cell survival. We found that both Mcl-1 mRNA and protein levels are rapidly induced upon stimulation with EGF. Promoter analysis revealed that an Elk-1 transcription factor-binding site is critical for EGF activation of the Mcl-1 promoter. Furthermore, we found that knockdown of Elk-1or inhibition of the Erk signalling pathway was sufficient to block EGF upregulation of Mcl-1 and EGF mediated cell survival. Using chromatin immunoprecipitation and biotin labelled probes of the Mcl-1 promoter, we found that Elk-1 and serum response factor are bound to the promoter after EGF stimulation. To determine whether Mcl-1 confers a survival advantage, we found that knockdown of Mcl-1 expression increased apoptosis whereas overexpression of Mcl-1 inhibited drug induced cell death. In human breast tumours, we found a correlation between phosphorylated Elk-1 and Mcl-1 protein levels. These results indicate that the EGF induced activation of Elk-1 is an important mediator of Mcl-1 expression and cell survival and therefore a potential therapeutic target in breast cancer