Anti-inflammatory effects of new human histamine H3 receptor ligands with flavonoid structure on BV-2 neuroinflammation.

OBJECTIVE: Microglia play an important role in the neuroinflammation developed in response to various pathologies. In this study, we examined the anti-inflammatory effect of the new human histamine H3 receptor (H3R) ligands with flavonoid structure in murine microglial BV-2 cells. MATERIAL AND METHODS: The affinity of flavonoids (E243 -flavone and IIIa-IIIc-chalcones) for human H3R was evaluated in the radioligand binding assay. The cytotoxicity on BV-2 cell viability was investigated with the MTS assay. Preliminary evaluation of anti-inflammatory properties was screened by the Griess assay in an in vitro neuroinflammation model of LPS-treated BV-2 cells. The expression and secretion of pro-inflammatory cytokines were evaluated by real-time qPCR and ELISA, respectively. The expression of microglial cell markers were determined by immunocytochemistry. RESULTS: Chalcone derivatives showed high affinity at human H3R with Ki values < 25 nM. At the highest nontoxic concentration (6.25 µM) compound IIIc was the most active in reducing the level of nitrite in Griess assay. Additionally, IIIc treatment attenuated inflammatory process in murine microglia cells by down-regulating pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α) at both the level of mRNA and protein level. Our immunocytochemistry studies revealed expression of microglial markers (Iba1, CD68, CD206) in BV-2 cell line. CONCLUSIONS: These results emphasize the importance of further research to accurately identify the anti-inflammatory mechanism of action of chalcones.

Staying Active While Staying Home: The Use of Physical Activity Technologies During Life Disruptions.

One impact of the Covid-19 lockdowns was a restriction on people's ability to engage in physical activity in previously routine ways. This paper presents a two-stage mixed-method study exploring how people used technology to stay physically active during this period. We found that activity trackers reminded people to be active, while virtual coaching (i.e., video tutorials and online classes) helped them stay connected. The lockdown increased people's awareness of their activity levels and removed barriers to exercise, for example by giving them greater control over their time. However, it also created new challenges, with lack of time and space, injuries due to sudden changes in activity, and anxiety around lockdown, putting limits on physical activity. We highlight future directions that must be addressed to maximise the benefits of physical activity technologies for people trying to stay active during major life disruptions.

Crowdsourcing as an Analytical Method: Metrology of Smartphone Measurements in Heritage Science.

This research assesses the precision, repeatability, and accuracy of crowdsourced scientific measurements, and whether their quality is sufficient to provide usable results. Measurements of colour and area were chosen because of the possibility of producing them with smartphone cameras. The quality of the measurements was estimated experimentally by comparing data contributed by anonymous participants in heritage sites with reference measurements of known accuracy and precision. Participants performed the measurements by taking photographs with their smartphones, from which colour and dimensional data could be extracted. The results indicate that smartphone measurements provided by citizen scientists can be used to measure changes in colour, but that the performance is strongly dependent on the measured colour coordinate. The same method can be used to measure areas when the difference in colour with the neighbouring areas is large enough. These results render the method useful in some heritage science contexts, but higher precision would be desirable.

Drawing Firmer Conclusions: Autistic Children Show No Evidence of a Local Processing Bias in a Controlled Copying Task.

Drawing tasks are frequently used to test competing theories of visuospatial skills in autism. Yet, methodological differences between studies have led to inconsistent findings. To distinguish between accounts based on local bias or global deficit, we present a simple task that has previously revealed dissociable local/global impairments in neuropsychological patients. Autistic and typical children copied corner elements, arranged in a square configuration. Grouping cues were manipulated to test whether global properties affected the accuracy of reproduction. All children were similarly affected by these manipulations. There was no group difference in the reproduction of local elements, although global accuracy was negatively related to better local processing for autistic children. These data speak against influential theories of visuospatial differences in autism.

Role of Donor Activating KIR-HLA Ligand-Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients.

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable.

Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients.

Among cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the "missing self" recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo- and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor-recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor ("missing licensing proof") induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the "missing licensing proof" in the malignant patient is strongly advisable.

Potential link between MHC-self-peptide presentation and hematopoiesis; the analysis of HLA-DR expression in CD34-positive cells and self-peptide presentation repertoires of MHC molecules associated with paroxysmal nocturnal hemoglobinuria.

The mechanisms of MHC allele associations with paroxysmal nocturnal hemoglobinuria (PNH) and its aplastic anemia subtype (AA/PNH) remain unclear. It might be dependent on MHC molecule functional properties, such as a scope and frequency of antigen sampling and presentation. For documented PNH-associated MHC alleles we analyzed current reference databases on MHC molecule-eluted peptide presentation repertoires and searched for a range of presented peptides. MHC class II expression was measured on CD34+ cells and appeared to be increased in PNH patients. Two class I alleles (HLA-A*24:02 and B*18:01) have been previously confirmed to associate with protection and increased risk of AA/PNH, respectively. Their product molecules presented immunodominant epitopes derived from proapoptotic (serine/threonine-protein phosphatase) and antiapoptotic (phospholipase D), respectively, intracellular enzymes dependent on phosphoinositide (PI) content. For total PNH and non-aplastic PNH (n/PNH) subtype-associated DRB1*15:01 and DRB1*04:01 class II molecules presentation of exceptionally broad arrays of their own peptide fragments has been found. We conclude that self antigen peptides presented with high frequency in the context of MHC molecules of increased expression may be involved in the immune recognition and the regulation of HSC in the periphery. The block in the normal plasma membrane PI production due to the PIG-A mutation can help explain the differences in the activation of intracellular regulatory pathways observed between PNH and normal HSC. This is evident in the variation in MHC association patterns and peptide presentation repertoires between these two groups of patients.

[Evaluation of motivation to quit smoking in outpatients attending smoking cessation clinic]. / Ocena motywacji do rzucenia palenia u pacjentów poradni antynikotynowej.

INTRODUCTION: The success in smoking cessation depends not only on a method of treatment but also on patient motivation. The aim of this study was to estimate the motivation and the main reason to quit smoking among outpatients attending smoking cessation clinic. MATERIAL AND METHODS: One hundred and eleven patients (50 men and 61 women), mean age 58, filled in a motivation test, nicotine dependence test and a questionnaire of the clinic. RESULTS: The main motivation to quit was for the health reasons (83%). Mean motivation test result was 6.93; mean nicotine addiction evaluated in dependence test was 5.49. Eighty seven percent of patients were ready to quit smoking during one month (36% in 24 hours; 23% in one week; 28% in four weeks). There was no significant difference between men and women. CONCLUSIONS: The main motivation to quit smoking were the health reasons as well among men as women. There was no correlation between the readiness to quit smoking determined as time to quit attempt and the motivation test.

[Prevalence of stroke in patients with obstructive sleep apnoea]. / Rozpowszechnienie udaru mózgu u pacjentów z obturacyjnym bezdechem sennym.

INTRODUCTION: Results of earlier population and clinical studies confirmed relationship between stroke and obstructive sleep apnea. Our previous study on epidemiology of sleep-disordered breathing in Warsaw based on 676 subjects, mean age 56.6 +/- 8.2 years, confirmed OSA in 76 subjects (11.3%) mean apnea hypopnea index (AHI) - 25.3 +/- 16.1 revealed low incidence of stroke in OSA group (2 pts; 2.6%) and in subjects without OSA (20 pts; 3.4%). The aim of this study was to assess prevalence of stroke in newly diagnosed OSA subjects qualified to CPAP therapy. MATERIAL AND METHODS: We studied 342 consecutive pts (263 males and 79 females)--mean age--55.4 +/- 10.1 years with severe disease--AHI 39.7 +/- 22.5 and obesity--body mass index 35 +/- 6.6. History of stroke was confirmed in 16 pts before continuous positive airway pressure (CPAP) introduction (4.7%) - group 1. Group 2 (without history of stroke) comprised of 326 pts (95.3%). RESULTS: Multiple linear regression analysis revealed significant correlation between stroke and time spent in desaturation below 90% during polysomnography-- T90 (beta = -0.22, p = 0.009), diabetes (b = 0.16, p = 0.006), Epworth sleepiness score (beta = 0.14, p = 0.02) and coronary artery disease (b = 0.14, p = 0.03). CONCLUSIONS: Stroke in OSA pts before CPAP treatment was related to overnight and daytime oxygenation, diabetes, daytime sleepiness and coronary artery disease. Incidence of stroke in our group was low (4.7%) and similar to previous data from population study.

[Obstructive sleep apnea in patient with Prader-Willi syndrome]. / Obturacyjny bezdech senny u pacjenta z zespolem Pradera-Williego.

Prader-Willi syndrome (PWS) is a genetic disorder caused by loss of function of genes situated within the 15q11-q13 region of chromosome 15. The disorder is characterized by central obesity, short stature, dysfunction of several hypothalamic centers. These symptoms lead to progressive metabolic, respiratory, circulatory and orthopedic complications. Because of the etiology of the disorder there is no known causal treatment. Patients should comply with dietary restrictions and behavioral modifications as it may reduce the risk of obesity related diseases. In this paper we present case of a 34-years old obese patient with PWS who was diagnosed with obstructive sleep apnea, and whom CPAP treatment was offered.

[A case of hereditary over-hydrated stomatocytosis with stomatospherocytes and spherocytes in the blood]. / Przypadek diedzicznej uwodnionej stomatocytozy z obecnoscia stomatosferocytów i sferocytów we krwi.

UNLABELLED: A patient of 31 years of age with an atypical overhydrated hereditary stomatocytosis is described. The diagnosis was established on the basis of a markedly increased red cell volume with low MCHC, high osmotic fragility of red cells, but increased binding of eosin-5-maleimide (EMA) to red cells, presence of stomatospherocytes and large spherocytes in blood and a high sodium and low potassium concentration in erythrocytes. A double band 7 was found by SDS-PAGE of the erythrocyte membrane, but even when only one them was taken into account, the level of stomatin was normal. Expression of stomatospherocytes in patient's blood was erratic: in blood films prepared in 2005, both stomatospherocytes and large spherocytes were present but in those from 2008 large erythrocytes of spherocyte morphology predominated. Clinically, the disease symptoms were typical for haemolytic anemia. When heparinized blood of the patient was kept at 0 degrees Celsius for 24 h, the haemolysis of red cells amounted only to 2%. The patient's son, 5 years old, suffers from the same disease. CONCLUSION: In spite of its rarity, hereditary stomatocytosis and allied disorders should be taken into consideration in differential diagnosis of haemolytic anemia including newborns. The diagnosis is supported by finding increased binding of eosin-5-maleimide (EMA) dye to patients' erythrocytes associated with their elevated osmotic fragility. Absence of a significant count of stomatocytes in the blood does not exclude the diagnosis of overyhydrated hereditary stomatocytosis.

Sneddon's syndrome as a disorder of small arteries with endothelial cells proliferation: ultrastructural and neuroimaging study.

We report a 18-year-old female patient with livedo reticularis and neurological disturbances. CT scan showed two big ischemic focuses in the pons, moreover MRI revealed small disseminated ischemic focuses in the pons and deep structures of both brain hemispheres. MRA demonstrated no changes in the big extracranial and intracranial arteries. Since the clinical data and neuroimaging results suggested Sneddon's syndrome, the skin and skeletal muscle biopsy was taken to examine. The immunohistochemical and ultrastructural investigations of the skin biopsy revealed a significant reduction of the lumen of the capillaries and small to medium-sized arteries. Cells surrounding the vascular lumen, frequently with multilayer arrangement and their nuclei placed perpendicularly to the lumen, were CD31, CD34, and sporadically SMA positive. At the ultrastructural level, these proliferating cells showed typical features of endothelial cells: abundant intermediate filaments and Weibel-Palade bodies. Between the endothelial cells some junctions were detached as well in the capillaries as in the small arteries. The smooth muscle cells of the small arteries were electron denser than usual and their cytoplasmic protrusions penetrated to the endothelial cells. The ultrastructural picture of some vessels with a considerably narrow lumen was typical of vessels newly formed during angiogenesis. Neuroimaging including TC, MRI, MRA besides histological, immunohistochemical and ultrastructural evaluation may be useful for diagnosis of Sneddon's syndrome.