BACKGROUND: This inter-comparison exercise was performed to demonstrate the variability of quantitative SPECT/CT imaging for lutetium-177 (177Lu) in current clinical practice. Our aim was to assess the feasibility of using international inter-comparison exercises as a means to ensure consistency between clinical sites whilst enabling the sites to use their own choice of quantitative imaging protocols, specific to their systems. Dual-compartment concentric spherical sources of accurately known activity concentrations were prepared and sent to seven European clinical sites. The site staff were not aware of the true volumes or activity within the sources-they performed SPECT/CT imaging of the source, positioned within a water-filled phantom, using their own choice of parameters and reported their estimate of the activities within the source. RESULTS: The volumes reported by the participants for the inner section of the source were all within 29% of the true value and within 60% of the true value for the outer section. The activities reported by the participants for the inner section of the source were all within 20% of the true value, whilst those reported for the outer section were up to 83% different to the true value. CONCLUSIONS: A variety of calibration and segmentation methods were used by the participants for this exercise which demonstrated the variability of quantitative imaging across clinical sites. This paper presents a method to assess consistency between sites using different calibration and segmentation methods.

• Publikační typ
• časopisecké články MeSH

WrbA is a novel multimeric flavodoxin-like protein of unknown function. A recent high-resolution X-ray crystal structure of E. coli WrbA holoprotein revealed a methionine sulfoxide residue with full occupancy in the FMN-binding site, a finding that was confirmed by mass spectrometry. In an effort to evaluate whether methionine sulfoxide may have a role in WrbA function, the present analyses were undertaken using molecular dynamics simulations in combination with further mass spectrometry of the protein. Methionine sulfoxide formation upon reconstitution of purified apoWrbA with oxidized FMN is fast as judged by kinetic mass spectrometry, being complete in ∼5 h and resulting in complete conversion at the active-site methionine with minor extents of conversion at heterogeneous second sites. Analysis of methionine oxidation states during purification of holoWrbA from bacterial cells reveals that methionine is not oxidized prior to reconstitution, indicating that methionine sulfoxide is unlikely to be relevant to the function of WrbA in vivo. Although the simulation results, the first reported for WrbA, led to no hypotheses about the role of methionine sulfoxide that could be tested experimentally, they elucidated the origins of the two major differences between apo- and holoWrbA crystal structures, an alteration of inter-subunit distance and a rotational shift within the tetrameric assembly.

• MeSH
• apoproteiny chemie   izolace a purifikace   metabolismus   MeSH
• flavinmononukleotid chemie   metabolismus   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• kinetika MeSH
• konformace proteinů MeSH
• methionin analogy a deriváty   chemie   metabolismus   MeSH
• oxidace-redukce MeSH
• proteiny z Escherichia coli chemie   izolace a purifikace   metabolismus   MeSH
• represorové proteiny chemie   izolace a purifikace   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• stabilita proteinů MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations.

• MeSH
• biologické markery krev   MeSH
• kometový test metody   MeSH
• lidé MeSH
• poškození DNA genetika   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• kožní absorpce MeSH
• rizikové faktory MeSH
• vystavení vlivu životního prostředí MeSH

• Konspekt
• Veřejné zdraví a hygiena
• NLK Obory
• dermatovenerologie
• environmentální vědy
• NLK Publikační typ
• publikace WHO

PURPOSE OF THE STUDY The aim of this prospective randomised study was to compare and statistically analyse two methods of condylar twist angle (CTA) measurement in total knee arthroplasty in order to assess their applicability in routine practice. MATERIAL AND METHODS The study included 238 patients with 256 sites undergoing total knee arthroplasty (TKA) in the period from January 2009 to May 2011. There were 93 men (nine with bilateral TKA) and 145 women (nine with bilateral TKA) with an average age of 69.3 years and a range of 47 to 88 years. The implants NexGen (Zimmer) and ADVANCE? Medial-Pivot Knee (Wright) were used. In each patient, CTA was measured before surgery by the radiologist on a multidetector CT SOMATOM 64 (Siemens) using the Yoshioki method. The other CTA measurement was made intra-operatively by the surgeon using our modification of the Hofmann method which involved the identification of a reference line for optimal rotational alignment of the femoral component. A STATISTICA 9.0 software package was used for statistical analysis. In addition to basic statistical data, selected data were presented in graphical forms as Box and Whisker's plots and histograms. Changes in CTA and differences between the groups were evaluated using the Wilcoxon signed-rank test. Relationships among the variables were studied using Spearman's correlation coefficient. RESULTS The statistical analysis showed that the pre-operative CTA value obtained from CT scans was, on the average, higher by 0.5 degrees than the value from intra-operative measurement, as assessed at the level of significance p = 0.001 (signed-rank test). The intra-individual variability was lower than the inter-individual one (14.4% and 30.8%, respectively). This means that both methods are suitable for CTA measurement in the knee joint replacement procedures. Spearman's correlation coefficient was 0.6, which is the value of medium strong correlation. The post-operative CTA assessed on CT scans was in the range of 0 to 2 degrees in 87.5% of the patients. Both the pre-operative and intra-operative CTA values were significantly higher in women than in men (Wilcoxon two-sample test). There was no statistical difference between the left and the right side. DISCUSSION Malrotation of the femoral component is one of the causes leading to patellar subluxation and pain in the front part of the knee. The post-operative CTA value should be zero. Optimal rotational alignment of the femoral component varies with each patient; in our study it was found in the range of 0 to 7 degrees on the basis of CTA values. We do not recommend 7 degrees of external rotation to be exceeded because of the risk associated with balancing the flexion gaps; nor do we recommend to set internal rotation of the femoral component for the risk of patellar complications. The difference of 0.5 degree found in the CTA value between the two measuring methods can be explained by individual differences in the anatomy of the medial epicondylar region, and by the use of only selected whole numbers (0, 3, 5, 7) in intra-operative measurements. This difference does not play any role in routine surgical procedures. CONCLUSIONS The statistical evaluation of the results of CTA measurement with the two methods showed that both were equally suitable for routine total knee arthroplasty. The results of intra-operative CTA measurements are comparable with those obtained on CT scans; in addition, the intra-operative method is less expensive and eliminates exposure of the patient to radiation. CT-based CTA measurements are useful in the patients with chronic problems afterTKA in whom femoral component malrotation needs to be either confirmed or ruled out.

• Klíčová slova
• CTA, condylar twist angle, Advance Medial - Pivot Knee, NexGen,
• MeSH
• chirurgie operační metody   využití   MeSH
• financování organizované MeSH
• interpretace statistických dat MeSH
• kolenní kloub chirurgie   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peroperační péče statistika a číselné údaje   využití   MeSH
• počítačová rentgenová tomografie statistika a číselné údaje   MeSH
• prospektivní studie MeSH
• protézy a implantáty využití   MeSH
• protézy kolene statistika a číselné údaje   využití   MeSH
• reprodukovatelnost výsledků MeSH
• rotace škodlivé účinky   MeSH
• rozsah kloubních pohybů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• výsledky a postupy - zhodnocení (zdravotní péče) statistika a číselné údaje   MeSH
• zobrazování trojrozměrné MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

Western lifestyle leading to obesity and type 2 diabetes has been associated with increased risk of colorectal cancer (CRC). Diet and related factors may affect the risk by modifying plasma insulin levels. Thus, the inter-individual variation in insulin signaling may play a plausible role in the development of CRC. We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. We studied the association of five single nucleotide polymorphisms (SNPs) with the risk of CRC using a hospital-based case-control design with 712 cases and 748 controls from the Czech Republic. The INSR A-603G promoter SNP, which is located within a known Sp1-binding site, was associated with the risk of CRC, with carriers of the G allele having a decreased risk (odds ratios (OR) 0.71, 95% confidence interval (CI) 0.54-0.93). Carrying the variant allele of the IRS1 Gly972Arg SNP further decreased the risk among the INSR-603G allele carriers (OR 0.28, 95% CI 0.11-0.70). SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. In conclusion, genetic variation in the insulin signaling pathway genes may affect the risk of CRC.

• MeSH
• CD antigeny * genetika   metabolismus   MeSH
• dospělí MeSH
• fosfoproteiny genetika   MeSH
• genetická predispozice k nemoci MeSH
• inzulin genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * fyziologie   MeSH
• karcinom * genetika   MeSH
• kolorektální nádory * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• promotorové oblasti (genetika) * MeSH
• proteiny insulinového receptorového substrátu MeSH
• receptor inzulinu * genetika   metabolismus   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce * genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.

• MeSH
• 3' nepřekládaná oblast genetika   MeSH
• adjuvantní chemoterapie MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory krev   genetika   mortalita   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru epidemiologie   prevence a kontrola   MeSH
• messenger RNA krev   genetika   MeSH
• mikro RNA krev   metabolismus   MeSH
• následné studie MeSH
• přenašeče organických aniontů genetika   MeSH
• prognóza MeSH
• proteiny přenášející organické kationty genetika   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• transportér organických kationtů 2 genetika   MeSH
• vazebná místa genetika   MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

BACKGROUND: Treponema pallidum subspecies pertenue (TPE) is the causative agent of human and nonhuman primate (NHP) yaws infection. The discovery of yaws bacterium in wild populations of NHPs opened the question of transmission mechanisms within NHPs, and this work aims to take a closer look at the transmission of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Our study determined eleven whole TPE genomes from NHP isolates collected from three national parks in Tanzania: Lake Manyara National Park (NP), Serengeti NP, and Ruaha NP. The bacteria were isolated from four species of NHPs: Chlorocebus pygerythrus (vervet monkey), Cercopithecus mitis (blue monkey), Papio anubis (olive baboon), and Papio cynocephalus (yellow baboon). Combined with previously generated genomes of TPE originating from NHPs in Tanzania (n = 11), 22 whole-genome TPE sequences have now been analyzed. Out of 231 possible combinations of genome-to-genome comparisons, five revealed an unexpectedly high degree of genetic similarity in samples collected from different NHP species, consistent with inter-species transmission of TPE among NHPs. We estimated a substitution rate of TPE of NHP origin, ranging between 1.77 × 10-7 and 3.43 × 10-7 per genomic site per year. CONCLUSIONS/SIGNIFICANCE: The model estimations predicted that the inter-species transmission happened recently, within decades, roughly in an order of magnitude shorter time compared to time needed for the natural diversification of all tested TPE of Tanzanian NHP origin. Moreover, the geographical separation of the sampling sites (NPs) does not preclude TPE transmission between and within NHP species.

• MeSH
• Cercopithecus aethiops MeSH
• Cercopithecus mikrobiologie   MeSH
• frambézie * mikrobiologie   přenos   MeSH
• fylogeneze * MeSH
• genom bakteriální MeSH
• lidé MeSH
• nemoci opic mikrobiologie   přenos   MeSH
• Papio anubis mikrobiologie   MeSH
• Papio cynocephalus mikrobiologie   genetika   MeSH
• primáti mikrobiologie   MeSH
• sekvenování celého genomu * MeSH
• Treponema pallidum genetika   izolace a purifikace   klasifikace   MeSH
• Treponema MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Tanzanie MeSH

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

• MeSH
• dospělí MeSH
• konektom * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie * metody   MeSH
• mladý dospělý MeSH
• mozek patologie   patofyziologie   MeSH
• mozková kůra patologie   patofyziologie   MeSH
• nervová síť patologie   patofyziologie   diagnostické zobrazování   MeSH
• nervové dráhy patofyziologie   patologie   MeSH
• schizofrenie * patologie   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The recent geographical expansion of phlebotomine vectors of Leishmania infantum in the Mediterranean subregion has been attributed to ongoing climate changes. At these latitudes, the activity of sand flies is typically seasonal; because seasonal phenomena are also sensitive to general variations in climate, current phenological data sets can provide a baseline for continuing investigations on sand fly population dynamics that may impact on future scenarios of leishmaniasis transmission. With this aim, in 2011-2013 a consortium of partners from eight Mediterranean countries carried out entomological investigations in sites where L. infantum transmission was recently reported. METHODS/PRINCIPAL FINDINGS: A common protocol for sand fly collection included monthly captures by CDC light traps, complemented by sticky traps in most of the sites. Collections were replicated for more than one season in order to reduce the effects of local weather events. In each site, the trapping effort was left unchanged throughout the survey to legitimate inter-seasonal comparisons. Data from 99,000 collected specimens were analyzed, resulting in the description of seasonal dynamics of 56,000 sand flies belonging to L. infantum vector species throughout a wide geographical area, namely P. perniciosus (Portugal, Spain and Italy), P. ariasi (France), P. neglectus (Greece), P. tobbi (Cyprus and Turkey), P. balcanicus and P. kandelakii (Georgia). Time of sand fly appearance/disappearance in collections differed between sites, and seasonal densities showed variations in each site. Significant correlations were found between latitude/mean annual temperature of sites and i) the first month of sand fly appearance, that ranged from early April to the first half of June; ii) the type of density trend, varying from a single peak in July/August to multiple peaks increasing in magnitude from May through September. A 3-modal trend, recorded for P. tobbi in Cyprus, represents a novel finding for a L. infantum vector. Adults ended the activity starting from mid September through November, without significant correlation with latitude/mean annual temperature of sites. The period of potential exposure to L.infantum in the Mediterranean subregion, as inferred by adult densities calculated from 3 years, 37 sites and 6 competent vector species, was associated to a regular bell-shaped density curve having a wide peak center encompassing the July-September period, and falling between early May to late October for more than 99% of values. Apparently no risk for leishmaniasis transmission took place from December through March in the years considered. We found a common pattern of nocturnal females activity, whose density peaked between 11 pm and 2 am. CONCLUSIONS: Despite annual variations, multiple collections performed over consecutive years provided homogeneous patterns of the potential behavior of leishmaniasis vectors in selected sites, which we propose may represent sentinel areas for future monitoring. In the investigated years, higher potential risk for L. infantum transmission in the Mediterranean was identified in the June-October period (97% relative vector density), however such risk was not equally distributed throughout the region, since density waves of adults occurred earlier and were more frequent in southern territories.

• MeSH
• hmyz - vektory parazitologie   fyziologie   MeSH
• Leishmania infantum fyziologie   MeSH
• leishmanióza epidemiologie   parazitologie   přenos   MeSH
• lidé MeSH
• podnebí MeSH
• populační dynamika MeSH
• Psychodidae parazitologie   fyziologie   MeSH
• roční období MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Středomoří MeSH