Permutation methods are commonly used to test the significance of regressors of interest in general linear models (GLMs) for functional (image) data sets, in particular for neuroimaging applications as they rely on mild assumptions. Permutation inference for GLMs typically consists of three parts: choosing a relevant test statistic, computing pointwise permutation tests, and applying a multiple testing correction. We propose new multiple testing methods as an alternative to the commonly used maximum value of test statistics across the image. The new methods improve power and robustness against inhomogeneity of the test statistic across its domain. The methods rely on sorting the permuted functional test statistics based on pointwise rank measures; still, they can be implemented even for large data. The performance of the methods is demonstrated through a designed simulation experiment and an example of brain imaging data. We developed the R package GET, which can be used for the computation of the proposed procedures.
- MeSH
- Humans MeSH
- Linear Models MeSH
- Brain * diagnostic imaging MeSH
- Neuroimaging * MeSH
- Computer Simulation MeSH
- Research Design MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Although there is evidence that shows worse cognitive functioning in male patients with multiple sclerosis (MS), the role of brain pathology in this context is under-investigated. OBJECTIVE: To investigate sex differences in cognitive performance of MS patients, in the context of brain pathology and disease burden. METHODS: Brain MRI, neurological examination, neuropsychological assessment (Brief International Cognitive Assessment in MS-BICAMS, and Paced Auditory Verbal Learning Test-PASAT), and patient-reported outcome questionnaires were performed/administered in 1052 MS patients. RESULTS: Females had higher raw scores in the Symbol Digit Modalities Test (SDMT) (57.0 vs. 54.0; p < 0.001) and Categorical Verbal Learning Test (CVLT) (63.0 vs. 57.0; p < 0.001), but paradoxically, females evaluated their cognitive performance by MS Neuropsychological Questionnaire as being worse (16.6 vs 14.5, p = 0.004). Females had a trend for a weaker negative correlation between T2 lesion volume and SDMT ([Formula: see text] = - 0.37 in females vs. - 0.46 in men; interaction p = 0.038). On the other hand, women had a trend for a stronger correlation between Brain Parenchymal Fraction (BPF) and a visual memory test (Spearman's [Formula: see text] = 0.31 vs. 0.21; interaction p = 0.016). All these trends were not significant after correction for false discovery rate. CONCLUSIONS: Although, females consider their cognition as worse, males had at a group level slightly worse verbal memory and information processing speed. However, the sex differences in cognitive performance were smaller than the variability of scores within the same sex group. Brain MRI measures did not explain the sex differences in cognitive performance among MS patients.
- MeSH
- Cognition MeSH
- Cognitive Dysfunction * MeSH
- Cognition Disorders * diagnosis MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Brain diagnostic imaging MeSH
- Neuropsychological Tests MeSH
- Sex Characteristics MeSH
- Multiple Sclerosis * complications diagnostic imaging MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cíl studie: Cílem naší studie bylo srovnat sérové hladiny vybraných markerů kostního metabolismu a mikroprostředí kostní dřeně s aktivitou mnohočetného myelomu (MM). Typ studie: prospektivní analýza Materiál a metody: Náš soubor 94 jedinců sestával z: 58 pacientů s aktivním mnohočetným myelomem (AMM), 12 s doutnajícím myelomem (SMM) a 24 jedinců s monoklonální gamapatií nejasného významu (MGUS). Byly hodnoceny tyto parametry mikroprostředí kostní dřeně a kostního metabolismu: Hepatocytární růstový faktor (HGF), Syndekan-1 (SYN-1), Osteoprotegerin (OPG), Makrofágový zánětlivý protein 1 α (MIP-1 α ), Aktivin A, Annexin A2, Sklerostin, Matrixová metalopro - teináza 9 (MMP 9), Dickkopf protein 1 (DKK 1). Jejich hladiny byly korelovány s aktivitou onemocnění. Pro účely statistiky jsme použili Mann-Whitney U test s Bonferroniho korekcí při hladině významnosti p < 0,05. Výsledky: Při srovnání MM a MGUS bylo zjištěno, že u pacientů s AMM jsou signifikantně vyšší sérové hladiny HGF (medián = M 2997 vs 1748 ng/l, p = 0,0002), MIP-1 α (M 25,5 vs 22,4 ng/l , p = 0,018), SYN-1 (M 67,1 vs 21,1 μg/l, p <0,0001) a DKK-1 (M 3303 vs 2733 ng/l, p = 0,029). Při srovnání AMM a SMM byla u AMM signifikantně vyšší hodnota sérové hladiny DKK-1 (M 3303 vs 2196 ng/l, p = 0,042) a annexinu A2 (M 37,5 vs 26,5 μg/l, p = 0,015). Při porovnání MGUS a SMM bylo shledáno, že u SMM jsou vyšší hladiny SYN-1 (M 67,1 vs 33,1 μg/l, p = 0,023). Závěr: Byl prokázán vztah vybraných ukazatelů kostního metabolismu k aktivitě mnohočetného myelomu. Jako nejvíce perspektivní se jeví sérové hladiny těchto ukazatelů: HGF, MIP-1 a, SYN-1, DKK-1 a annexinu A2. Jejich hodnocení naznačuje potenciální přínos k odlišení počátku transformace onemocnění z MGUS do aktivního mnohočetného myelomu či z doutnajícího myelomu do aktivního onemocnění
Objective: Our aim was to compare serum levels of selected markers of bone metabolism and bone marrow microenvironment to the activity of multiple myeloma (MM). Material and methods: Our 94 patients' cohort consisted of 58 patients with active multiple myeloma (AMM), 12 with smoldering myeloma (SMM) and 24 individuals with monoclonal gammapathy of undetermined significance (MGUS). Following parameters of bone marrow microenvironment and bone metabolism were assessed: Hepatocyte growth factor (HGF), Syndecan-1 (SYN-1), Osteoprotegerin (OPG), Macrophage inflammatory protein 1 α (MIP-1 α ), Activin A, Annexin A2, Sclerostin, Matrix metalloproteinase 9 (MMP9), Dickkopf-related protein 1 (DKK-1), and compared within AMM, SMM and MGUS. For statistics we used Mann-Whitney U test with Bonferroni correction at p < 0.05. Results: In comparison of MM and MGUS we found in MM significantly higher serum levels of HGF (median = M 2997 vs 1748 ng/L, p=0.0002), MIP-1 α (M 25.5 vs 22.4 ng/L, p=0.018), SYN-1 (M 67.1 vs 21.1 μg/L, p<0,0001) and DKK-1 (M 3303 vs 2733 ng/L, p=0.029). In comparison of AMM and SMM we found in AMM higher serum levels of DKK-1 (M 3303 vs 2196 ng/L, p=0.042) and Annexin A2 (M 37.5 vs 26.5 μg/L, p=0.015). In comparison of MGUS and SMM we found in SMM higher levels of SYN-1 (M 67.1 vs 33.1 μg/L, p=0.023). Conclusion: Analysis of serum levels of parameters of bone marrow microenvironment and bone metabolism showed thein relationship to activity of monoclonal gammopathies, especially in the case of HGF, MIP-1 α , SYN-1, DKK-1 and Annexin A2
- Keywords
- myelomová kostní nemoc,
- MeSH
- Biomarkers MeSH
- Clinical Studies as Topic MeSH
- Bone Marrow * metabolism physiopathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma * complications MeSH
- Paraproteinemias MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Serologic Tests methods MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by the uncontrolled clonal proliferation of bone marrow (BM) plasma cells. The poor prognosis of patients is associated with the presence of extramedullary disease (EMD). Previously, different mechanisms involved in the colonization of BM niches by MM cells and their escape during EMD have been described. Thus, we aimed to investigate the expression of selected cytokines in the BM plasma of MM patients as well as EMD patients to reveal novel molecules involved in EMD pathogenesis. Expression of 120 different cytokines was measured in BM plasma of 13 MM and 11 EMD patients using Proteome Profiler Antibody Arrays. The correlation between statistically significant cytokines and clinicopathological parameters of patients was determined using the Spearman correlation analysis. Finally, protein-protein interactions were analyzed, and GO and KEGG pathways enrichment analysis was performed. In total, 27 cytokines were found to be differently expressed between MM and EMD patients. After the Benjamini-Hochberg correction for multiple testing, the statistical significance of two cytokines downregulated in EMD (EGF, BDNF) and six cytokines upregulated in EMD (NAP-2, ADIPOQ, CRP, MIG, BAFF, and THBS1) was maintained. Correlation analysis proved a significant association between the expression of these molecules and selected clinical-pathological features of MM/EMD patients. Protein association network analysis revealed important protein-protein interactions between THBS1/EGF, MIG/NAP-2, THBS1/NAP-2, EGF/NAP-2, and ADIPOQ/CRP. Finally, identified cytokines were proved to be significantly involved in focal adhesion, PI3K/AKT, and MAPK signaling pathways, and regulation of cell development, localization, proliferation, migration, differentiation, immune system processes, and stress response. Obtained results confirm the key function of the BM microenvironment in the pathogenesis of MM and indicate the essential role of numerous cytokines in disease progression and EMD development. However, the exact mechanisms need to be further clarified.
- MeSH
- Bone Marrow MeSH
- Humans MeSH
- Multiple Myeloma * pathology MeSH
- Tumor Microenvironment MeSH
- Disease Progression MeSH
- Proteome * MeSH
- Proteomics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Výskyt monoklonální gamapatie (MG) stoupá s věkem. U jedinců starších 80 let můžeme diagnostikovat přítomnost monoklonálního imunoglobulinu až v 10 % případů. Nejen maligní onemocnění typu mnohočetného myelomu, ale i benigní formy jako MGUS (monoklonální gamapatie nejistého významu) mohou vést k postižení ledvin. Nejvíce ledviny poškozují lehké řetězce imunoglobulinů, protože ty se v důsledku své molekulové hmotnosti volně filtrují do moči. Detekce přítomnosti monoklonálního imunoglobulinu se opírá zejména o kombinaci imunofixační elektroforézy séra (IELFO) a moči a o stanovení volných lehkých řetězců kappa a lambda a jejich poměru (κ/λ) v séru. Kombinace těchto testů s 99% senzitivitou odhalí přítomnost monoklonálního imunoglobulinu. Poškození ledvin u MG může být způsobeno přímou depozicí monoklonálního imunoglobulinu v glomerulech (např. AL amyloidóza, nemoc z ukládání lehkých řetězců imunoglobulinů) či tubulech (v distálním tubulu jako myelomová ledvina nebo v proximálním tubulu jako Fanconiho syndrom či proximální tubulopatie). Typickým močovým nálezem u těchto chorob bývá velká proteinurie až nefrotický syndrom. Akutní poškození ledvin (AKI) lze očekávat zejména při zvýšení koncentrace volných lehkých řetězců v séru nad 500 mg/l. Pro stanovení přesné diagnózy, a tím i zahájení správné léčby, je klíčové provedení renální biopsie. Léčba těchto typů poškození ledvin zahrnuje stejné léčebné režimy, které se používají v léčbě mnohočetného myelomu, včetně inhibitorů proteasomu či daratumumabu.
The incidence of monoclonal gammopathy (MG) increases with age. In individuals over 80 years of age, we can diagnose the presence of monoclonal immunoglobulin (MIg) in up to 10 % of cases. Not only malignant diseases such as multiple myeloma (MM), but also benign forms such as MGUS (monoclonal gammopathy of undetermined significance) can lead to renal involvement. The light chains of immunoglobulins (LC) are the most damaging to the kidneys, as they are freely filtered into the urine due to their molecular weight. Detection of MIg relies mainly on a combination of immunofixation electrophoresis of serum (IELFO) and urine and determination of free light chains (FLC) of kappa and lambda and their ratio (κ/λ) in serum. The combination of these tests will detect the presence of MIg with 99 % sensitivity. Renal damage in MG may be caused by direct deposition of MIg in the glomeruli (e.g. AL amyloidosis, LC deposition disease) or tubules (in the distal tubule as a myeloma kidney or in the proximal tubule as Fanconi syndrome or proximal tubulopathy). Typical urinary findings in these diseases are moderate or severe proteinuria or nephrotic syndrome. Acute kidney injury (AKI) can be expected especially when serum FLC is >500 mg/l. Renal biopsy is crucial to establish an accurate diagnosis and thus initiate the correct treatment. Treatment of these types of renal damage involves the same treatment regimens used in the treatment of MM, including proteasome inhibitors or daratumumab.
- MeSH
- Amyloidosis etiology complications MeSH
- Kidney Failure, Chronic * etiology MeSH
- Renal Dialysis methods MeSH
- Immunoglobulins adverse effects MeSH
- Humans MeSH
- Multiple Myeloma * complications MeSH
- Monoclonal Gammopathy of Undetermined Significance * etiology complications MeSH
- Plasmapheresis methods MeSH
- Check Tag
- Humans MeSH
BACKGROUND: Functional electric stimulation (FES) is recommended for foot drop in multiple sclerosis, although little is known about its therapeutic effect. AIM: The aim of this study is to evaluate a therapeutic effect immediately and two months after program termination (persistent and delayed effect) of a new approach using FES in combination with correcting the patients' postural system. More specifically, we evaluate the effects of this approach on the patients' clinical functions and compared it with individual physiotherapy. DESIGN: Parallel randomized blind trial. SETTING: Two-month-long treatments, functional electric stimulation in posturally corrected position (group 1) and neuroproprioceptive facilitation and inhibition physiotherapy called motor program activating therapy (group 2). POPULATION: Forty-four subjects with multiple sclerosis. METHODS: Primary outcomes: gait (the 2-Minute Walk Test; Timed 25-Foot Walk test; Multiple Sclerosis Walking Scale-12) and balance (by e.g. Berg Balance Scale [BBS], the Activities-Specific Balance Confidence Scale [ABC], Timed Up-and-Go Test [TUG]). SECONDARY OUTCOMES: mobility, cognition, fatigue and subjects' perceptions (e.g. Multiple Sclerosis Impact Scale [MSIS], Euroqol-5 dimensions-5 levels [EQ-5D-5L]). RESULTS: Group 1 showed immediate therapeutic effect in BBS (P=0.008), ABC (P=0.04) and EQ-5D-5L (self-care, P=0.019, mobility P=0.005). The improvement in EQ-5D-5L persisted and in TUG-cognitive we documented a delayed effect (P=0.005). Group 2 showed an immediate improvement in BBS (P=0.025), MSIS (P=0.043) and several aspects of daily life (the effect on health today was significantly higher than in group 1, significant difference between groups P=0.038). CONCLUSIONS: FES in the posturally corrected position has an immediate therapeutic effect on balance and patients' perceptions comparable to motor program activating therapy, and higher persistent and even delayed therapeutic effect. CLINICAL REHABILITATION IMPACT: The study results point to the importance of correcting the patients' posture when applying FES, the possibility to treat foot drop by individual physiotherapy and the activation of the patients' auto reparative processes.
- MeSH
- Adult MeSH
- Electric Stimulation Therapy methods MeSH
- Single-Blind Method MeSH
- Middle Aged MeSH
- Humans MeSH
- Gait Disorders, Neurologic therapy MeSH
- Peroneal Neuropathies therapy MeSH
- Postural Balance physiology MeSH
- Disability Evaluation MeSH
- Multiple Sclerosis therapy MeSH
- Walk Test MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
Antifosfolipidový syndrom (APS), též někdy nazývaný Hughesův syndrom, je poměrně časté autoimunitní onemocnění charakterizované opakovanými arteriálními nebo venózními trombózami a/nebo poruchami těhotenství s charakteristickým nálezem antifosfolipidových protilátek. Pro diagnózu APS musí být splněno jedno klinické kritérium (tzn. průkaz trombózy nebo opakovaných potratů či preeklamsie) a jedno laboratorní kritérium, tedy průkaz některé z antifosfolipidových protilátek v minimálním časovém odstupu 12 týdnů mezi jednotlivými laboratorními analýzami. Antifosfolipidové protilátky zasahují do homeostázy krevní koagulace a různými mechanizmy způsobují hyperkoagulační stav. APS se může vyskytovat u pacientů s revmatickými chorobami, v tomto případě mluvíme o sekundárním APS. Pokud není přítomno jiné základní onemocnění, mluvíme o primárním antifosfolipidovém syndromu (PAPS). V rámci APS může být postižen také centrální nervový systém, pokud je toto postižení charakteru opakovaných tepenných uzávěrů s atakovitým průběhem, může imitovat například roztroušenou sklerózu (RS) a stanovení správné diagnózy může být obtížné. Důkazem je i následující kazuistika ženy, která byla 10 let léčena pro roztroušenou sklerózu. Během těžké ataky provázené zhoršením vizu a kmenovou symptomatikou bylo vzhledem k známkám multiorgánového postižení zvažováno systémové autoimunitní onemocnění s konečným závěrem PAPS, který imitoval RS. Rozpoznání správné diagnózy má v tomto případě zásadní význam pro strategii léčby a sekundární prevenci dalších trombotických komplikací.
Antiphospholipid syndrome (APS, also called as Hughes syndrome) is a relatively common autoimmune disorder characterized by recurrent arterial or venous thromboses and/or pregnancy-related complications with a characteristic finding of antiphospholipid antibodies. To diagnose APS, the following criteria must be met: one clinical criterion (i. e., the presence of thrombosis or repeated abortions or preeclampsia) and one laboratory criterion, i. e., the demonstration of some of the antiphospholipid antibodies within a minimal time interval of 12 weeks between individual laboratory tests. Antiphospholipid antibodies interfere with the homeostasis of blood coagulation and cause hypercoagulation state by a variety of mechanisms. When APS occurs in patients with rheumatic disease, it is referred to as secondary APS. The term „primary antiphospholipid syndrome“ (PAPS) is used when no other underlying disease is found. Within APS, CNS can be involved as well. If this involement is characterized by recurrent arterial occlusions with attack–like course, it can mimic for example multiple scelrosis (MS) and establishment of correct diagnosis can be difficult. The following case report of a woman, who has been treated with MS for 10 years, is an evidence thereof. During severe brainstem attack, due to signs of multiorgan involvment a systemic autoimmune disease was considered, with final conclusion of PAPS, which mimicked MS. The recognition of the correct diagnosis is of major relevance to treatment planning and secondary prevention of further thrombotic complications.
- MeSH
- Antiphospholipid Syndrome diagnosis physiopathology MeSH
- Anticoagulants therapeutic use MeSH
- Autoimmune Diseases diagnosis MeSH
- Diagnosis, Differential MeSH
- Financing, Organized MeSH
- Pregnancy Complications, Hematologic MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Sclerosis diagnosis MeSH
- Thrombosis etiology complications MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Bone mineral density (BMD) is an important indicator of bone health, particularly in patients with conditions such as multiple myeloma. This study aims to compare three methodologies for quantifying BMD in vertebral regions affected by lytic lesions: two using data from conventional CT with different corrections for tissue composition, and one using data acquired on a dual-energy CT system. Method 1 is based on conventional CT with corrections using reference values for muscle and fat, Method 2 uses conventional CT with corrections based on the measured CT values of paraspinal muscle, and Method 3 is based on dual-energy CT. The Wilcoxon signed-rank test was used for statistical comparison, as the dataset did not follow a normal distribution. The results indicated significant differences between Methods 1 and 2 for BMD in regions of interest (ROIs) within lytic lesions, while no significant differences were found for other comparisons in this group. For vertebrae affected by multiple myeloma, significant differences were found between Methods 1 and 2, and Methods 2 and 3, but not between Methods 1 and 3. In healthy vertebrae, a significant difference was found only between Methods 2 and 3. When all ROIs were combined, significant differences were found between Methods 1 and 2, and Methods 2 and 3, with no difference between Methods 1 and 3. Future research will focus on objectively assessing the accuracy of these methods by comparing their results with a calibration phantom.
BACKGROUND/AIMS: In surgical sepsis, the rapid identification of source of infection at an early stage after surgery or serious trauma is crucial for favorable outcome. The discrimination between local and generalized infection is critical for correct treatment. METHODOLOGY: In a randomized, controlled, single-centre study we investigated 72 patients with severe sepsis after major abdominal surgery or surgery for multiple trauma. Patients were divided in 2 groups: in the first group (PCT, n=38), more important role in the treatment decision was given to PCT level (severe sepsis with PCT >2 ng/mL signalled bacteremia and pushed us to change antibiotics and intravascular devices, severe sepsis with PCT < or =2 ng/mL prompted use of ultrasonography and/or CT, followed by repeated surgery in patients with localized infection). The control group (CON, n=34) was treated by standard evaluation of all parameters by consultant surgeon. We investigated 28-day all-cause mortality, sepsis-related complications, the duration of stay in the intensive care unit, and ventilated days. RESULTS: The hospital mortality was in PCT group 26% and 38% in control group (p = 0.28). Average SOFA score was 7.9 +/- 2.8 in PCT group vs. 9.3 +/- 3.3 (p = 0.06). The decline of ICU days (16.1 +/- 6.9 vs. 19.4 +/- 8.9; p = 0.09) and ventilated days (10.3 +/- 7.8 vs. 13.9 +/- 9.4; p = 0.08) in PCT group was observed, but the difference was not significant. CONCLUSIONS: We observed a clear tendency to decrease extent of multiple organ dysfunction syndrome in patients, in which therapeutic decision was made earlier using procalcitonin as an additional marker separating local infection from generalized one.
- MeSH
- Biomarkers blood MeSH
- Abdomen surgery MeSH
- Adult MeSH
- Financing, Organized MeSH
- Cross Infection surgery mortality MeSH
- Intensive Care Units MeSH
- Calcitonin blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Decision Support Techniques MeSH
- Multiple Organ Failure diagnosis surgery mortality MeSH
- Multiple Trauma surgery mortality MeSH
- Postoperative Complications surgery mortality MeSH
- Predictive Value of Tests MeSH
- Protein Precursors blood MeSH
- Reoperation MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Sepsis surgery mortality MeSH
- Injury Severity Score MeSH
- Respiration, Artificial MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Randomized Controlled Trial MeSH
V práci jsou jako metody počítačové diagnostiky zkoumány mechanismy vlivu metody biorezonanční korekce B. Iorkiho na fyzické a psychické vlastnosti lidského těla.
In the given work as methods компьюерной diagnostics are studied mechanisms of infl uence of a method of bioresonant correction of B.Iorki on physical and psychological properties of a human body. The method of bioresonant correction of Bartel Iork allows to receive positive result through development by the subject of a technique of self-control of work of own nervous system. Acquisition of skills of selfmanagement and self-organizing is perspective methods of formation and health correction.
