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This 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles., Purpose: To demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis., Methods: This 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80-125% (for 95% CIs associated with geometric LS mean ratios)., Results: Equivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: - 0.139 [- 0.826, 0.548] in the full analysis set and - 0.280 [- 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab., Conclusions: CT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints., (© 2024. The Author(s).)

Machine learning (ML) algorithms can handle complex genomic data and identify predictive patterns that may not be apparent through traditional statistical methods. They become popular tools for medical applications including prediction, diagnosis or treatment of complex diseases like rheumatoid arthritis (RA). RA is an autoimmune disease in which genetic factors play a major role. Among the most important genetic factors predisposing to the development of this disease and serving as genetic markers are HLA-DRB and non-HLA genes single nucleotide polymorphisms (SNPs). Another marker of RA is the presence of anticitrullinated peptide antibodies (ACPA) which is correlated with severity of RA. We use genetic data of SNPs in four non-HLA genes (PTPN22, STAT4, TRAF1, CD40 and PADI4) to predict the occurrence of ACPA positive RA in the Polish population. This work is a comprehensive comparative analysis, wherein we assess and juxtapose various ML classifiers. Our evaluation encompasses a range of models, including logistic regression, k-nearest neighbors, naïve Bayes, decision tree, boosted trees, multilayer perceptron, and support vector machines. The top-performing models demonstrated closely matched levels of accuracy, each distinguished by its particular strengths. Among these, we highly recommend the use of a decision tree as the foremost choice, given its exceptional performance and interpretability. The sensitivity and specificity of the ML models is about 70% that are satisfying. In addition, we introduce a novel feature importance estimation method characterized by its transparent interpretability and global optimality. This method allows us to thoroughly explore all conceivable combinations of polymorphisms, enabling us to pinpoint those possessing the highest predictive power. Taken together, these findings suggest that non-HLA SNPs allow to determine the group of individuals more prone to develop RA rheumatoid arthritis and further implement more precise preventive approach., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dudek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation affecting up to 2.0% of adults around the world. The molecular background of RA has not yet been fully elucidated, but RA is classified as a disease in which the genetic background is one of the most significant risk factors. One hallmark of RA is impaired DNA repair observed in patient-derived peripheral blood mononuclear cells (PBMCs). The aim of this study was to correlate the phenotype defined as the efficiency of DNA double-strand break (DSB) repair with the genotype limited to a single-nucleotide polymorphism (SNP) of DSB repair genes. We also analyzed the expression level of key DSB repair genes. The study population contained 45 RA patients and 45 healthy controls. We used a comet assay to study DSB repair after in vitro exposure to bleomycin in PBMCs from patients with rheumatoid arthritis. TaqMan SNP Genotyping Assays were used to determine the distribution of SNPs and the Taq Man gene expression assay was used to assess the RNA expression of DSB repair-related genes. PBMCs from patients with RA had significantly lower bleomycin-induced DNA lesion repair efficiency and we identified more subjects with inefficient DNA repair in RA compared with the control (84.5% vs. 24.4%; OR 41.4, 95% CI, 4.8-355.01). Furthermore, SNPs located within the RAD50 gene (rs1801321 and rs1801320) increased the OR to 53.5 (95% CI, 4.7-613.21) while rs963917 and rs3784099 (RAD51B) to 73.4 (95% CI, 5.3-1011.05). These results were confirmed by decision tree (DT) analysis (accuracy 0.84; precision 0.87, and specificity 0.86). We also found elevated expression of RAD51B, BRCA1, and BRCA2 in PBMCs isolated from RA patients. The findings indicated that impaired DSB repair in RA may be related to genetic variations in DSB repair genes as well as their expression levels. However, the mechanism of this relation, and whether it is direct or indirect, needs to be elucidated.

In the present article, we describe a multimodal radiobioconjugate that contains a chemotherapeutic agent (doxorubicin, DOX), a β-emitter ( 198 Au), and a guiding vector (trastuzumab, Tmab) for targeted therapy of cancers overexpressing HER2 receptors. To achieve this goal, radioactive gold nanoparticles ( 198 AuNPs) with a mean diameter of 30 nm were synthesized and coated with a poly(ethylene glycol) (PEG) linker conjugated to DOX and monoclonal antibody (Tmab) via peptide bond formation. In vitro experiments demonstrated a high affinity of the radiobioconjugate to HER2 receptors and cell internalization. Cytotoxicity experiments performed using the MTS assay showed a significant decrease in the viability of SKOV-3 cells. A synergistic cytotoxic effect due to the simultaneous presence of DOX and 198 Au was revealed after 48 h of treatment with 2.5 MBq/mL. Flow cytometry analysis indicated that DOX- 198 AuNPs-Tmab mainly induced cell cycle arrest in the G2/M phase and late apoptosis. Dose-dependent additive and synergistic effects of the radiobioconjugate were also shown in spheroid models. Ex vivo biodistribution experiments were performed in SKOV-3 tumor-bearing mice, investigating different distributions of the 198 AuNPs-DOX and DOX- 198 AuNPs-Tmab after intravenous (i.v.) and intratumoral (i.t.) administration. Finally, in vivo therapeutic efficacy studies on the same animal model demonstrated very promising results, as they showed a significant tumor growth arrest up to 28 days following a single intratumoral injection of 10 MBq. Therefore, the proposed multimodal radiobioconjugate shows great potential for the local treatment of HER2+ cancers.

Single nucleotide polymorphisms in non- HLA genes are involved in the development of rheumatoid arthritis (RA). SNPS in genes: PADI4 ( rs2240340 ), STAT4 ( rs7574865 ), CD40 ( rs4810485 ), PTPN22 ( rs2476601 ), and TRAF1 ( rs3761847 ) have been described as risk factors for the development of autoimmune diseases, including RA. This study aimed to assess the prevalence of polymorphisms of these genes in the Polish population of patients with rheumatoid arthritis as compared to healthy controls. 324 subjects were included in the study: 153 healthy subjects and 181 patients from the Department of Rheumatology, Medical University of Lodz who fulfilled the criteria of rheumatoid arthritis diagnosis. Genotypes were determined by Taqman SNP Genotyping Assay. rs2476601 (G/A, OR = 2.16, CI = 1.27-3.66; A/A, OR = 10.35, CI = 1.27-84.21), rs2240340 (C/T, OR = 4.35, CI = 2.55-7.42; T/T, OR = 2.80, CI = 1.43-4.10) and rs7574865 (G/T, OR = 1.97, CI = 1.21-3.21; T/T, OR = 3.33, CI = 1.01-11.02) were associated with RA in the Polish population. Rs4810485 was also associated with RA, however after Bonferroni's correction was statistically insignificant. We also found an association between minor alleles of rs2476601 , rs2240340, and rs7574865 and RA (OR = 2.32, CI = 1.47-3.66; OR = 2.335, CI = 1.64-3.31; OR = 1.88, CI = 1.27-2.79, respectively). Multilocus analysis revealed an association between CGGGT and rare (below 0.02 frequency) haplotypes (OR = 12.28, CI = 2.65-56.91; OR = 3.23, CI = 1.63-6.39). In the Polish population, polymorphisms of the PADI4 , PTPN22, and STAT4 genes have been detected, which are also known risk factors for RA in various other populations.

Recently, targeted nanoparticles (NPs) have attracted much attention in cancer treatment due to their high potential as carriers for drug delivery. In this article, we present a novel bioconjugate (DOX-AuNPs-Tmab) consisting of gold nanoparticles (AuNPs, 30 nm) attached to chemotherapeutic agent doxorubicin (DOX) and a monoclonal antibody, trastuzumab (Tmab), which exhibited specific binding to HER2 receptors. The size and shape of synthesized AuNPs, as well as their surface modification, were analyzed by the TEM (transmission electron microscopy) and DLS (dynamic light scattering) methods. Biological studies were performed on the SKOV-3 cell line (HER2+) and showed high specificity of binding to the receptors and internalization capabilities, whereas MDA-MB-231 cells (HER2-) did not. Cytotoxicity experiments revealed a decrease in the metabolic activity of cancer cells and surface area reduction of spheroids treated with DOX-AuNPs-Tmab. The bioconjugate induced mainly cell cycle G2/M-phase arrest and late apoptosis. Our results suggest that DOX-AuNPs-Tmab has great potential for targeted therapy of HER2-positive tumors.

Rheumatoid arthritis (RA) is a chronic, multifactorial autoimmune disease characterized by chronic arthritis, a tendency to develop joint deformities, and involvement of extra-articular tissues. The risk of malignant neoplasms among patients with RA is the subject of ongoing research due to the autoimmune pathogenesis that underlies RA, the common etiology of rheumatic disease and malignancies, and the use of immunomodulatory therapy, which can alter immune system function and thus increase the risk of malignant neoplasms. This risk can also be increased by impaired DNA repair efficiency in individuals with RA, as reported in our recent study. Impaired DNA repair may reflect the variability in the genes that encode DNA repair proteins. The aim of our study was to evaluate the genetic variation in RA within the genes of the DNA damage repair system through base excision repair (BER), nucleotide excision repair (NER), and the double strand break repair system by homologous recombination (HR) and non-homologous end joining (NHEJ). We genotyped a total of 28 polymorphisms in 19 genes encoding DNA repair-related proteins in 100 age- and sex-matched RA patients and healthy subjects from Central Europe (Poland). Polymorphism genotypes were determined using the Taq-man SNP Genotyping Assay. We found an association between the RA occurrence and rs25487/XRCC1 , rs7180135/RAD51 , rs1801321/RAD51 , rs963917/RAD51B , rs963918/RAD51B , rs2735383/NBS1 , rs132774/XRCC6 , rs207906/XRCC5 , and rs861539/XRCC3 polymorphisms. Our results suggest that polymorphisms of DNA damage repair genes may play a role in RA pathogenesis and may be considered as potential markers of RA.

Despite development of radiologic imaging, detection and follow-up of neuroendocrine neoplasms (NENs) still pose a diagnostic challenge, due to the heterogeneity of NEN, their relatively long-term growth, and small size of primary tumor. A set of information obtained by using different radiological imaging tools simplifies a choice of the most appropriate treatment method. Moreover, radiological imaging plays an important role in the assessment of metastatic lesions, especially in the liver, as well as, tumor response to treatment. This article reviews the current, broadly in use imaging modalities which are applied to the diagnosis of GEP-NETs, (the most common type of NENs) and put emphasis on the strengths and limitations of each modality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Półtorak-Szymczak, Budlewski, Furmanek, Wierzba, Sklinda, Walecki and Mruk.)

Numerous studies have shown that cf nDNA significantly rises in stress caused by exercise. However, during nuclear decondensation, released DNA is followed by histones. Histones are also a common disease marker. After PAD4 mediated hypercitrullination extracellular H3Cit exhibits high toxicity contributing to tissue damage which, in cases of systemic inflammation, may lead to multiorgan failure and finally to death. We tested whether circulating histones rise in response to strenuous exercise. Eleven average-trained men performed three treadmill exercise tests to exhaustion at speed corresponding to 70% VO2max separated by 72 h of resting. Blood was collected before and just after each bout of exercise and plasma proteins were measured using enzyme-linked immunosorbent assay, whereas platelet activity was estimated with Light Transmission Aggregometry. Both, circulating histones and PAD4 raised in response to exercise. Plasma citrullinated histones increased from 3.1 ng/mL to 5.96 ng/mL ( p = 0.0059), from 3.65 ng/mL to 6.37 ng/mL ( p = 0.02), and from 3.86 ng/mL to 4.75 ng/mL ( p = 0.033) after the first, second, and third treadmill run, respectively. However despite the parallel increase, no significant correlation between citrullinated histone and aggregation or cell-free nDNA was found. Furthermore, positive correlations of cf nDNA with aggregation and PAD4, lactate with aggregation, and lactate with citrullinated histone have been observed.

It is believed that neutrophils extracellular traps (NETs) formation is responsible for the increase in cf DNA after exercise. Since T1DM is accompanied by enhanced NETs generation, we compared exercise-induced increase in cf DNA in 14 men with T1DM and 11 healthy controls and analyzed its association with exercise load. Subjects performed a treadmill run to exhaustion at speed corresponding to 70% of their personal VO2max. Blood was collected before and just after exercise for determination of plasma cf nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, blood cell count and metabolic markers. Exercise resulted in the increase in median cf n-DNA from 3.9 ng/mL to 21.0 ng/mL in T1DM group and from 3.3 ng/mL to 28.9 ng/mL in controls. Median exercise-induced increment (∆) in cf n-DNA did not differ significantly in both groups (17.8 ng/mL vs. 22.1 ng/mL, p = 0.23), but this variable correlated with run distance (r = 0.66), Δ neutrophils (r = 0.86), Δ creatinine (r = 0.65) and Δ creatine kinase (r = 0.77) only in controls. Pre- and post-exercise cf mt-DNA were not significantly different within and between groups. These suggest low usefulness of Δ cf n-DNA as a marker of exercise intensity in T1DM men.

Background: Radioiodine (RAI) treatment for hyperthyroidism is a very common modality, chosen by physicians worldwide. The outcome of the therapy, however, is not always predictable. While rendering a patient hypo- or euthyroid is meant as a therapeutic success, the latter does not require lifelong hormonal supplementation. The aim of our study is to determine predictors of euthyreosis in patients who underwent RAI treatment., Methods: Medical records of 144 patients who had undergone RAI therapy were examined. Laboratory and clinical data were analyzed statistically. Ultrasonography findings, such as thyroid volume, nodules' size and characteristics had been collected at the beginning of treatment and 6 months after the administration of radioiodine 131 I - . Moreover, scintigraphy results were taken into account. Multivariate logistic regression analysis model has been used to find predictors of euthyroidism after 12 months of follow-up. The predictors of normal thyroid function have also been analyzed separately for patients with GD (Graves' disease) and TMNG (toxic multinodular goiter)., Results: The analysis showed that age (OR 1,06; 95%CI 1.025-1.096, p = 0,001), thyroid gland volume (OR 1,04; 95%CI 1,02-1,06; p < 0.001) and iodine uptake level (OR 0,952; 95%CI 0,91-0,98; p = 0,004) were significant factors of achieving normal thyroid function after RAI therapy. According to multivariate logistic regression analysis, in GD patients only age has been shown to be a significant factor (OR 1,06; 95%CI 1,001-1,13; p = 0.047), while in TMNG patients' age (OR 1,04; 95%CI 1-1,09; p = 0.048), thyroid gland volume (OR 1.038; 95%CI 1.009-1.068; p = 0.009) and iodine uptake level (OR 0.95; 95%CI 0.9-0.99; p = 0.02) all have been proven to be significant predictors of achieving euthyroidism., Conclusions: The more advanced age, larger volume of thyroid gland and lower iodine uptake level are predictors of euthyreosis after RAI treatment.

Strenuous exercise increases circulating cell free DNA (cfDNA) and stimulates blood phagocytes to generate reactive oxygen species (ROS) which may induce DNA strand breaks. We tested whether: (A) elevated cfDNA in response to three repeated bouts of exhaustive exercise has decreased integrity; (B) each bout of exercise increases luminol enhanced whole blood chemiluminescence (LBCL) as a measure of ROS production by polymorphonuclear leukocytes. Eleven men performed three treadmill exercise tests to exhaustion separated by 72 hours of resting. Pre- and post-exercise concentrations and integrity of cf nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) and resting (r) and fMLP (n-formyl-methionyl-leucyl-phenylalanine)-stimulated LBCL were determined. Each bout increased concentrations of cf n-DNA by more than 10-times which was accompanied by about 2-times elevated post-exercise rLBCL and fMLP-LBCL. Post-exercise cf n-DNA integrity (integrity index, I 229/97 ) decreased after the first (0.59 ± 0.19 vs. 0.48 ± 0.18) and second (0.53 ± 0.14 vs. 0.44 ± 0.17) bout of exercise. There were negative correlations between I 229/97 and rLBCL (ƍ = -0.37), and I 229/97 and fMLP-LBCL (ƍ = -0.40) - analysis of pooled pre- and post-exercise data (n = 66). cf mt- DNA integrity (I 218/78 ) did not alter in response to exercise. This suggests an involvement of phagocyte ROS in cf n-DNA strand breaks in response to exhaustive exercise.

Gliomas, particularly WHO grade IV glioblastoma multiforme, are one of the most common and aggressive primary tumors of the central nervous system. The neuropeptide, substance P (SP), is the physiological ligand of the neurokinin-1 (NK-1) receptor that is consistently overexpressed in glioblastoma cells. The aim of this work was to study physico-chemical and biological properties of different SP analogues labeled with technetium-99m and lutetium-177 radionuclides. The synthesized compounds were characterized in vitro by partition coefficients (log P ) and their stability was investigated in various physiological solutions. Biological properties ( K d , B max ) were characterized using the U373 MG cell line. The obtained lipophilicity values of the [ 99m Tc]NS₃/CN-SP and [ 177 Lu]DOTA-SP radiobioconjugates were in the range of -0.3 to +0.6 and -2.5 to -5.0, respectively. The studied radiobioconjugates were stable in PBS buffer and CSF, as well as in 10 mM histidine and/or cysteine solutions whereas in human serum showed enzymatic biodegradation. [ 177 Lu]DOTA-[Thi⁸,Met(O₂) 11 ]SP(1⁻11), [ 177 Lu]DOTA-SP(4⁻11) and [ 177 Lu]DOTA-[Thi⁸,Met(O₂) 11 ]SP(5⁻11) radiobioconjugates bound specifically to NK-1 receptors expressed on glioblastoma cells with affinity in the nanomolar range. To conclude, the shorter analogues of SP can be used as vectors, nevertheless they still do not fulfil all requirements for preparations in nuclear medicine., Competing Interests: The authors declare no conflict of interest.

Wstęp: Celem badania LanroNET była ocena wykorzystania zasobów medycznych oraz kosztów objawowego leczenia polskich chorych na nowotwory neuroendokrynne z zastosowaniem lanreotydu autogel 120 mg. Materiał i metody: LanroNET to wieloośrodkowe, nieinterwencyjne, obserwacyjne, prospektywne badanie przeprowadzone w 12 ośrod-kach w Polsce. W badaniu uczestniczyli dorośli chorzy na wydzielające nowotwory neuroendokrynne leczeni lanreotydem autogel 120 mg od przynajmniej 3 miesięcy przed włączeniem do badania. Podczas 24-miesięcznej obserwacji rzeczywistej praktyki klinicznej zbierano dane dotyczące wykorzystania zasobów medycznych oraz przebiegu terapii chorych z wydzielającymi nowotworami neuroendokrynnymi. WYNIKI: W badaniu uczestniczyło 54 chorych na wydzielające nowotwory neuroendokrynne. Przeciętny czas stosowania lanreotydu wynosił 1,7 roku (zakres 0,0-2,2 lata). Badanie ukończyło 33 pacjentów, najczęstszą przyczyną przedwczesnego zakończenia leczenia (8/16) była progresja choroby. Całkowity średni koszt wykorzystanych zasobów bez kosztów farmakoterapii oszacowano na 26 307 zł/EUR 6.030,35 na pacjenta/rok. W czasie badania średni odstęp między wstrzyknięciami lanreotydu wynosił 31,7 dni (6,7). Pod koniec obserwacji, po 24 miesiącach od follow-up, 7 pacjentów stosowało 42-dniowe odstępy między dawkami. Średni rzeczywisty koszt lanreotydu autogel 120 mg wyniósł 4216,30 zł/966,49 EUR na pacjenta/28 dni we wspólnej perspektywie płatnika i pacjenta i był niższy o 554,16 zł/127,02 EUR niż koszt stosowania standardowych 28-dniowych odstępów między dawkami. WNIOSKI: Badanie LanroNET jest pierwszym w Polsce obserwacyjnym dwuletnim badaniem chorych na czynne hormonalnie nowotwo-ry neuroendokrynne żołądkowo-jelitowo-trzustkowe oceniającym koszty codziennej praktyki klinicznej i koszty leczenia lanreotydem autogel.

Rationale: Relapsing polychondritis (RP) is a multisystemic, progressive disease of unknown etiology characterized by recurrent inflammation and progressive cartilage destruction. It can involve all types of cartilage including ears and nose, tracheobronchial tree, joints, and any other tissue rich in proteoglycans such as heart, eyes, and blood vessels. Recurrent chondritis can be life-threatening if the respiratory tract, heart valves, or blood vessels are affected. To date there is no data in the literature on the post solid organ transplantation RP., Patient Concerns: We present a 59-year-old male liver transplant recipient with primary sclerosing cholangitis who developed RP of the earlobes and nose despite post-transplant immunosuppression., Diagnoses: Based on the clinical criteria, scintigraphy and biopsy from the left auricle his condition was diagnosed as RP., Interventions: Pulses of methylprednisolone followed by high-dose oral steroids along with azathioprine were administered., Outcomes: Such therapy diminished local cartilage inflammation, improved patient's general condition and the laboratory results. Significant loss of ear cartilage and characteristic "saddlenose" were observed after remission of acute symptoms. The control scintigraphy proved very good treatment response., Lessons: To the best of our knowledge this is the first report on the RP in liver transplant recipient. Based on our patient presentation, we suggest that RP should be suspected in any transplant recipient with cartilage inflammation, and that the Michet's clinical criteria and scintigraphy seem to be the best diagnostic tools for solid organ transplant recipients suspected of RP.

Objective: Acute single strenuous exercise increases circulating cell free DNA (cf DNA). We tested whether three repeated bouts of exhaustive exercise induced the cf DNA response without development of tolerance in healthy men., Methods: Eleven average-trained men (age 34.0±5.2 years, body mass index 26.2±3.1 kg/m2, maximal oxygen consumption-VO2max 49.6±4.5 ml/kg*min) performed three treadmill exercise tests to exhaustion at speed corresponding to 70% VO2max separated by 72 hours of resting. Blood was collected before and after each bout of exercise for determination of cell free nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, selected markers of muscle damage, and blood cell count., Results: Each bout induced the increase (p<0.05) in plasma cf n-DNA: from 3.4±1.4 to 38.5±27.5, from 4.1±3.3 to 48.5±26.2, and 3.1±1.6 to 53.8±39.9 ng/mL after the first, second, and third exercise, respectively. In a congruent way, cf mt-DNA rose significantly after the second (from 229±216 to 450±228*103 GE/mL) and third bout of exercise (from 173±120 to 462±314*103 GE/mL). Pre-exercise cf mt-DNA decreased (p<0.05) by 2-times (from 355±219 before the first bout to 173±120*103 GE/mL before the third bout) over the study period and were accompanied by significant increase in white blood cells, platelets, creatine kinase, creatinine and lactate after each bout. However, the exercise induced percentage increment of cf n-DNA was always many times higher than corresponding increments of the afore-mentioned markers at any occasion., Conclusions: Repeated bouts of exhaustive exercise induced remarkable increase in circulating cf n-DNA without signs of tolerance development. Baseline cf mt-DNA decreased in response to series of strenuous exercise. Since percentage increments of cf n-DNA in response to exercise were many times higher than those observed for other markers, measurement of circulating cf n-DNA could be a sensitive tool for monitoring acute exercise effects in human body.

Background: In lymphedema, tissue fluid steadily accumulates in the subcutaneous space containing loose connective tissue. We documented previously that deformation of the structure of subcutaneous collagen bundles and fat by excess fluid leads to formation of "lakes" and interconnected channels with irregular shape. Since there is no force that could mobilize and propel stagnant fluid to the regions where lymphatics absorb and contract, this task should be taken over by external massage. The most effective in this respect seems to be the sequential intermittent pneumatic compression (IPC)., Aim: The aim of the study was to observe whether IPC would enhance and accelerate formation of tissue fluid channels., Methods: Together with the Biocompression Systems (Moonachie, NJ), we designed a high pressure intermittent compression device and used in it our therapy protocol for patients with obstructive lymphedema of lower limbs. The study was carried out on 18 patients with lymphedema stages II-IV. The IPC was applied daily for 1-2 hours. The follow up time was 24-36 months. Lymphoscintigraphy and immunohistopathology of tissue biopsies were used for evaluation of channel formation process., Results: The forced fluid flow brought about increase of the area of fluid channels in the thigh and groin, with a decrease in the calf. Concomitantly, with decrease of channel area in the calf, there was a decrease of calf circumference. No new lymphatic collectors were observed., Conclusions: Compression of limb lymphedema tissues leads to formation of tissue channels as pathways for evacuation of edema fluid.

Background: Periodontal disease is an inflammatory process which results in increased cardiovascular risk in patients with type 2 diabetes mellitus (DM2). It is not clear, however, whether periodontal inflammation may be associated with increased markers of atherosclerosis in these patients., Aim: This cross-sectional study aimed to answer the question of whether periodontal disease in DM2 is associated with increased markers and risk factors of atherosclerosis., Methods: One hundred and twenty one patients were included in the study. Sixteen were classified as periodontally healthy (BGI-H), 87 as having gingivitis (BGI-G), and 18 as having periodontitis with moderate bleeding (BGI-P2), according to the new Offenbacher classification. In all patients, intima-media thickness (IMT), pulse wave velocity (PWV), lipids, and C-reactive protein (CRP) were assessed., Results: Patients with periodontitis and gingivitis had a higher IMT value compared to the BGI-H group (0.804 ± 0.112 and 0.772 ± 0.127 vs 0.691 ± 0.151 mm, p < 0.01 and p < 0.05, respectively, odds ratio 5.25 for having IMT ≥ 0.8 mm, 95% CI 1.1; 25). Patients from the BGI-P2 group also had higher blood pressure (BP) compared to the BGI-G and BGI-H groups, and higher CRP compared to the BGI-G group (4.6 ± 2.3 vs 3.8 ± 4.8 mg/L, p < 0.01). Lipid parameters and PWV were comparable in all the groups., Conclusions: Periodontal inflammation in patients with DM2 seems to be associated with increased IMT and BP, but not with greater arterial stiffness. These results support the hypothesis that periodontal disease may be associated with a vascular pathology.

Subclinical hypothyroidism is associated with an increased risk of atherosclerosis. The aim of this study was to investigate the concentration of plasma soluble intercellular adhesion molecule-1 and adiponectin in relation to insulin sensitivity in patients with subclinical hypothyroidism and to estimate if L-thyroxine treatment had an influence on these parameters. 13 women with subclinical hypothyroidism and 14 euthyroid controls were included in the study. A physical examination was conducted, hyperinsulinemic euglycemic clamp and plasma soluble intercellular adhesion molecule-1, adiponectin and lipids profiles were measured at baseline in both groups and in the group with subclinical hypothyroidism the above procedures were performed after L-thyroxine therapy (mean time of treatment 5.0 months) in stable euthyroid state. Insulin sensitivity and adiponectin were not different at baseline in the two studied groups. Plasma soluble intercellular adhesion molecule-1 concentration was significantly higher in the patients with subclinical hypothyroidism (P = 0.011). The comparison of lipids profiles revealed that only LDL-cholesterol concentration was higher (P = 0.011) in the group with subclinical hypothyroidism. After therapy, we observed an improvement of insulin sensitivity (P = 0.012) and a decrease of plasma glucose (P = 0.019) and soluble intercellular adhesion molecule-1 (P = 0.01), whereas adiponectin concentration remained unchanged. We concluded that L-thyroxine treatment in patients with subclinical hypothyroidism might exert a beneficial effect by reducing cardiovascular risk factors.

Introduction: This study aimed to answer the question of whether chronic periodontitis in subjects with type 2 diabetes mellitus is associated with increased left ventricular mass (LVM) and systemic and central blood pressure (CBP)., Material and Methods: One hundred and fifty-five subjects with type 2 diabetes (67 F, 88 M, mean age 61.1±6.9 years, BMI 32.7±5.7 kg/m(2)) were divided according to their periodontal status into biofilm-gingival interface - healthy (BGI-H, 14 subjects), BGI-gingivitis (BGI-G, 119 subjects) and BGI-periodontitis (BGI-P, 22 subjects) groups. In all subjects, LVM, systemic and CBP were measured. The LVM index (LVMI) was calculated., Results: (1) BGI-P and BGI-G subjects, respectively, had higher (mean; 95% CI) LVM (238.6 g; 206.6-267.4 and 222.8 g; 207.0-238.2) versus BGI-H subjects (170.3 g; 125.5-217.8).
(2) BGI-P and BGI-G subjects, respectively, had higher (mean; 95% CI) LVM1 (95.2 g/m(2) ; 82.9-107.4) and 87.8 g/m(2) ; 81.5-94.1) versus BGI-H subjects (63.7 g/m(2) ; 45.2-62.3).
(3) BGI-P subjects had higher central and systemic systolic and diastolic blood pressure than subjects from BGI-G and BGI-H groups., Conclusion: In subjects with type 2 diabetes, periodontitis and gingivitis are associated with increased LVM and periodontitis is associated with increased central and systemic blood pressure., (© 2010 John Wiley & Sons A/S.)

Introduction: So far only scarce data have been published regarding serum vitamin D concentrations in elderly women in Poland., Objectives: We aimed to assess prevalence of vitamin D deficiency in a population of women aged 60 to 90 years and living in Warsaw., Patients and Methods: The study comprised 274 women from the general population (mean age 69.1 -/+5.7 years, body mass index [BMI] 28.9 -/+4.6 kg/m2, serum creatinine concentration 0.7 -/+0.12 mg/dl). Subjects who had been treated with glucocorticoids or antifracture drugs, or supplemented with vitamin D or calcium, were excluded. The study was conducted in winter. Serum vitamin D, calcium, phosphate, and parathyroid hormone (PTH) concentrations were measured., Results: The mean vitamin D concentration was 13.6 ng/ml in the whole examined population. Vitamin D levels above 30 ng/ml were detected in 4% of subjects. Vitamin D insufficiency (20-30 ng/ml) was found in 12.8% of subjects, and its deficiency (<20 ng/ml) in 83.2% of subjects. Vitamin D concentrations in women under and over 70 years of age did not differ significantly. There were no associations of vitamin D concentrations with age, BMI, renal function, or serum calcium concentrations. However, we observed a significant inverse correlation between vitamin D concentrations and PTH., Conclusions: The prevalence of low vitamin D concentrations in an urban population of elderly women in Poland is very high. Lower vitamin D levels are associated with a higher PTH concentration.

Background and Purpose: The aim of our study was to evaluate brain perfusion in patients with vertigo using the SPECT technique., Methods: The study involved a group of 32 patients and was performed in the Neurological Department of the Medical University in Bialystok. Patients with vertigo of peripheral origin like middle ear pathology were excluded from the study. Tomographic pictures were taken with Nucline X-Ring camera after administration of Tc99m-ECD. Perfusion maps were estimated by qualitative and semi-quantitative methods., Results: In 8 patients (25%) perfusion maps were normal in the hemispheres, cerebellum and subcortical structures. In 10 patients (31.2%) there was a substantial decrease in perfusion in the left temporal region, in 8 patients (25%) -- hypoperfusion was seen in the right temporal region. In 4 patients (12.5%) there was a substantial decrease in perfusion in the cerebellum, in two persons -- in the frontal lobes., Conclusions: The results obtained so far confirm the major role of ischemia in etiology of the central origin vertigo and balance disturbances. It involves not only the brainstem and cerebellar structures, but the temporal lobes as well. The test has also proved that the qualitative and semi-quantitative methods of assessing brain perfusion with a SPECT are satisfactory in diagnostics of vertigo.

Subclinical hyperthyroidism is a state of increased thyroid function with few or no clinical definitive signs or symptoms of hyperthyroidism. It is characterised by a decrease of serum (TSH) concentration below 0.1 mU/L, when serum levels of total and free thyroxin and triiodothyronin concentration are within normal reference ranges. It is not a rare finding and rates between 0.02% and 11.3% have been reported in different groups. The clinical diagnosis of subclinical hyperthyroidism is very difficult in the absence of the typical symptoms of hyperthyroidism. Therefore the diagnostic evaluation is important, especially with the use of radioisotope scan. In nuclear medicine department we can confirm the provisional diagnosis by the use of thyroid scan. Recent studies reported the effects of subclinical hyperthyroidism on cardiovascular system, skeletal system, cognitive function, on quality of life and life expectancy especially in the elderly patient. Treatment is indicated in the presence of palpitation, or atrial fibrillation, in postmenopausal osteoporosis in women not on hormone replacement therapy, and in elderly patients in whom surgery is contraindicated. According to the opinions of European clinicians and clinician members of the American Thyroid Association, the majority recommend radical treatment for these patients. Radioiodine therapy is considered to be the treatment of choice in most of the patients with nodular goiter.

Background: The effect of radioiodine (131I) in Graves' disease (GD) is probably due to the direct physical destruction of thyrocytes by beta radiation, and by the indirect action through stimulation of apoptosis in these cells. The aim of our study was to investigate the changes in serum concentrations of sFas and sFasL as stimulators of apoptosis, and Bcl-2 as an inhibitor of apoptosis in patients with GD following 131I administration., Material and Methods: The study was performed on 30 patients with GD (29 female and 1 male aged 25-45). All patients were euthyroid (biochemical and clinical) prior to radioiodine therapy. The target absorbed dose ranged between 90 and 160 Gy. We assessed markers of apoptosis and hormone concentrations (fT3, fT4 and TSH) in the following manner: before 131I administration, then two weeks, one month, two, three, four, and five months after 131I administration., Results: After four months, the concentrations of sFas and sFasL rose by 50% and decreased during the next month. Pretherapeutic concentrations of Bcl-2 were elevated, and peaked two weeks after ingestion, showing a gradual decrease with time. We found a significant increase in serum TSH, and a decrease of fT3 and fT4 concentrations by the end of the third month of radioiodine therapy., Conclusions: Decreases in serum levels of sFas and sFasL and increases of Bcl-2 are regarded as characteristic for GD patients before radioiodine therapy. Radioiodine therapy reverses the ratio of estimated markers after four months. The concentrations of hormones reflect actual thyroid function, whereas concentrations of markers of apoptosis may suggest morphological changes.

The pulmonary embolism (PE) is the common and severe complication of the deep vein thrombosis of the lower limbs. The lack of accurate diagnosis of PE is a cause of 5-10% of the hospital deaths. The aim of the study was to assess the incidence of the pulmonary embolism in patients with the deep vein thrombosis of the lower limbs with no clinical symptoms of pulmonary embolism. Pulmonary perfusion scintigraphy was performed in 25 patients with angiographic findings confirmative to the deep vein thrombosis of the lower limbs. The results of the study were analysed according to the PIOPED criteria. In the group of patients with common thrombosis of the deep vein a high probability of lung embolism was assessed in 70%, medium and low by 12% in each group, and very low in 6%. In the group of patients with femoral thrombosis of the deep vein a high probability of lung embolism was assessed in 60%, medium in 20% and very low in 20%. In the group of patients with calf thrombosis of the deep vein high, medium and very low probability of lung embolism was assessed by 25% in each group. Results of this study indicate the need of searching the pulmonary embolism in patients with thrombosis of the deep vein of the lower limbs despite the lack of clinical symptoms of the pulmonary embolism.

Radioisotope methods play a special role in cardiological diagnostics. At present, studies of myocardial perfusion also allow the estimation of cardiomyocyte metabolism. These methods are suitable for the detection of stunned, hibernating or scarred myocardium as well. The radiopharmaceuticals which accumulate in myocardium proportionally to regional blood flow (thallium-201, MIBI-Tc99m, teboroxime-Tc99m, tetrophosmin-Tc99m, furifosmin-tc99m) are used for the estimation of perfusion. In the nuclear medicine departments myocardial perfusion imaging can be performed with planar or tomographic (SPECT) methods. The techniques have high sensitivity (80%, 90%) and specificity (90%, 80%) for detection of coronary artery diseases. The radioisotopic methods have higher sensitivity than other noninvasive techniques (ECG sensitivity-60%, specificity-85%, ECHO sensitivity-81%, specificity-89%). Positron emission tomography is still the "gold" standard for the estimation of myocardial viability. This method uses substrates for different metabolic pathways (acetate-C-11, amino-acids-C-11, fatty acids-C-11, fluorodeoxyglocuse-F-18) labelled with positron emitters. Modifications in thallium protocols make estimation of myocardial metabolism possible. Recently MIBI-Tc99m has also been used in the assessment of myocardial viability. Results of these studies are of great clinical importance. They allow to predict a success of a surgical revascularysation and the return of normal myocardial function.