The concept of unstable atherosclerotic plaque and pharmacological therapeutic strategies

Główną przyczyną umieralności w Polsce są choroby układu sercowo-naczyniowego. W patogenezie miażdżycy początkiem są zaburzenia funkcji śródbłonka naczyniowego. Miażdżyca jako proces zapalny, obejmujący ścianę naczynia, rozwija się poprzez wiele szlaków sygnałowych. Zaburzenia gospodarki lipidowej dodatkowo przyspieszają jej rozwój. Również zaburzenia przepływu krwi, definiowane jako małe i oscylacyjne naprężenia ścinające, wpływają przez proces mechanotransdukcji na zwiększenie ekspresji genów odpowiedzialnych za odkładanie się złogów w ścianie naczyń. W konsekwencji dochodzi do nasilenia reakcji wolnorodnikowych. Nadal jednak brak jednoznacznych informacji na temat mechanizmów progresji od zmian bezobjawowych do blaszek niestabilnych o wysokim ryzyku pęknięcia. Biorąc pod uwagę tak wiele mechanizmów uczestniczących w patogenezie rozwoju miażdżycy dysponujemy już wieloma farmakologicznymi strategiami zapobiegania i leczenia jej powikłań. W niniejszym artykule omówiono główne grupy leków o udokumentowanej skuteczności w stabilizacji blaszki miażdżycowej. Pojawiają się nowe możliwości jakie dają nanoleki, które poprzez potencjalne zwiększenie efektywności terapii jednocześnie minimalizują jej powikłania, działając bezpośrednio w miejscu docelowym.The main cause of mortality in Poland are diseases of the cardiovascular system. Vascular endothelial dysfunction is the beginning of atherosclerosis development. Atherosclerosis, as an inflammatory process involving the vessel wall, evolves through multiple signaling pathways. While the dyslipidemia accelerate its development. Also, blood flow disorders defined as small and oscillating shear stress through the process of mechanotransduction, increases expression of genes, which are responsible for accumulating deposits in vessel walls. Consequently potentiates free radical reactions. There is still lack of clarity about mechanisms of progression from asymptomatic lesions to unstable plaques with high risk of rapture. Considering so many mechanisms participating in the pathogenesis of atherosclerosis we already have a lot of pharmacological strategies for preventing and treating its complications. This article discusses the main groups of drugs with documented effectiveness in the stabilization of atherosclerotic plaque. There are new opportunities offered by nanodrugs due to an effectiveness increase of the treatment while minimizing its complications by acting directly at the target site

Pachydermodactyly : a report of two cases

Pachydermodactyly (PDD) is a rare and benign form of digital soft tissues fibromatosis, which affects the skin of the fingers. The disorder is characterized by asymptomatic, symmetric, progressive soft tissue swelling of the proximal interphalangeal (PIP) joints of the fingers. The etiology of disease remains unknown. It is usually acquired, even though there are some publications that document family cases. It affects mainly adolescent men. We report two boys with the bilateral swelling of the of the PIP joints of the fingers and skin and subcutaneous tissue thickening. Based on clinical manifestations, radiological study and histopathological examination, pachydermodactyly was diagnosed. PDD is a rare and benign disorder, although it is important to consider other diseases, especially rheumatic conditions, in the differential diagnosis in order to avoid unnecessary additional tests and treatments

Monitoring of tacrolimus concentration after kidney or heart transplantation - the importance of intra-subject variability parameters

Background. Properly managed immunosuppression in post-transplant therapy is a necessary for minimizing the risk of organ rejection. Aim of the study. Steady-state tacrolimus (TAC) trough concentration (Cssmin) analysis in the first month following heart or kidney transplantation. The intra-individual coefficient of variation (CV) was calculated, correlations with biochemical parameters were searched and recommendations/current guidelines for optimizing TAC dosing based on evidence-based medical databases (EBM) were presented. Material and methods. 24 patients aged 24-79 years (mean 47,1±13,9 years) were selected for retrospective analysis; 12 after heart transplant and 12 after kidney transplant. TAC dosing was the same in the patient groups and did not change during the analysis (first month); in heart recipients it was 2 mg/day and 1 mg/day in kidney recipients. Whole blood Cssmin TAC (steady state) was measured four times in all patients; the first in the 15th day of treatment, the second in 16-18, the third in 17-19, the fourth in 18-21. The QMS Tacrolimus immunoassay was used to analyze TAC concentration using the Indiko Plus automated chemistry analyzer. Results. The median Cssmin TAC value was 6,9-15,6 ng/mL after heart transplant and 8,7-16,0 ng/mL after kidney transplant. The CV range of patients after heart transplantation was 4-60%, while after kidney transplantation it was 8-40%. CV>30% (a higher risk of acute rejection) after heart transplant concerned 25% of patients and 15% after kidney transplant. The analysis of organ survival in heart and kidney recipients showed 83% and 100%, respectively, at an average of 2,7±0,5 and 3,25±2,5 years after transplantation. There were no significant correlations (p>0,05) between CV and selected biochemical parameters. Conclusion. CV>30% may indicate a large variability in the pharmacokinetics of TAC and thus, the need to optimize the dosage/physiological parameters affecting its concentration values. It seems necessary to improve the personalization of immunosuppressive therapy with TAC, taking into account individual parameters of extra- and intra-individual variability, in order to obtain better therapeutic results and avoid acute/chronic rejection, accelerated in time of organ transplant loss and/or the occurrence of additional side effects of TAC

Haematological side effects in patients with chronic viral hepatitis C during treatment with alpha interferon and ribavirin

Wstęp: Współczesna terapia przeciwwirusowa w leczeniu przewlekłego wirusowego zapalenia wątroby typu C (PZW C) cechuje się wysokim kosztem, licznymi działaniami ubocznymi oraz skutecznością sięgającą 50%. Poznanie patogenezy działań niepożądanych interferonu alfa (IFN) i rybawiryny (RBV) umożliwi zwiększenie bezpieczeństwa i skuteczności terapii. Zaburzenia hematologiczne występujące u leczonych IFN i RBV są najczęstszą przyczyną zmniejszenia dawki leku lub przerwania terapii. Cel pracy: Celem pracy była ocena zmian hematologicznych w trakcie terapii IFN i RBV oraz próba identyfikacji czynników kształtujących te zaburzenia. Materiał i metody: Badaniem objęto 46 chorych z PZW C leczonych pegylowanym IFN alfa 2a i RBV. Oceniano elementy morfotyczne krwi w kolejnych miesiącach leczenia oraz takie czynniki, jak: stopień włóknienia miąższu wątroby, genotyp wirusa i wiremia, wiek, płeć oraz wskaźnik masy ciała. Wyniki: Nie potwierdzono istotnego wpływu czynników charakteryzujących badaną grupę na zmiany w układzie elementów morfotycznych krwi obwodowej. Wyniki wskazują, że pod wpływem leczenia IFN następuje zróżnicowane hamowanie krwiotworzenia układu białokrwinkowego, z największą supresją eozynofili i neutrofili, przy mniejszym oddziaływaniu na linie limfocytów i monocytów. Nie stwierdzono istotnych klinicznie powikłań związanych z neutropenią i małopłytkowością. U chorych leczonych IFN i RBV zaobserwowano niedokrwistość hemolityczną z odczynem megaloblastycznym. Profil zmian leukocytów, erytrocytów i płytek krwi obserwowany w przeprowadzonym badaniu był podobny do publikowanych przez innych autorów. Wnioski: Neutropenia ze względną limfocytozą i brak powikłań klinicznych u chorych leczonych IFN z RBV sugeruje możliwość zmiany dotychczas zalecanych progów redukcji dawki IFN. Poznanie patogenezy niedokrwistości hemolitycznej z odczynem megaloblastycznym może ułatwić zapobieganie jej występowaniu i zwiększyć skuteczność terapii.Introduction: Current antiviral treatment of chronic viral hepatitis type C is expensive, effective in approximately 50% of cases and has many side effects. Knowledge about pathogenesis of side effects of alpha interferon (IFN) and ribavirin (RBV) is needed to increase safety of this therapy. Haematological complications in patients treated with IFN and RBV are the most frequent reasons for dose reduction or discontinuation of therapy. The aim of the study was to evaluate haematological disturbances as well as factors influencing risk of developing them during treatment with IFN and RBV. Material and methods: 46 patients with chronic viral hepatitis type C treated with pegylated alpha 2a IFN and RBV were studied. We evaluated blood cell counts every month of treatment, and also severity of liver fibrosis, genotype HCV, viral load, age, sex and body mass index. Results: No significant relationship between all studied factors and changes in blood cell count was shown. It was found that treatment with IFN has various inhibitory effects on different leukocyte populations with inhibition of eosinophils and neutrophils, whereas lymphocytes and monocytes were less affected. No clinically significant complications related to neutropenia or thrombocytopenia were noted. In patients treated with IFN and RBV haemolytic megaloblastic anaemia was observed. Changes in leukocyte, erythrocyte and platelet counts reported in this study confirmed the previously published data. Conclusions: Lack of clinical complications, despite observed neutropenia with relative lymphocytosis in studied patients, suggests a change in currently recommended IFN dose reduction. Further studies on pathogenesis of haemolytic anaemia with megaloblastic reaction are needed; they may enable development of its prophylaxis and increase treatment efficac

New mtDNA Association Model, MutPred Variant Load, Suggests Individuals With Multiple Mildly Deleterious mtDNA Variants Are More Likely to Suffer From Atherosclerosis

The etiology of common complex diseases is multifactorial, involving both genetic, and environmental factors. A role for mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation has been suggested in the pathogenesis of common complex traits. The aim of this study was to investigate a potential role of mtDNA variants in the development of obesity, diabetes, and atherosclerosis in the Polish population. Whole mtDNA sequences from 415 Polish individuals representing three disease cohorts and a control group were obtained using high-throughput sequencing. Two approaches for the assessment of mtDNA variation were applied, traditional mitochondrial haplogroup association analysis and the mutational or variant load model using the MutPred pathogenicity prediction algorithm for amino acid substitutions in humans. We present a possible association between mildly deleterious mtDNA variant load and atherosclerosis that might be due to having more than one likely mildly deleterious non-synonymous substitution. Moreover, it seems largely dependent upon a few common haplogroup associated variants with MutPred score above 0.5

Laryngeal embryonal rhabdomyosarcoma in an adult - A case presentation in the eyes of geneticists and clinicians

<p>1. Abstract</p> <p>Background</p> <p>Rhabdomyosarcoma is a solid tumor, resulting from dysregulation of the skeletal myogenesis program. For rhabdomyosarcomas (RMS) with a predilection for the head and neck, genitourinary tract, extremities, trunk, retroperitoneum, the larynx is still an unusual site. Till now only several cases of this laryngeal tumor have been described in world literature in the adult population. The entire spectrum of genetic factors underlying RMS development and progression is unclear until today. Multiple signaling pathways seem to be involved in ERMS development and progression.</p> <p>Case presentation</p> <p>In this paper we report an interesting RMS case in which the disease was located within the glottic region. We report an embryonal rhabdomyosarcoma of the larynx in 33 year-old man. After unsuccessful chemotherapy hemilaryngectomy was performed. In follow up CT no signs of recurrence were found. Recently patient is recurrence free for 62 months.</p> <p>Conclusions</p> <p>Considering the histological diagnosis and the highly aggressive nature of the lesion for optimal diagnosis positron electron tomography (PET) and computerized tomography (CT) of the neck and thorax should be performed. At this time surgical treatment with adjuvant radiotherapy seems to be the treatment of choice for this disease. Rhabdomyosarcoma of the larynx has a better prognosis than elsewhere in the body, probably because of its earlier recognition and accessibility to radical surgery.</p

Wind induced vibration analysis of composite footbridge

In the work, we describe a simplified method for numerical analysis of a FRP composite footbridge in the field of wind induced vibrations. We consider a simply supported structure with a span length of 16 m and U-shape cross-section. Firstly, a two dimensional flow analysis is performed of the fixed bridge cross-section which is subjected to a lateral wind action with 10 m/s velocity. Calculations are performed using ANSYSSYSSYS FLUENT 14 software. Results of the flow analysis (Strouhal’s number) are compared with the results presented in a monograph by A. Flaga, entitled Inżynieria Wiatrowa. Podstawy i zastosowania (Wind Engineering. The bases and applications) (in Polish), Arkady, Warszawa, 2008, in order to validate calculations. After that, a three dimensional spatial model of the footbridge is built in ABAQUS 6.12-3 finite element method software. A modal dynamics problem is solved, where the loading conditions are adopted on the basis of the flow analysis and applied as an evenly distributed pressure on the bridge deck surface. Finally, the users’ vibration comfort criterion is checked for the considered structure.[b]Keywords[/b]: composite shell footbridge, wind flow, modal method, footbridges vibration

Analiza drgań kładki kompozytowej wywołanych działaniem wiatru

In the work, we describe a simplified method for numerical analysis of a FRP composite footbridge in the field of wind induced vibrations. We consider a simply supported structure with a span length of 16 m and U-shape cross-section. Firstly, a two dimensional flow analysis is performed of the fixed bridge cross-section which is subjected to a lateral wind action with 10 m/s velocity. Calculations are performed using ANSYSSYSSYS FLUENT 14 software. Results of the flow analysis (Strouhal’s number) are compared with the results presented in a monograph by A. Flaga, entitled Inżynieria Wiatrowa. Podstawy i zastosowania (Wind Engineering. The bases and applications) (in Polish), Arkady, Warszawa, 2008, in order to validate calculations. After that, a three dimensional spatial model of the footbridge is built in ABAQUS 6.12-3 finite element method software. A modal dynamics problem is solved, where the loading conditions are adopted on the basis of the flow analysis and applied as an evenly distributed pressure on the bridge deck surface. Finally, the users’ vibration comfort criterion is checked for the considered structure.[b]Keywords[/b]: composite shell footbridge, wind flow, modal method, footbridges vibration

Transfusion related acute lung injury after ovaries puncture for in vitro fertilization procedure – a case report

Transfusion related acute lung injury (TRALI) is a serious blood transfusion complication characterized by the acute onset of non-cardiogenic pulmonary edema. In the pathogenesis of TRALI antibodies directed toward Human Leukocyte Antigens or Human Neutrophil Antigens are listed. Cases of TRALI have often gone unrecognized. The study gives an example of a 22 year-old patient without a significant history of the disease who received transfusions of large amounts of blood products because of shock in the course of bleeding after a puncture of the ovaries. The puncture was performed to retrieve ova for in vitro fertilization after hormonal stimulation. In the Department of Gynaecology, 2 laparotomies were performed because of massive bleeding and oth ovaries were removed. During the operation, 6 units of packed red blood cells, 1 unit of platelets concentrate and 5 units of fresh frozen plasma were transfused. Because of increasing respiratory failure, the patient was transferred to the Intensive Care Unit where 6 units of packed red blood cells, 3 units of plateletsconcentrate and 4 units of fresh frozen plasma were additionally transfused. During hospitalization, disseminated intravascular coagulation (DIC) appeared. It was decided to give the patient a Novo Seven preparation. The chest X-ray examination showed features of pulmonary edema. Tests also revealed low rates of respiratory (hypoxemia) and the need for a high FiO2, PEEP >10 cmH2O. Due to the clinical picture and the temporal relationship of pulmonary edema with transfusion, TRALI was diagnosed.Ostre potransfuzyjne uszkodzenie płuc (TRALI – transfusion related acute lung injury) jest poważnym powikłaniem poprzetoczeniowym, charakteryzującym się ostrym niekardiogennym obrzękiem płuc. W patogenezie TRALI wymienia się obecność w osoczu dawcy przeciwciał przeciw antygenom zgodności tkankowej (HLA – human leukocyte antigen) lub przeciw swoistym ludzkim antygenom neutrofilowym (HNA – human neutrophil antigens). Przypadki TRALI są często nierozpoznane lub źle zdiagnozowane. W piśmiennictwie polskim opisano tylko kilka przypadków. W pracy przedstawiono opis przypadku 22-letniej kobiety bez istotnej przeszłości chorobowej, której przetoczono dużą ilość preparatów krwi z powodu wstrząsu w przebiegu krwawienia po punkcji jajników. Punkcja była wykonywana w celu pobrania komórek jajowych do zapłodnienia in vitro po hormonalnej stymulacji. Na oddziale ginekologicznym wykonano 2 laparotomie z powodu masywnego krwawienia. Pacjentce usunięto oba jajniki. W okresie okołooperacyjnym przetoczono: 6 j. KKCZ (koncentrat krwinek czerwonych), 1 KKP (koncentrat krwinek płytkowych) i 5 j. FFP (osocze świeżo mrożone). Z powodu narastającej niewydolności oddechowej pacjentka została przekazana na oddział intensywnej terapii, gdzie dodatkowo przetoczono: 6 j. KKCz, 3 j. KKP i 4 j. FFP. W trakcie hospitalizacji wystąpił zespół rozsianego wykrzepiania wewnątrznaczyniowego (DIC – disseminated intravascular coagulation). Zdecydowano się podać aktywowany ludzki rekombinowany czynnik VII – eptakog alfa (NovoSeven, Novo Nordisk, Dania). W badaniu radiologicznym klatki piersiowej wykazano cechy obrzęku płuc. Badania gazometryczne wykazały również niski wskaźnik oksygenacji z koniecznością terapii 100% tlenem oraz PEEP > > 10 cm H2O (dodatnie ciśnienie końcowo-wydechowe). Ze względu na obraz kliniczny i związek czasowy obrzęku płuc z transfuzją rozpoznano TRALI. Dalszy przebieg leczenia był niepowikłany i chora została przekazana na oddział ginekologii w 11 dobie pobytu, w stanie ogólnym dobrym