Modulatory effect of sodium nitroprusside and 8Br-cGMP on mastoparan-7 induced contraction

I n t r o d u c t i o n. Mastoparan-7 activates G-protein and stimulates apoptosis, but in smooth muscle cells leads to increase in perfusion pressure. Main a i m of this study was to evaluate the modulatory effect of 8Br-cGMP and sodium nitroprusside on vascular smooth muscle contraction induced by direct stimulation of G-protein with mastoparan-7. Ma t e r i a l  a n d  m e t h o d s. Experiments were performed on isolated and perfused tail artery of Wistar rats. Contraction force in our model was measured by increased level of perfusion pressure with a constant flow. R e s u l t s. Concentration-response curves obtained for mastoparan-7 presented an sigmoidal relation. In presence of SNP and 8Br-cGMP the significant and dose dependent leftward shift with significant reduction in maximal responses was present. Moreover, analyzing function of calcium stores the significant inhibition of influx from both, intra- and extracellular calcium stores was present. C o n c l u s i o n. Results of our experiments suggest that contraction induced by direct activation of G-protein with mastoparan-7 may by effectively inhibited in the presence of donors of nitric oxide such as sodium nitroprusside and in the presence of 8Br-cGMP.  Mastoparan-7 jest aktywatorem białka G, stymulującym apoptozę. W mięśniach gładkich naczyń krwionośnych zwiększa kurczliwość. C e l e m prowadzonego badania było określenie wpływu nitroprusydku sodowego oraz 8Br-cGMP na skurcz mięśni gładkich wywołany bezpośrednią stymulacją białka G przez mastoparan-7. M a t e r i a ł  i  m e t o d y. Badania przeprowadzono na izolowanych i perfundowanych tętnicach ogonowych szczurów szczepu Wistar. Wykładnikiem skurczu w układzie doświadczalnym były zmiany ciśnienia perfuzyjnego. W y n i k i. Krzywe zależności efektu od stężenia agonisty uzyskane dla mastoparanu-7 miały przebieg odpowiadający krzywej sigmoidalnej. W obecności nitroprusydku sodowego i 8Br-cGMP zaobserwowano istotne przesunięcie krzywych w stronę prawą, tj. w stronę wyższych stężeń agonisty z jednoczesną redukcja efektu maksymalnego. Oceniając efektywność skurczu wyzwalanego napływem wapnia z przestrzeni wewnątrzkomórkowej i zewnątrzkomórkowej, stwierdzono istotne zmniejszenie napływu jonów wapnia z obydwu wymienionych magazynów. Wn i o s k i. Wyniki przeprowadzonych doświadczeń sugerują, że skurcz wyzwolony przez bezpośrednią aktywację białka G przez mastoparam-7 może być skutecznie hamowany przez donory tlenku azotu, jak np. nitroprusydek sodowy a także w obecności 8Br-cGMP

Effect of acetylcholine on vascular smooth muscle contraction induced by phenylephrine, angiotensin II and mastoparan-7

Background. The reactivity of blood vessels depends on their structure and the presence of calcium ions. It is modulated by numerous factors which activate specific signalling pathways leading to contraction or relaxation of smooth muscle. The action of various vasodilatation substances may be altered under the influence of similar or quite different modulators. Main aim of this study was to assess the role of acetylcholine and calcium ions in modulating the contraction induced by angiotensin II (ANG II), phenylephrine (PHE) and mastoparan-7, a direct activator of G-protein. Material and methods. Experiments were performed on isolated and perfused tail arteries of Wistar rats. Contraction force in our model was measured by increased level of perfusion pressure with a constant flow. Results. ANG II caused an increase in perfusion pressure in physiological salt solution (PSS) and calcium free PSS (FPSS).Under the influence of increasing concentrations of acetylcholine, a statistically significant reduction in perfusion pressure in both types of fluid was noted. In the presence of nitro-L-arginine (nitric oxide synthase inhibitor, L-NNA) in both solutions, no changes in contraction stimulated by ANG II or spasmolytic effect of acetylcholine were observed. PHE, in a similar manner to ANG II, caused contraction in FPSS and PSS, which was similarly modulated by acetylcholine. In the mastoparan-7 induced contraction, the pattern of tissue response was similar. For all groups, maximal perfusion pressure in PSS was higher than for FPSS. Conclusions. The results of our experiments suggest that acetylcholine by activation of vascular endothelium is able to induce dose-dependent vasodilatation not only in contraction related to typical metabotropic receptor agonists, but also after direct stimulation of G-protein with mastoparan-7. This effect may be reversed in the presence of inhibitors of endothelial synthase of nitric oxide

Szczepienia ochronne u dzieci w trakcie i po leczeniu onkologicznym oraz w wybranych chorobach hematologicznych: rekomendacje Polskiego Towarzystwa Onkologii i Hematologii Dziecięcej

Zakażenia są jednym z największych zagrożeń dla chorych w trakcie i po leczeniu chorób nowotworowych. Dla dzieci z nieonkologicznymi schorzeniami hematologicznymi infekcje wiążą się ze zwiększonym ryzykiem powikłań, a także mogą być czynnikiem spustowym wystąpienia lub zaostrzenia problemu zdrowotnego. Jedynym skutecznym i bezpiecznym sposobem zapobiegania zakażeniom są szczepienia ochronne. Zalecenia odnośnie do ich realizacji zmieniają się w czasie, w zależności od aktualnej sytuacji epidemiologicznej, dostępu do szczepionek, a także danych dotyczących bezpieczeństwa ich stosowania w grupach ryzyka. Prezentowana praca przedstawia aktualne rekomendacje Polskiego Towarzystwa Hematologii i Onkologii Dziecięcej, dotyczące zasad immunizacji dzieci z chorobami nowotworowymi i schorzeniami hematologicznymi

Improvement of cure after hematopoietic stem cel transplantations in children

Background. Hematopoietic stem cell transplantation (HSCT) is an established procedure for many acquired and congenital disorders of the hematopoietic system, including malignancies, bone marrow failure syndromes, disorders of the immune system, and metabolic disorders. Objective. Analysis of results of hematopoietic stem cell transplantations performed over a period of 12 years in a single pediatric center. Patients and methods. All transplants performed between 2003 and 2015 in the Department of Pediatric Hematology and Oncology in Bydgoszcz were included in this analysis. The results of therapy with stem cell transplantation were analyzed in three time periods: 2004-2007, 2008-2011 and 2012-2015. Results. A total number of transplants was 318, including 132 auto-HSCT and 186 allo-HSCT. Among allogeneic transplants, 68 were done from matched-sibling donor and 118 from alternative donor. The mean survival for all patients estimated by Kaplan-Meier method was 8.1 years. Probability of overall survival (pOS) after all transplants was 0.64±0.03. pOS after allo-HSCT was 0.62±0.04, and 0.67±0.05 after auto-HSCT. Overall survival for patients transplanted in the second (2008-2011) and third (2012-2015) time period was comparable both for auto- and allo-HSCT. However, it was significantly higher than for patients transplanted in the first period of time (2004-2007) for all patients, and for those undergoing auto-HSCT. In allo-HSCT patients, in spite of increase of over 20% in pOS (43% vs 66% vs 64% in respective time periods), the difference was not statistically significant. Conclusion. Presented results of HSCT obtained in our center are comparable with those from other international registries and centers.Wstęp. Transplantacja komórek krwiotwórczych (HSCT) jest ważną metodą terapeutyczną w wielu wrodzonych i nabytych chorobach, w tym nowotworowych, zespołach niewydolności szpiku oraz zaburzeniach immunologicznych i metabolicznych. Celem pracy jest analiza wyników HSCT w pojedynczym ośrodku pediatrycznym w okresie 12 lat. Pacjenci i metodyka. Analizie poddano wyniki przeszczepień wykonanych w latach 2003-2015 w Klinice Pediatrii, Hematologii i Onkologii w Bydgoszczy. Transplantacje analizowano w trzech przedziałach czasowych: 2004-2007, 2008-2011 oraz 2012-2015. Wyniki. Wykonano 318 HSCT, w tym 186 alloge-nicznych (68 zgodnych rodzinnych i 118 od dawców alternatywnych) oraz 132 autologiczne. Średnie przeżycie po HSCT, wyznaczone metodą Kaplana-Meiera wyniosło 8,1 lat. Całkowite prawdopodobieństwo przeżycia (pOS) wyniosło 0,64±0,03; pOS po allo-HSCT wynosi 0,62±0,04, a po auto-HSCT 0,67±0,05. Nie wykazano znamiennych różnic w pOS zarówno po allo-HSCT, jak i po auto-HSCT pomiędzy drugim (2008-2011) i trzecim (2012-2015) analizowanym okresie. Jednakże, pOS było wyższe w dru-gim i trzecim okresie w stosunku do okresu pierwszego (2004-2007), zarówno dla wszystkich pacjentów, jak i u pacjentów po auto-HSCT. W grupie pacjentów allo-HSCT, uzyskano wzrost pOS o ponad 20% (43% vs 66% vs 64% w kolejnych przedziałach czasu; ns). Wnioski. Wyniki HSCT uzyskiwane aktualnie w na-szym ośrodku są porównywalne z wynikami podawanymi w międzynarodowych rejestrach

National experience with adenosine deaminase deficiency related SCID in Polish children

IntroductionDeficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient’s general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis.Material and methodsWe retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022.ResultsAll patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy.ConclusionsIt is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID

Acute non-hematological toxicity of intensive chemotherapy of acute lymphoblastic leukemia in children

IntroductionLeukemia belong to 31% of all childhood malignancies. Acute lymphoblastic leukemia (ALL) is the most frequent type of pediatric leukemia accounting for 80–85% of all cases. Progress in diagnostics and therapy of leukemia is dependent on international cooperation. The objective of the study was the analysis of non-hematological toxicity during intensive chemotherapy according to two consecutive intercontinental protocols. Patients and methodsA total number of 210 children diagnosed for ALL who were treated in single center between 2002 and 2018 were divided in two groups defined by therapeutic protocol: ALL IC-BFM 2002 (group 1) and ALL IC-BFM 2009 (group 2). Data were entered prospectively from 2002 into international ALL IC-BFM 2002 and ALL IC-BFM 2009 registry. Non-hematological toxicity was analyzed according to the criteria followed in protocols, compatible with CTCAE criteria. ResultsThe most frequent toxicities included hepatic toxicity with transaminitis and hyperbilirubinemia, infections, oral mucositis and gut toxicity with vomiting, and/or diarrhea. Non-hematological toxicity episodes calculated as a ratio per patient were comparably often observed in both the groups; however, the distribution was different. There were more grade III and less grade II toxicities. This was mainly related to significant increase in the rates of infections and transaminitis. However, there was a significant decrease in vomiting and central and peripheral neurotoxicity. ConclusionsIntensive treatment of ALL is burdened with frequent severe toxic and infectious complications. Further progress in therapy of pediatric ALL is dependent on sophisticated supportive therapy and very well experienced and knowledgeable therapeutic team

High risk of invasive fungal disease in children undergoing hematopoietic cell transplantation or complex anticancer therapy: the adverse role of post-transplant CMV replication

Introduction: We analyzed the epidemiology and outcomes of treatment of invasive fungal disease (IFD) in children during anticancer therapy (PHO, pediatric hematology and oncology) or after hematopoietic cell transplantation (HCT) over a period of eight consecutive years in a single-center study. Material and methods: Overall, a total of 254 HCTs were performed, and 415 children were newly diagnosed for malignancy. Incidence, epidemiology and outcome of IFD were analyzed. Results: The cumulative incidence of any IFD was 32.6% in allo-HCT, 22.2% in PHO, and 6.0% in auto-HCT patients. The incidence of proven +probable IFD was 12.6%, 10.4%, and 6.0%, respectively. As many as 77.0% HCT and 67.4% PHO of fungal episodes occurred in acute leukemia patients: the highest incidence of any IFD was observed for acute lymphoblastic leukemia (29.3% in HCT; 40.5% in PHO) and for acute myeloblastic leukemia (51.1% in HCT; 65.0% in PHO) patients. There were no significant differences in the incidence of fungal infections in both allo-HCT and PHO patients between the 2-year periods. Factors contributing to an increased risk of IFD in allo-HCT patients were: CMV replication, and acute and chronic graft-versus-host disease (GvHD). Survival from IFD was 91.9% in PHO, and 78.1% in HCT patients. Fungal pneumonia in HCT patients resolved in 62.9%, while in PHO patients it resolved in 93.5%. Conclusions: The risk of IFD in allo-HCT patients is much higher than in auto-HSCT and PHO patients. The outcome of IFD is better in PHO and auto-HCT than in allo-HCT settings

Relapsed childhood acute myeloid leukemia: prognostic factors and outcomes: experience from a single oncology center

Introduction: Over recent decades, significant progress in the treatment of childhood acute myeloid leukemia (AML) has been made. However, the relapsed disease remains a challenge. The aim of this study was to analyze therapy results in pediatric patients treated for relapsed AML in a single oncology center, with a particular focus on prognostic factors. Materials and methods: Data from patients younger than 19 years with AML diagnosed between January 1994 and December 2020 treated in the Department of Pediatric Hematology and Oncology in Bydgoszcz, Poland was analyzed, with detailed analysis of patients with relapsed disease. Results: A total of 77 children were diagnosed with AML in the analyzed period and 21 had a relapsed disease (27.3%). Bone marrow relapse was the most common. The risk factors of relapse included white blood cells >100 G/L at initial diagnosis and classification to the high risk group. Late relapse was related to poorer outcomes. The 5-year probability of overall survival for the entire group was 28.6%, and this was significantly higher in patients who achieved second remission compared to those who did not (44.9% vs. 0.0%, p <0.001). The main reason for death was progression of disease, which occurred in 10 patients. Conclusions: Outcomes in relapsed AML in children are still dismal. Lack of second remission suggests the need for experimental therapy

Changing risk factors in childhood acute lymphoblastic leukemia: experience from Kujawsko-Pomorski region 1976–2018

Introduction: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Risk factors in childhood ALL have changed during recent decades, mostly due to treatment personalization. The aim of this study was to analyze therapy results and prognostic factors in childhood ALL in the Kujawsko-Pomorski region of Poland between 1976 and 2018. Material and methods: Data from 495 patients (0–18 years old) diagnosed with ALL from the Kujawsko-Pomorski region between 1976 and 2018 was analyzed. Prognostic factors were analyzed separately in specific therapeutic groups, which were defined by several therapy protocols. Results: Prognostic factors have changed over the course of consecutive therapeutic periods. Between 1976 and 1988 (the first and second therapeutic protocols), central nervous system involvement was the most important risk factor. During the third therapeutic period, an unsatisfactory treatment response on days 8 and 14 was related to a poor outcome. In 1995–2002, the risk factors were hepatomegaly, splenomegaly, lymph nodes involvement, and unsatisfactory therapy response on days 15 and 33. Between 2002 and 2011, immunophenotype other than ‘common’ and hemoglobin level at diagnosis were the risk factors, and a lack of BCR-ABL aberration was related to better therapy results. During the final analyzed period (2011–2018), failure to achieve remission on day 33 was a risk factor, and patients classified as non-high risk group and those aged <6 years had better outcomes. Conclusions: The changing profile of risk factors in ALL has reflected progress in ALL therapy, with the gradual elimination of factors related to poor outcomes, mostly due to modifications in treatment and the development of diagnostic methods as well as therapy monitoring