Synthesis,Characterization, and Cytotoxicity of Some New 5-Aminopyrazole and Pyrazolo[1,5-a]pyrimidine Derivatives

5-Amino-N-aryl-3-[(4-methoxyphenyl)amino]-1H-pyrazole-4-carboxamides 4a–c were synthesized by the reaction of N-(aryl)-2-cyano-3-[(4-methoxyphenyl)amino]-3-(methylthio)acrylamides 3a–c with hydrazine hydrate in ethanol. The reaction of 5-amino-N-aryl-1H-pyrazoles 4a–c with acetylacetone 5 or 2-(4-methoxybenzylidene)malononitrile 8 yielded the pyrazolo[1,5-a]pyrimidine derivatives 7a–c and 10a–c, respectively. The structures of the synthesized compounds were established based on elemental analysis and spectral data (IR, MS, ¹H-NMR, and ¹³C-NMR). Representative examples of the new synthesized products were screened for their in vitro cytotoxic activity against Ehrlich Ascites Carcinoma (EAC) cells.     

Blastic Plasmacytoid Dendritic Cell Neoplasm: Single Center Experience on a Rare Hematological Malignancy

PurposeBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and poor prognostic hematological malignancy. There is still no standard treatment established for BPDCN patients. We aim to summarize the main clinical, biological features and treatment of 9 BPDCN patients.MethodsNine patients with BPDCN who had been diagnosed between July 2008 and December 2018 in Ankara University School of Medicine, were retrospectively evaluated.ResultsAll patients (n = 9) were male, median age was 64 (21–80). Five patients (55.6%) had bone marrow infiltration, 5 patients (55.6%) cutaneous lesions, 6 patients (66.7%) lymph node involvement, 2 patients (22.2%) central nervous system involvement and 2 patients (22.2%) spleen involvement at time of diagnosis. Complex karyotype was observed in 2 patients. CHOP was given to 5 patients (55.6%), hyper-CVAD to 2 patients (22.2%), fludarabine, cyclophosphamide and mitoxantrone to 1 patient (11.1%) and cyclophosphamide, etoposide, methylprednisolone to 1 patient (11.1%) as first line chemotherapy. Four patients (44.4%) underwent allogeneic hematopoietic stem cell transplantation (AHSCT) in complete remission (CR) 1. Venetoclax was given to a transplant ineligible patient who had skin and lymph node involvement, with the off-label use. The median follow-up time was 15.9 months (3–48.6 months). Estimated median overall survival was 15.9 + 1.6 (95% CI 12.7–19.1) months.ConclusionIntensive induction therapies followed by AHSCT in CR seems to be best approaches for patients with BPDCN. Thus, more effective treatment strategies particularly targeted therapies should be warranted to improve the survival of patients with this rare disease.     

Discrimination between non-functioning pituitary adenomas and hypophysitis using machine learning methods based on magnetic resonance imaging‑derived texture features

Purpose

Hypophysitis is a heterogeneous condition that includes inflammation of the pituitary gland and infundibulum, and it can cause symptoms related to mass effects and hormonal deficiencies. We aimed to evaluate the potential role of machine learning methods in differentiating hypophysitis from non-functioning pituitary adenomas.

Methods

The radiomic parameters obtained from T1A-C images were used. Among the radiomic parameters, parameters capable of distinguishing between hypophysitis and non-functioning pituitary adenomas were selected. In order to avoid the effects of confounding factors and to improve the performance of the classifiers, parameters with high correlation with each other were eliminated. Machine learning algorithms were performed with the combination of gray-level run-length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray-level co-occurrence entropy.

Results

A total of 34 patients were included, 17 of whom had hypophysitis and 17 had non-functioning pituitary adenomas. Among the 38 radiomics parameters obtained from post-contrast T1-weighted images, 10 tissue features that could differentiate the lesions were selected. Machine learning algorithms were performed using three selected parameters; gray level run length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray level co-occurrence entropy. Error matrices were calculated by using the machine learning algorithm and it was seen that support vector machines showed the best performance in distinguishing the two lesion types.

Conclusions

Our analysis reported that support vector machines showed the best performance in distinguishing hypophysitis from non-functioning pituitary adenomas, emphasizing the importance of machine learning in differentiating the two lesions.

     

Does the Myocardial Performance Index Affect Pulmonary Artery Pressure in Patients With Mitral Stenosis? A Tissue Doppler Imaging Study

BACKGROUND: The relation between systolic pulmonary artery pressure (PAP) and mitral stenosis (MS) has been poorly understood. Although the mitral valve area (MVA) is an important factor affecting the PAP, there is a wide spectrum of the PAP in patients with MS despite a similar MVA. So, we analyzed whether the left and right ventricular myocardial performance index (MPI) correlated with the PAP. METHODS: Two-dimensional Doppler echocardiography was performed in 46 patients with MS. The left atrial diameter, mean mitral gradient, and MVA were measured. The PAP was derived from the tricuspid regurgitant jet velocity. The ejection time (ET), isovolumetric relaxation time (IRT), and contraction time (ICT) were measured on annulus of interventricular septum, lateral, inferior and anterior wall of left ventricle, and right ventricle free wall from apical two- and four-chamber views in patients with MS and 40 age-matched healthy patients by tissue Doppler imaging (TDI). Then the MPI was calculated as (IRT + ICT)/ET for both left and right ventricle. The correlation of PAP with MVA, mean mitral gradient, left atrial diameter, and left and right ventricular MPI was evaluated. RESULTS: MVA and PAP were measured as 1.57 +/- 0.39 cm2 (0.8-2.5 cm2)and 42 +/- 16 mmHg, respectively. It was determined that the MPI increased in patients with MS(0.59 +/- 0.1 vs 0.48 +/- 0.07, P < 0.001). It was also demonstrated that the MVA, left atrial diameter, mean diastolic gradient, and left ventricular MPI were correlated with PAP(r =-0.39 [P = 0.007], r = 0.43 [P = 0.003], r = 0.58 [P < 0.001], and r = 0.65 [P < 0.001], respectively). In multivariate analysis, although the PAP correlated with mean diastolic gradient and MPI (r = 0.39 [P = 0.013], and r = 0.48 [P < 0.001]), it did not correlate with left atrial diameter and MVA. The PAP also correlated with right ventricular MPI(r = 0.63 [P < 0.001]). CONCLUSION: This study demonstrates that the left ventricular MPI obtained by TDI is an important marker of PAP, and right ventricular MPI correlates with the PAP in patients with MS.     

Experimental alterations of endorphin levels in rat pituitary

Endorphin (END) levels in rat pituitary were assessed with the opiate receptor binding assay. Procedures reported to alter hormone secretion from END-rich intermediate or anterior lobes were examined for their effect on END content. Lesions of the paraventricular nucleus (PVN) had no significant effect on END content. Ingestion of 2% NaCl reduced END levels in a significant majority of the animals. Suckling, a natural physiological stimulus, significantly elevated neurointermediate lobe END. Footshock and immobilization each evoked 40--50% reductions in anterior lobe END content. Pituitary ENDs are thus affected by many of the same stimuli that also promote release of a number of peptide hormones derived from the same biosynthetic precursor. However, separate mechanisms likely exist for control of secretion of these peptides from anterior and neurointermediate lobe.     

Impact of a double dose of sulphadoxine-pyrimethamine to reduce prevalence of pregnancy malaria in southern Mozambique

Malarial infection during pregnancy increases the risks of severe sequelae for the pregnant woman and the risk of delivering a low birthweight baby. The aim of this intervention study was to reduce significantly the prevalence of malaria parasitaemia in adolescent parturients in Matola and Boane in Mozambique. The study was focused upon the most malaria-vulnerable group, adolescent nulliparous and primiparous women. After completing the usual antenatal clinic and giving informed consent, 600 pregnant women were randomly chosen in a double blind manner to one of two regimens comparing the prevailing routine (placebo) for malaria prevention with a two dose regimen of sulphadoxine-pyrimethamine (SP). The first dose was given at enrollment with a second dose at the beginning of the third trimester. At delivery maternal and placental malaria parasitaemia as well as birthweight and gestational duration were analysed. At booking the prevalence of malaria parasitaemia was 35.3% in the placebo group and 30.6% in the SP group. At the second dose, the prevalence of malaria parasitaemia in the placebo group and SP group was 19.7% and 8.7%, respectively. This implies a relative risk (RR) of 2.24 with 95% CI (1.34, 3.75). The corresponding figures at delivery were 13.6% and 6.3% with an RR of 2.22 (1.07, 4.60) and in placenta 13.3% and 2.4% with an RR of 4.87 (1.58, 15.0). Newborns with malaria within 7 days were significantly more frequent in the placebo group, 6.4% and 0.7% respectively, with an RR of 6.55 (1.20, 35.7). Almost all (approximately 98%) of the women studied had Plasmodium falciparum, the remainder had P. malariae and P. ovale. The mean birthweight in the SP group was 3077 g and in the placebo group 2926 g. The estimated mean difference between the two groups was 151 g with 95% CI (51, 252). The mean placental weight in the placebo group was 596 and 645 g in the SP group, implying a difference of 49 g with a 95% CI (11, 88). The mean gestational duration was 6.1 days longer in the SP group, 95% CI (1.5, 10.6). In the placebo group there were two cases of urticaria and one case of nausea; in the SP group there was one case of vomiting. No newborn showed any sign of serious SP side-effect. Two doses of SP were enough to significantly reduce the prevalence of peripheral and placental malaria parasitaemia among young nulliparous and primiparous pregnant women in Matola and Boane.     

Exercise-induced changes in QT interval duration and dispersion in patients with isolated myocardial bridging

BACKGROUND: Isolated myocardial bridging (MB) often is considered to be an unimportant angiographic finding; however, its association with cardiovascular event has been shown. In this study we aimed to assess exercise-induced electrocardiographic (ECG) changes and susceptibility to arrhythmia in patients with MB. METHOD: 21 consecutive patients who had angiographically proven MB (group I) and 25 subjects (group II) who had normal coronary arteries underwent exercise test using Bruce protocol. Before and after the exercise test the changes in QT interval duration and dispersion were compared. RESULTS: Baseline characteristics of both groups were similar. Heart rate significantly increased after exercise test in both groups. In group I, after exercise mean QT(max) and QT(min) durations did not change significantly compared to baseline values, respectively. (QT(max): 411+/-20 vs. 421+/-18 ms, p>0.05 and QT(min): 380+/-12 vs. 378+/-10 ms, p>0.05). However, following exercise test QT dispersion (QT(d)) and corrected QT dispersion (QT(cd)) significantly increased when compared to baseline values, respectively. (34+/-13 vs. 66+/-14 ms, p<0.05 and 37+/-14 vs. 69+/-17 ms, p<0.05) On the other hand, in control group QT(max) and QT(min) durations, QT(c) and QT(cd) did not change significantly compared to baseline values, respectively. (QT(max): 408+/-18 vs. 412+/-17 ms, p>0.05 and QT(min): 390+/-11 vs. 387+/-10 ms, p>0.05; QT(d): 25+/-14 vs. 31+/-16 ms, p>0.05; QT(cd): 27+/-15 vs. 33+/-17 ms, p>0.05). CONCLUSION: Treadmill exercise test significantly increased QT dispersion in patients with MB. This increase may result from exercise-induced ischemia at the area perfused by bridged artery.     

Haematological disorders and occupational hazards: a British Society for Haematology/Health and Safety Executive study

Summary. During a 3-year period 229 patients in the U.K. with haematological disorders thought to be associated with occupational hazards were notified to the British Society for Haematology/Health and Safety Executive office. Most were suffering from malignant or premalignant states or aplastic anaemia. Benzene and ionizing radiation were the most common agents recorded. While no estimate can be made of the incidence of chemical or radiation induced disease at the present time, the data suggests that routine documentation of exposure at work is an important step in allowing more specifically focused studies.     

Thrombin activatable fibrinolysis inhibitor activity, thrombin-antithrombin complex and D-dimer levels in preterm neonates with early respiratory distress syndrome

Intraalveolar fibrin deposition found in neonates with respiratory distress syndrome (RDS) is explained by the activation of the coagulation system and inefficient fibrinolysis. However, thrombin activatable fibrinolysis inhibitor activity (TAFIa), an inhibitor of fibrinolysis, and the ratio of D-dimer to thrombin-antithrombin complex (D-dimer/TAT), an index of fibrinolytic activity, have not been reported previously in neonatal RDS. Aim of this study is to evaluate the influence of plasma TAFIa levels on the fibrinolytic state in neonatal RDS. The RDS group (Group 1) consisted of 29 neonates, and 18 neonates served as the control group (Group 2). Plasma TAFIa levels and D-dimer/TAT ratios were evaluated in all neonates in the first 6 hr of life. Neonates in the RDS group were further divided into two subgroups; Group 1a consisted of 12 neonates with evidence of mild asphyxia (Apgar score at 5 min <7 and cord pH <7.26), and Group 1b consisted of 17 nonasphyxiated neonates. No significant difference was found in TAFIa levels and D-dimer/TAT ratios between Groups 1 and 2 [214% (56.2-361%) and 124.3 (4.4-3,921) in Group 1 and 201% (60.3-381%) and 147 (5.9-1,426) in Group 2]. There were negative correlations between cord pH and TAFIa levels in both groups. Increased TAFIa levels and decreased D-dimer/TAT ratios and platelet counts were detected in mildly asphyxiated neonates when compared with nonasphyxiated ones. TAFIa is not responsible for the hypofibrinolytic state reported in RDS. However, asphyxia influences TAFIa levels and increased TAFIa levels depress fibrinolysis.