Synthesis,evaluation, and molecular docking studies of aryl urea‐triazole‐based derivatives as anti‐urease agents

Considering the importance of urease inhibitors in the treatment of ureolytic bacterial infections, in this work, the synthesis of novel, aryl urea‐triazole‐based derivatives as effective urease inhibitors is described. Dichloro‐substituted derivative 4o , with IC₅₀ = 22.81 ± 0.05 μM, is found to be the most potent urease inhibitor, determined by Berthelot colorimetric assay. Docking studies were also carried out for compound 4o to confirm the effective interactions with the urease active site.

     

The role of MSX1 in tooth agenesis in Iranians

INTRODUCTION: MSX1 gene has a critical role in craniofacial development, the aim of this case-control study is to test the hypothesis that MSX1 mutation contributes to congenital tooth agenesis in Iranians. MATERIALS AND METHODS: The study group consisted of 20 affected individuals with tooth agenesis of lower second premolars or upper lateral incisors with mean age of 24.6. The control group consisted of 20 unaffected individuals. DNA was extracted from all 40 individuals; the polymerase chain reaction (PCR) for MSX1 was carried out with Phenol: Chloroform: Isoamylalchol (PCI) extraction method. Ban II restriction digest and agarose gel electrophoresis of the 20 affected individuals verified the presence of mutation in all 20 affected individuals. The unaffected controls did not show any mutation. Statistical analysis performed by the chi-squared method. RESULTS: Ban II did not digest PCR product (DNA) in the control group (195 bp band on electrophoresis gel) but digested the affected allele (106 bp and 89 bp bands). There is a statistically significant correlation between tooth agenesis and MSX1 mutation (P < 0.001). CONCLUSION: The results indicated that MSX1 gene mutation contributes to tooth agenesis in Iranian individuals. As the timing of tooth calcification can vary, radiographic finding of congenital tooth agenesis can be confirmed by this molecular method during different dental ages to achieve certainty.     

Molecular docking and 3D-QSAR studies on the MAPKAP-K2 inhibitors

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) has been identified as a drug target for the treatment of inflammatory diseases. Therefore, there is an urgent need to develop new classes of MAPKAP-K2 inhibitors. To understand the structure activity correlation of MAPKAP-K2 inhibitors, we have carried out a molecular docking study and three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling. Both comparative molecular field analysis ( $r_{\text{cv}}^{2}$  = 0.602, $r_{\text{ncv}}^{2}$  = 0.955) and comparative molecular similarity indices analysis ( $r_{\text{cv}}^{2}$  = 0.546, $r_{\text{ncv}}^{2}$  = 0.891) models were generated using the training set on the basis of the common substructure-based alignment and gave reasonable results. The structural insights obtained from both the 3D-QSAR contour maps and molecular docking help to better interpret the structure activity relationship. The results obtained from this study will be useful in the design of potent MAPKAP-K2 inhibitors.     

Diagnosing pneumonia in rural Thailand: Digital cameras versus film digitizers for chest radiograph teleradiology.

BACKGROUND: Accurate surveillance for pneumonia requires standardized classification of chest radiographs. Digital imaging permits rapid electronic transfer of data to radiologists, and recent improvements in digital camera technology present high quality, yet cheaper, options. METHODS: We evaluated the comparative utility of digital camera versus film digitizer in capturing chest radiographs in a pneumonia surveillance system in rural Thailand using a panel of radiologists; the gold standard was the hard-copy radiograph. We calculated sensitivity and specificity and conducted a receiver operator characteristics (ROC) analysis. RESULTS: Of the 192 radiographs from patients with clinical pneumonia, 166 (86%) were classified as pneumonia on the hard copies. Sensitivity and specificity for identifying pneumonia were 89% and 73% for the camera and 90% and 65% for the digitizer. In the ROC analysis, there was no statistically significant difference in the area under the curve (camera, 0.86; film digitizer, 0.91, p = 0.29). The digital camera set cost 965 dollars compared to 3000 dollars for the film digitizer. CONCLUSION: Detection of pneumonia was not measurably compromised by using digital cameras compared with film digitizers. The 3-fold lower cost of the digital camera makes this technology an affordable and widely accessible alternative for surveillance systems, vaccine trials, and perhaps clinical use.     

Diagnosis of aortic stenosis in the elderly: role of echocardiography

Doppler echocardiography provides accurate hemodynamic information for the diagnosis, assessment and follow-up of patients with aortic stenosis, making diagnostic cardiac catheterization redundant in most cases. Considering the rapid growth of the aging population and the high incidence of aortic stenosis, as the most common valvular heart disease in the age group, the authors have described the utility of the Doppler technique with a brief discussion of the clinical evaluation of these patients. Close observation of patients with asymptomatic aortic stenosis has been emphasized. Decision-making about the appropriate timing for aortic valve replacement is of immense clinical significance, which may be facilitated and achieved by the periodic follow-up and the use of this noninvasive method. Following a comprehensive echo-Doppler evaluation, the patient would only need coronary arteriography prior to surgery. The utility of hemodynamic and anatomic information by echocardiography in this type of surgery is emphasized.     

Thrombolysis and Counterpulsation to Improve Survival in Myocardial Infarction Complicated by Hypotension and Suspected Cardiogenic Shock or Heart Failure: Results of the TACTICS Trial

Background: Sustained hypotension, cardiogenic shock, and heart failure all imply a poor prognosis in acute myocardial infarction (MI). We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation (IABP) to standard treatment for MI, in an international trial among hospitals without primary angioplasty capabilities.Methods: We randomized 57 patients with MI complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure to receive either fibrinolytic therapy and IABP or fibrinolysis alone. The primary end point was all-cause mortality at 6 months.Results: In all, IABP was inserted in 27 of 30 assigned patients a median 30 minutes after fibrinolysis began and continued for a median 34 hours. Of the 27 patients assigned to fibrinolysis alone, 9 deteriorated such that IABP was required. The IABP group was at slightly higher risk at baseline, but the incidence of the primary end point did not differ significantly between groups (34% for combined treatment versus 43% for fibrinolysis alone; adjusted P = 0.23). Patients with Killip class III or IV showed a trend toward greater benefit from IABP (6-month mortality 39% for combined therapy versus 80% for fibrinolysis alone; P = 0.05).Conclusions: While early IABP use was not associated with a definitive survival benefit when added to fibrinolysis for patients with MI and hemodynamic compromise in this small trial, its use suggested a possible benefit for patients with the most severe heart failure or hypotension.Abbreviated Abstract. We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation to fibrinolytic therapy among 57 patients with acute myocardial infarction complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure. The primary end point, mortality at 6 months, did not differ between groups (34% for combined treatment versus 43% for fibrinolysis alone [n = 27]; adjusted P = 0.23), although patients with Killip class III or IV did show a trend toward greater benefit from IABP (39% for combined therapy versus 80% for fibrinolysis; P = 0.05).     

Digital droplet PCR (ddPCR) for the precise quantification of human T-lymphotropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of HAM/TSP patients and identification of viral mutations

An elevated human T cell lymphotropic virus 1 (HTLV)-1 proviral load (PVL) is the main risk factor for developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-1 infected subjects, and a high cerebrospinal fluid (CSF) to peripheral blood mononuclear cell (PBMC) PVL ratio may be diagnostic of the condition. However, the standard method for quantification of HTLV-1 PVL—real-time PCR—has multiple limitations, including increased inter-assay variability in compartments with low cell numbers, such as CSF. Therefore, in this study, we evaluated a novel technique for HTVL-1 PVL quantification, digital droplet PCR (ddPCR). In ddPCR, PCR samples are partitioned into thousands of nanoliter-sized droplets, amplified on a thermocycler, and queried for fluorescent signal. Due to the high number of independent events (droplets), Poisson algorithms are used to determine absolute copy numbers independently of a standard curve, which enables highly precise quantitation. This assay has low intra-assay variability allowing for reliable PVL measurement in PBMC and CSF compartments of both asymptomatic carriers (AC) and HAM/TSP patients. It is also useful for HTLV-1-related clinical applications, such as longitudinal monitoring of PVL and identification of viral mutations within the region targeted by the primers and probe.     

Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation

Anti-T-cell lymphocyte globulin (ATLG) and posttransplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical Center Hamburg-Eppendorf (UKE) compares PTCy (n=123) and ATLG (n=476) after myeloablative allogeneic peripheral blood stem cell transplant. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations, GVHD and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. day 10, P<0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher Epstein-Barr virus reactivation in the ATLG arm and comparable cytomegalovirus reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was seen more often after PTCy (44% vs. 38%, P=0.005). ATLG resulted in a faster reconstitution of CD8+ T, NK, NKT and gdT cells while CD4 T cells and B cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B cells. Non-relapse mortality relapse incidence, disease-free survival, and overall survival did not differ significantly between both arms. Even though differences in IR were related to a decreased incidence of infection and moderate/severe cGVHD in the ATLG group they had no impact on any of the other long-term outcomes. However, it remains undetermined which regimen is better as GVHD prophylaxis.