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Multiple factors are causally responsible and/or contribute to the progression of Alzheimer's and Parkinson's diseases. The protein kinase Dyrk1A was identified as a promising target as it phosphorylates tau protein, α-synuclein, and parkin. The first goal of our study was to optimize our previously identified Dyrk1A inhibitors of the 6-hydroxy benzothiazole urea chemotype in terms of potency and selectivity. Our efforts led to the development of the 3-fluorobenzyl amide derivative 16b, which displayed the highest potency against Dyrk1A (IC50 = 9.4 nM). In general, the diversification of the benzylamide moiety led to an enhanced selectivity over the most homologous isoform, Dyrk1B, which was a meaningful indicator, as the high selectivity could be confirmed in an extended selectivity profiling of 3b and 16b. Eventually, we identified the novel phenethyl amide derivative 24b as a triple inhibitor of Dyrk1A kinase activity (IC50 = 119 nM) and the aggregation of tau and α-syn oligomers. We provide evidence that the novel combination of selective Dyrk1A inhibition and suppression of tau and α-syn aggregations of our new lead compound confers efficacy in several established cellular models of neurotoxic mechanisms relevant to neurodegenerative diseases, including α-syn- and 6-hydroxydopamine-induced cytotoxicities.

Background Up to 30% of patients with sickle cell disease (SCD) develop chronic liver disease via etiologies including sickle cell hepatopathy, acquired viral hepatitis, or secondary hemochromatosis. It is unclear how many patients with SCD ultimately undergo liver transplantation (LT) and what factors are associated with survival after LT. In this study, we examined LT outcomes in these patients by reviewing the Scientific Registry of Transplant Recipients (SRTR) and our institutional experience. Methods Analysis of the SRTR identified 23 LT recipients and five simultaneous liver and kidney transplantation (SLKT) recipients with SCD. Patient demographics and graft and patient survival were analyzed. Two patients with SCD at our institution underwent SLKT. Results Review of the SRTR revealed that recipients with SCD had significantly higher model for end-stage liver disease scores (33 versus 21, P = 0.004), preoperative intensive care unit admission (43.5% versus 19.1%, P = 0.007), preoperative dialysis (17.4% versus 4.9%, P = 0.009), and were more likely to be status 1 (26.1% versus 12.1%, P = 0.041) when compared with the reference population of African American LT recipients. Despite being higher risk at the time of LT, patients with SCD had equivalent posttransplant graft and patient survival when compared with the reference population (P = 0.5 and P = 0.2, respectively) and a 2:1 propensity score–matched group (P = 0.5 and P = 0.2, respectively). Two recent SLKT recipients with SCD from our institution have performed well with stable allograft function. Conclusions Data from the SRTR demonstrate that patients with SCD can expect equivalent graft and patient survival after LT despite exhibiting more comorbidities at the time of LT. The low number of patients with SCD who underwent LT in the SRTR in comparison with the rate of chronic liver disease in this population raises the question as to whether a disparity in access to LT exists for this complex population.

Standard prone position (PP) during percutaneous nephrolithotomy (PNL) has multiple drawbacks. We aimed to compare PNLs performed in split-leg (SL) modified lateral position (MLP) and those performed in standard PP. A prospective, randomized, unblind, double arm trial was conducted at a tertiary care academic medical center in Egypt, between November 2017 and October 2019. Adult patients with renal stones undergoing PNL were included. According to renal anatomy and stone complexity, stratified randomization was performed and study participants were allocated into either SL-MLP group or PP group. The stone free rate (SFR), total operative time, track formation time, fluoroscopy time, auxiliary procedures, and complications were compared. There were 61 patients in SL-MLP group and 63 patients in PP group. Both groups had similar baseline characteristics. The SFR was comparable between groups: 75.4% in SL-MLP group and 77.8% in PP group (p = 0.755). The mean total operative time was shorter and mean track formation time was longer in SL-MLP group (55.33 ± 20.73 vs. 98.49 ± 9.23, p

Background Many medications (including most antihypertensives) and physiological factors affect the aldosterone/renin ratio (ARR) when screening for primary aldosteronism (PA). We sought to validate a novel equilibrium angiotensin II (eqAngII) assay and compare correlations between the aldosterone/angiotensin II ratio (AA2R) and the current ARR under conditions affecting the renin-angiotensin system. Methods Among 78 patients recruited, PA was excluded in 22 and confirmed in 56 by fludrocortisone suppression testing (FST). Peripheral levels of eqAngII, plasma renin activity (PRA) and direct renin concentration (DRC) were measured. Results EqAngII showed good consistency with DRC and PRA independent of PA diagnosis, posture, and fludrocortisone administration. EqAngII showed close (P Conclusions Dynamic changes of eqAngII and the AA2R show good consistency and close correlations with renin and the ARR. The eqAngII assay shows better sensitivity than DRC and PRA assays, especially at low concentrations. Whether the AA2R can reduce the impact of some factors that influence the diagnostic power of the ARR warrants further study.

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) with potential clinical benefits for all stages of breast cancer. TAM is primarily metabolized to more potent metabolites via polymorphic CYP2D6. This affects the clinical outcome of TAM treatment. Herein we report novel TAM analogues that can avoid metabolism via CYP2D6. The novel analogues bear a flexible skeleton. Compounds have either an ester group on ring C or homodiaminoalkoxy groups on rings B and C. Compound 6 (E/Z-4-[1-[4-(2-diethylaminoethoxy)phenyl]-3-(4-methoxyphenyl)-2-methyl[propenyl]phenol) was found to be ten-fold more potent than TAM on MCF-7 cells (GI

The emergence of bacterial resistance has triggered a multitude of efforts to develop new antibacterial agents. There are many compounds in literature that were reported as potent antibacterial agents, however, they lacked the required safety to mammalian cells or no clear picture about their toxicity profile was presented. Inspired by discovered hit from our in-house library and by previously reported 2,4-diaminosubstituted quinazolines, we describe the design and synthesis of novel 2,4-disubstituted-thioquinazolines (3–13 and 36), 2-thio-4-amino substituted quinazolines (14–33) and 6-substituted 2,4-diamonsubstituted quinazolines (37–39). The synthesized compounds showed potent antibacterial activity against a panel of Gram-positive, efflux deficient E.coli and Mycobacterium smegmatis. The panel also involved resistant strains including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium, in addition to Mycobacterium smegmatis. The newly synthesized compounds revealed MIC values against the tested strains ranging from 1 to 64 µg/mL with a good safety profile. Most of the 2-thio-4-amino substituted-quinazolines showed significant antimycobacterial activity with the variations at position 2 and 4 offering additional antibacterial activity against the different strains. Compared to previously reported 2,4-diaminosubstituted quinazolines, the bioisosteric replacement of the 2-amino with sulfur offered a successful approach to keep the high antibacterial potency while substantially improving safety profile as indicated by the reduced activity on different cell lines and a lack of hemolytic activity.

A series of 2-arylthiazolidine-4-carboxylic acid amide derivatives were synthesized and their cytotoxic activity against three cancer cell lines (PC-3, SKOV3 and MDA-MB231) was evaluated. Various structural modifications were tried including modifications of the length of the amide chain and modifications of the 2-aryl part using disubstituted phenyl and thiophene derivatives. The structure activity relationship was evaluated based on the in vitro biological evaluation against the above mentioned three cancer cell lines. The most selective compounds towards cancer cells were further evaluated against DLD-1, NCI-H520, Du145, MCF-7 and NCI-N87 cancer cells. The dodecyl amide having the 4-bromothienyl as the 2-aryl, compound 2e, exhibited the highest selectivity for cancer cells vs non-tumor cells. Mechanistic studies of the anticancer effect of compound 2e in prostate cancer PC-3 and colorectal cancer DLD-1 cells revealed that 2e could prevent the cell cycle in the G0/G1 phase by up-regulating the expression of p21 and reducing the expression of CDK2 and cyclin E. It increased the pro-apoptotic protein Bax and cleaved caspase 3, and down-regulated the expression of anti-apoptotic protein Bcl-2 to induce apoptosis. In addition, 2e also downregulated AKT, N-cadherin, and vimentin proteins expression giving indication that 2e inhibit the PI3K/AKT pathway to regulate cell cycle arrest and induce apoptosis, and can regulate the expression of epithelial-mesenchymal transition-related proteins.

A ligand-based approach involving systematic modifications of a trisubstituted pyrazoline scaffold derived from the COX2 inhibitor, celecoxib, was used to develop novel PDE5 inhibitors. Novel pyrazolines were identified with potent PDE5 inhibitory activity lacking COX2 inhibitory activity. Compound d12 was the most potent with an IC50 of 1 nM, which was three times more potent than sildenafil and more selective with a selectivity index of >10,000-fold against all other PDE isozymes. Sildenafil inhibited the full-length and catalytic fragment of PDE5, while compound d12 only inhibited the full-length enzyme, suggesting a mechanism of enzyme inhibition distinct from sildenafil. The PDE5 inhibitory activity of compound d12 was confirmed in cells using a cGMP biosensor assay. Oral administration of compound d12 achieved plasma levels >1000-fold higher than IC50 values and showed no discernable toxicity after repeated dosing. These results reveal a novel strategy to inhibit PDE5 with unprecedented potency and isozyme selectivity.

PURPOSE OF REVIEW: To review the indications for extra-corporeal membrane oxygenation (ECMO) in liver transplantation (LT) recipients and their optimal management on ECMO. RECENT FINDINGS: Recent studies have reported a 30–40% survival rate among LT recipients that receive ECMO. Increasingly, case reports have documented successful outcomes of LT performed for patients on pre-operative ECMO. Outcomes appear to be superior with patients in the immediate peri-LT period with reversible causes of severe, acute respiratory and/or cardiovascular collapse. Mortality is most commonly secondary to infection. Volume optimization with CRRT may improve outcomes and perfusion to the graft, especially for patients on veno-arterial (VA) ECMO. There is little consensus on management of anti-coagulation in these patients, but it can likely be held temporarily while the patient is coagulopathic and/or experiencing bleeding complications. SUMMARY: ECMO should be considered in the peri-LT period for patients with severe, acute, and reversible causes of respiratory and/or cardiovascular collapse, with acceptable outcomes in patients that would otherwise not be expected to survive. Management of the post-LT patient on ECMO is challenging with a slowly enlarging body of literature to inform decision making.

Clks have been shown by recent studies to be promising targets for cancer therapy, as they are considered key regulators in the process of pre-mRNA splicing, which in turn affects every aspect of tumor biology. In particular, Clk1 and -4 are overexpressed in several human tumors. Most of the potent Clk1 inhibitors reported in the literature are non-selective, mainly showing off-target activity towards Clk2, Dyrk1A and Dyrk1B. Herein, we present new 5-methoxybenzothiophene-2-carboxamide derivatives with unprecedented selectivity. In particular, the introduction of a 3,5-difluoro benzyl extension to the methylated amide led to the discovery of compound 10b (cell-free IC50 = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound 1b. Moreover, 10b showed an improved growth inhibitory activity with T24 cells (GI50 = 0.43 µM). Furthermore, a new binding model in the ATP pocket of Clk1 was developed based on the structure-activity relationships derived from new rigidified analogues.

Bacterial resistance to currently used antibiotics demands the development of novel antibacterial agents with good safety margins and sufficient efficacy against multi-drug resistant isolates. We have previously described the synthesis of N-butyl-2-(butylthio)quinazolin-4-amine (I) as an optimized hit with broad-spectrum antibacterial activity and low cytotoxicity. In addition, we have identified a potential growing vector for this series of compounds. Herein, we describe further hit optimization which includes systematic diversifications of both the benzenoid part and the substituents at position 6 and 7 of compound I. Growing of the molecule beside the core modifications yielded several compounds with remarkable anti(myco)bacterial activity against a panel of pathogenic bacteria, including drug-resistant strains. Compound 12 showed a 2-4 fold improvement in activity than I against S. aureus Newman, S. pneumoniae DSM-20566 and E. faecalis DSM-20478. The compounds also showed a good safety profile towards human HepG2 cells.

Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66-5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66-3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.

The discovery of potent STAT3 inhibitors has gained noteworthy impetus in the last decade. In line with this trend, considering the proven biological importance of 1,2,4-triazoles, herein, we are reporting the design, synthesis, pharmacokinetic profiles, and in vitro anticancer activity of novel C3-linked 1,2,4-triazole-N-arylamide hybrids and their in silico proposed mechanism of action via inhibition of STAT3. The 1,2,4-triazole scaffold was selected as a privilege ring system that is embedded in core structures of a variety of anticancer drugs which are either in clinical use or still under clinical trials. The designed 1,2,4-triazole derivatives were synthesized by linking the triazole-thione moiety through amide hydrophilic linkers with diverse lipophilic fragments. In silico study to predict cytotoxicity of the new hybrids against different kinds of human cancer cell lines as well as the non-tumor cells was conducted. The multidrug-resistant human breast adenocarcinoma cells (MDA-MB-231) was found most susceptible to the cytotoxic effect of synthesized compounds and hence were selected to evaluate the in vitro anticancer activity. Four of the designed derivatives showed promising cytotoxicity effects against selected cancer cells, among which compound 12 showed the highest potency (IC

The objective of this study is to compare the endothelial safety of femtosecond laser (FSL) energy at two different dissection depths in FSL-assisted deep anterior lamellar keratoplasty (FSDALK) for keratoconus. This prospective double-armed interventional study included 25 eyes from 21 patients with advanced keratoconus who underwent FSDALK (big bubble technique) at a trephination depth of 110 µm in group I (11 eyes) and 80 µm in group II (14 eyes)—all of which were anterior to the Descemet’s membrane (DM). Visual acuity measurement, anterior and posterior segment examination, corneal tomography, and specular microscopy were performed preoperatively and at 3, 6, and 12 months, postoperatively. Endothelial cell density, coefficient of variation, percentage of cell hexagonality, and pachymetry were used to evaluate endothelial safety. No statistically significant difference in any of the endothelial safety parameters was found between the two groups. The mean 12-month postoperative endothelial cell loss rate was 17.46% and 12.91% in group I and II, respectively (P = 0.345). Most of the endothelial cell loss occurred during the first 3 months after surgery. Group II showed statistically greater improvement in the mean keratometry values at all follow-up visits. The endothelial safety profiles of lamellar FSL cuts at 110 µm and 80 µm anterior to the DM are comparable. Cuts as deep as 80 µm anterior to the DM can be safely applied without causing significant injury to the endothelium. Further studies are needed to compare the endothelial safety profiles of different FSL platforms available in the market. Trial registration PACTR201901615323963. Registered 24 November 2018—retrospectively registered.

Detecting cognitive profiles is critical to efficient adaptive learning systems that automatically adjust the content delivered depending on the learner&rsquo, s cognitive states and skills. This study explores electroencephalography (EEG) and facial expressions as physiological monitoring tools to build models that detect two cognitive states, namely, engagement and instantaneous attention, and three cognitive skills, namely, focused attention, planning, and shifting. First, while wearing a 14-channel EEG Headset and being videotaped, data has been collected from 127 subjects taking two scientifically validated cognitive assessments. Second, labeling was performed based on the scores obtained from the used tools. Third, different shallow and deep models were experimented in the two modalities of EEG and facial expressions. Finally, the best performing models for the analyzed states are determined. According to the used performance measure, which is the f-beta score with beta = 2, the best obtained results for engagement, instantaneous attention, and focused attention are EEG-based models with 0.86, 0.82, and 0.63 scores, respectively. As for planning and shifting, the best performing models are facial expressions-based models with 0.78 and 0.81, respectively. The obtained results show that EEG and facial expressions contain important and different cues and features about the analyzed cognitive states, and hence, can be used to automatically and non-intrusively detect them.

A series of novel hybrid pyrazolo[3,4-d]pyramidine derivatives was designed and chemically synthesized in useful yields. The synthesized compounds were structurally characterized by the usual techniques. All the new synthesized compounds were biologically screened in vitro for their antiproliferative activities against a panel of four cancer cell lines, namely HepG-2, MCF-7, HCT-116, and Hela. The results of cytotoxic evaluation indicated that compound 14d was appeared to be the most prominent broad-spectrum cytotoxic activity and significantly more potent than sorafenib with IC50 values of 4.28, 5.18, 3.97, and 9.85 µM against four cell lines (HePG2, Hela, HCT-116 and MCF-7). In addition, compound 15 was displayed promising antiproliferative effect against all tested cell lines with IC50 value less than 11 µM compared with sorafenib as a control drug. Besides, structurally pharmacophoric features indicated that pyrazolo[3,4-d]pyrimidine scaffold having an amide linker and substituted with phenyl moiety at the 5-position was more potent than those possessing azomethine methyl, azomethine proton and carbomethene linkers, which lead to significant decrease in antiproliferative activity. The most potent compounds were further selected and evaluated for their activities against epidermal growth factor receptor (EGFR) kinase inhibitors according to homogenous time resolved fluorescence (HTRF) assay. The most potent compound 14d exhibited the most promising inhibitory activity against EGFRWT with IC50 value of 56.02 ± 1.38 µM compared with gefitinib as control drug with IC50 value of 41.79 ± 1.07 µM. Moreover, the inhibition of cell cycle progression and induction of apoptosis in the A549 cell line at G2/M and pre-G1 phases of cell cycle might contribute to cancer treatment that evaluated by Annexin V-FITC/PI double staining detection method. Finally, molecular docking studies were conducted to investigate that probable binding conformations of these anticancer agents and ADME properties were calculated to predict pharmacokinetics and toxic properties of the target compounds.

Three novel series of triazolophthalazine derivatives bearing hydrazone moiety were designed, synthesized, and evaluated for their anticancer activity against four human cancer cell lines by MTT assay. Six derivatives demonstrated comparable activity with Doxorubicin reference drug against the selected cancer cells. Especially, compound 16 showed the most potent activity with IC50 values of 5.70, 8.04, 11.15, and 4.25, µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Also, compound 26 exhibited comparable inhibitory effect with that of Doxorubicin against the selected cancer cell lines with IC50 values of 6.45, 8.63, 12.28, and 7.03 µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Investigation of the apoptotic activity of the two most active compounds revealed that compounds 16 and 26 could induce both the early and the late apoptosis of HePG2. Further mechanistic study of the HePG2 cell cycle confirmed the spectacular cytotoxic and apoptotic effects of both compounds. Compounds 16 and 26 showed a pronounced increase in cells in G2/M and Pre G1 phases with a concomitant reduction of cells in G0-G1 and S phases. A follow up enzymatic assay indicated that these two compounds have comparable activities with that of bromosporine as PCAF inhibitors with IC50 values of 8.13 and 5.31 µM respectively. Moreover, molecular docking study for all the synthesized compounds was performed to predict their binding affinities toward the active site of histone acetyltransferase GCN5. Results of molecular docking were strongly correlated with that of the cytotoxicity study.

A role of Dyrk1A in the progression of Down syndrome–related Alzheimer's disease (AD) is well supported. However, the involvement of Dyrk1A in the pathogenesis of Parkinson's disease (PD) was much less studied, and it is not clear whether it would be promising to test Dyrk1A inhibitors in relevant PD models. Herein, we modified our previously published 1-(6-hydroxybenzo[d]thiazol-2-yl)-3-phenylurea scaffold of Dyrk1A inhibitors to obtain a new series of analogues with higher selectivity for Dyrk1A on the one hand, but also with a novel, additional activity as inhibitors of α-synuclein (α-syn) aggregation, a major pathogenic hallmark of PD. The phenyl acetamide derivative b27 displayed the highest potency against Dyrk1A with an IC50 of 20 nM and high selectivity over closely related kinases. Furthermore, b27 was shown to successfully target intracellular Dyrk1A and to inhibit SF3B1 phosphorylation in HeLa cells with an IC50 of 690 nM. In addition, two compounds among the Dyrk1A inhibitors, b1 and b20, also suppressed the aggregation of α-synuclein (α-syn) oligomers (with IC50 values of 10.5 μM and 7.8 μM, respectively). Both compounds but not the Dyrk1A reference inhibitor harmine protected SH-SY5Y neuroblastoma cells against α-syn–induced cytotoxicity, with b20 exhibiting a higher neuroprotective effect. Compound b1 and harmine were more efficient in protecting SH-SY5Y cells against 6-hydroxydopamine–induced cell death, an effect that was previously correlated to Dyrk1A inactivation in cells but not yet verified using chemical inhibitors. The presented dual inhibitors exhibited a novel activity profile encouraging for further testing in neurodegenerative disease models.

The protein kinase Dyrk1A modulates several processes relevant to the development or progression of Alzheimer's disease (AD), e. g. through phosphorylation of tau protein, amyloid precursor protein (APP) as well as proteins involved in the regulation of alternative splicing of tau pre-mRNA. Therefore, Dyrk1A has been proposed as a potential target for the treatment of AD. However, the co-inhibition of other closely related kinases of the same family of protein kinases (e.g. Dyrk1B and Dyrk2) or kinases from other families such as Clk1 limits the use of Dyrk1A inhibitors, as this may cause unpredictable side effects especially over long treatment periods. Herein, we describe the design and synthesis of a series of amide functionalized 2,4-bispyridyl thiophene compounds, of which the 4-fluorobenzyl amide derivative (31b) displayed the highest potency against Dyrk1A and remarkable selectivity over closely related kinases (IC50: Dyrk1A = 14.3 nM; Dyrk1B = 383 nM, Clk1 > 2 μM). This degree of selectivity over the frequently hit off-targets has rarely been achieved to date. Additionally, 31b inhibited Dyrk1A in intact cells with high efficacy (IC50 = 79 nM). Furthermore, 31b displayed a high metabolic stability in vitro with a half-life of 2 h. Altogether, the benzamide and benzylamide extension at the 2,4-bispyridyl thiophene core improved several key properties, giving access to compound suitable for future in vivo studies.

Context Current threshold values for primary aldosteronism (PA) diagnostic testing are based on measuring aldosterone (PAC) using immunoassays. Quantification of PAC by liquid chromatography-tandem mass spectrometry (LC-MS/MS) yields lower values. Objective To compare aldosterone measurement by radioimmunoassay (RIA) with LC-MS/MS and evaluate performances of proposed LC-MS/MS–specific cutoffs for PA screening and confirmatory testing. Patients and Intervention Forty-one patients underwent aldosterone/renin ratio (ARR) testing to screen for, and fludrocortisone suppression testing (FST) to confirm or exclude, PA. Renin (DRC) was measured by chemiluminescent immunoassay. Results Median serum PACLC-MS/MS was 27.8% lower (P < 0.05) than plasma PACRIA in 164 pairs of FST samples. A positive correlation (Spearman coefficient, 0.894, P < 0.01; Pearson r coefficient, 0.861, P < 0.01) was observed between the two assays. Thirty-seven patients showed consistent FST diagnoses (29 positive, 8 negative), whereas four showed inconsistent FSTs by the two assays. Good agreement (κ coefficient, 0.736; P < 0.01) was observed between the current FST diagnostic PACRIA cutoff of 165 pmol/L and the proposed PACLC-MS/MS cutoff of 133 pmol/L. Among 37 patients with consistent FST results, no differences were observed in sensitivity (89.7% vs 93.1%) or specificity (87.5% vs 87.5%) for PA screening between the current ARR cutoff of 70 pmol/mU (PACRIA/DRC) and the proposed cutoff of 55 pmol/mU (PACLC-MS/MS/DRC). Conclusions Adjustment of the current cutoffs for PA diagnostic testing is necessary if PAC is measured by LC-MS/MS. Our preliminary results suggest that the proposed LC-MS/MS cutoffs for ARR and FST perform as well as current RIA cutoffs.

Supplemental Digital Content is Available in the Text., Purpose: To evaluate the effectiveness and safety of combined epithelium-off cross-linking (CXL) with photorefractive keratectomy (CXL Plus) for correction of the myopic and astigmatic components of keratoconus. Methods: Seventy-nine eyes of 46 patients who underwent CXL Plus were enrolled in this retrospective, multicenter, noncomparative clinical study. Uncorrected distance visual acuity, corrected distance visual acuity, refraction, keratometry, and pachymetry measurements were recorded preoperatively and at 3, 6, 12, and 18 months during follow-up. Results: The mean (±SD) preoperative uncorrected distance visual acuity and corrected distance visual acuity were 1.00 ± 0.22 logarithm of the minimum angle of resolution (logMAR) and 0.62 ± 0.38 logMAR, respectively, and improved to 0.71 ± 0.36 logMAR and 0.32 ± 0.18 logMAR postoperatively. The mean k value, mean corneal thickness at the thinnest location, and mean myopic and astigmatic components decreased from 46.58 ± 0.97 D, 473 ± 29 μm, 3.65 ± 1.72 D, and 1.83 ± 0.69 D preoperatively to 43.79 ± 1.17 D, 431 ± 38 μm, 1.02 ± 0.78 D, and 1.15 ± 0.26 D, respectively, during follow-up. Eleven eyes had delayed epithelial healing, 2 had stromal opacities, 1 had primary herpes simplex keratitis, and 5 showed progression of keratoconus. Conclusions: CXL Plus improved the refractive status of keratoconus during 18 months of follow-up, despite its potential early postoperative complications of delayed epithelial healing and corneal haze. CXL Plus reduced the myopic component more than the astigmatic component of keratoconus. However, the safety and stability of the procedure were offset by longer-term postoperative complications and a high rate of postoperative progression of keratoconus.

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ERα) agonists or antagonists depending on the target issue. Tamoxifen (TAM) (a non-steroidal triphenylethylene derivative) was the first SERM approved as anti-estrogen for the treatment of metastatic breast cancer. On the hunt for novel SERMs with potential growth inhibitory activity on breast cancer cell lines yet no potential to induce endometrial carcinoma, we designed and synthesized 28 novel TAM analogs. The novel analogs bear a triphenylethylene scaffold. Modifications on rings A, B, and C aim to attenuate estrogenic/anti-estrogenic activities of the novel compounds so they can potentially inhibit breast cancer and provide positive, beneficial estrogenic effects on other tissues with no risk of developing endometrial hyperplasia. Compound 12 (E/Z-1-(2-{4-[1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-propenyl]-phenoxy}-ethyl)-piperidine) showed an appreciable relative ERα agonistic activity in a yeast estrogen screen (YES) assay. It successfully inhibited the growth of the MCF-7 cell line with GI50 = 0.6 µM, and it was approximately three times more potent than TAM. It showed no potential estrogenicity on Ishikawa endometrial adenocarcinoma cell line via assaying alkaline phosphatase (AlkP) activity. Compound 12 was tested in vivo to assess its estrogenic properties in an uterotrophic assay in an ovariectomized rat model. Compared to TAM, it induced less increase in wet uterine wet weight and showed no uterotrophic effect. Compound 12 is a promising candidate for further development due to its inhibition activity on MCF-7 proliferation with moderate AlkP activity and no potential uterotrophic effects. The in vitro estrogenic activity encourages further investigations toward potential beneficial properties in cardiovascular, bone, and brain tissues.

A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).

Background: Plasma aldosterone/renin ratio (ARR) is the most popular screening test for primary aldosteronism (PA). Because both estrogen and progesterone (including in oral contraceptive agents) affect aldosterone and renin levels, we studied the effects of combined hormonal replacement therapy (HRT) on ARR; renin was measured as both direct renin concentration (DRC) and plasma renin activity (PRA). Methods: Fifteen normotensive, healthy postmenopausal women underwent measurement (seated, midmorning) of plasma aldosterone, DRC, PRA, electrolytes, and creatinine and urinary aldosterone, cortisol, electrolytes, and creatinine at baseline and after 2 weeks and 6 weeks of treatment with combined HRT (conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg daily). Results: Combined HRT was associated with statistically significant increases in aldosterone [median (range): baseline, 150 (85 to 600); 2 weeks, 230 (129 to 790); 6 weeks, 434 (200 to 1200) pmol/L; P < 0.001 (Friedman test)] and PRA [2.3 (1.2 to 4.3), 3.8 (1.4 to 7.0), 5.1 (1.4 to 10.8) ng/mL/h, respectively; P < 0.001] but decreases in DRC [21 (10 to 31), 21 (10 to 39), and 14 (8.0 to 30) mU/L, respectively; P < 0.01], leading to increases in ARR calculated by DRC [7.8 (3.6 to 34.8), 11.4 (5.4 to 48.5), and 30.4 (10.5 to 90.2), respectively; P < 0.001]. The ARR calculated by DRC exceeded the cutoff value (70) in three patients after 6 weeks. There were no significant changes in ARR calculated by PRA [79 (26 to 184), 91 (23 to 166), and 88 (50 to 230), respectively; P = 0.282], plasma electrolytes and creatinine, or any urinary measurements. Conclusion: The combined oral HRT used in this study is capable of significantly increasing ARR with a risk of false-positive results during screening for PA but only if DRC (and not PRA) is used to calculate the ratio.

Background: The most popular screening test for primary aldosteronism is the plasma aldosterone/ renin ratio (ARR). Medications, dietary sodium, posture, and time of day all affect renin and aldosterone levels and can result in false-negative or false-positive ARRs if not controlled. Most antihypertensive medications affect the ARR and can interfere with interpretation of results. To our knowledge, no study has been undertaken to evaluate the effects of moxonidine on the ARR. Methods: Normotensive, nonmedicated male volunteers (n = 20) underwent measurement (seated, midmorning) of plasma aldosterone (by high-performance liquid chromatography-tandem mass spectrometry), direct renin concentration (DRC), plasma renin activity (PRA), cortisol, electrolytes and creatinine; and urinary aldosterone, cortisol, electrolytes and creatinine at baseline and after 1 week of moxonidine at 0.2 mg/d and a further 5 weeks at 0.4 mg/d. Results: Compared with baseline, despite the expected significant falls in both systolic and diastolic blood pressure, levels of plasma aldosterone [median, 134 (range, 90 to 535) pmol/L], DRC [20 (10 to 37) mU/L], PRA [2.2 (1.0-3.8) ng/mL/h], and ARR using either DRC [8.0 (4.4 to 14.4)] or PRA [73 (36 to 218)] were not significantly changed after either 1 [135 (98-550) pmol/L, 20 (11-35) mU/L, 2.0 (1.2-4.1) ng/mL/h, 8.8 (4.2 to 15.9), and 73 (32-194), respectively] or 6 weeks [130 (90-500) pmol/L, 22 (8 to 40) mU/L, 2.1 (1.0 to 3.2) ng/mL/h, 7.7 (4.3 to 22.4), and 84 (32 to 192), respectively] of moxonidine. There were no changes in any urinary measurements. Conclusion: Moxonidine was associated with no significant change in the ARR and may therefore be a good option for maintaining control of hypertension when screening for primary aldosteronism.

The dopamine oxidation product cysteinyl-dopamine has attracted attention as a contributor to the death of dopaminergic neurons in Parkinson's disease. Treatment of cysteinyl-dopamine with hypochlorite yields an even more cytotoxic product. This product has potent redox-cycling activity and initiates production of superoxide in PC12 cells. Taurine, which scavenges hypochlorite, protects PC12 cells from cysteinyl-dopamine but not from the hypochlorite product, suggesting that the product, not cysteinyl-dopamine itself, is toxic. Furthermore, rotenone, which enhances expression of the hypochlorite-producing enzyme myeloperoxidase, increases the cytotoxicity of cysteinyl-dopamine but not of the hypochlorite product. This suggests that dopamine oxidation to cysteinyl-dopamine followed by hypochlorite-dependent conversion to a cytotoxic redox-cycling product leads to the generation of reactive oxygen species and oxidative stress and may contribute to the death of dopaminergic neurons.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a potential target in Alzheimer's disease (AD) because of the established correlation between its over-expression and generation of neurofibrillary tangles (NFT) as well as the accumulation of amyloid plaques. However, the use of Dyrk1A inhibitors requires a high degree of selectivity over closely related kinases. In addition, the physicochemical properties of the Dyrk1A inhibitors need to be controlled to enable CNS permeability. In the present study, we optimized our previously published 2,4-bispyridyl thiophene class of Dyrk1A inhibitors by the synthesis of a small library of amide derivatives, carrying alkyl, cycloalkyl, as well as acidic and basic residues. Among this library, the cyclopropylamido modification (compound 4b) was identified as being highly beneficial for several crucial properties. 4b displayed high potency and selectivity against Dyrk1A over closely related kinases in cell-free assays (IC50: Dyrk1A = 3.2 nM; Dyrk1B = 72.9 nM and Clk1 = 270 nM) and inhibited the Dyrk1A activity in HeLa cells with high efficacy (IC50: 43 nM), while no significant cytotoxicity was observed. In addition, the cyclopropylamido group conferred high metabolic stability and maintained the calculated physicochemical properties in a range compatible with a potential CNS activity. Thus, based on its favourable properties, 4b can be considered as a candidate for further in vivo testing in animal models of AD.

Many shreds of evidence have recently correlated A2B receptor antagonism with anticancer activity. Hence, the search for an efficient A2B antagonist may help in the development of a new chemotherapeutic agent. In this article, 23 new derivatives of [1,2,4]triazolo[4,3-a]quinoxaline were designed and synthesized and its structures were confirmed by different spectral data and elemental analyses. The results of cytotoxic evaluation of these compounds showed six promising active derivatives with IC

Stress urinary incontinence (SUI) and cystocele often occur concomitantly and thus may potentially be treated via a single surgical procedure. This study evaluated the efficacy and safety of concomitant transobturator tape (TOT) with anterior colporrhaphy versus subvesical transobturator mesh (TOM) for cystocele-associated SUI.This prospective, clinical trial included women with cystocele-associated SUI. Patients were randomly allocated into either group I (anterior colporrhaphy with concomitant TOT "in-out" fixation) or group II (implantation of a subvesical four-armed TOM). All patients were followed up at 1, 3, 6, 9, and 12 months postoperatively. Statistical tests were performed to compare the group outcomes based on objective, subjective, and anatomical variables.There were 81 patients in group I and 83 in group II. Median follow-up duration was 12 months. The demographic data and baseline clinical characteristics of both groups were comparable. There were no significant differences between groups regarding the success rates of SUI and cystocele repair. Groups I and II had similar cure rates of SUI (82.9 and 88.4%, respectively; p = 0.369) and incidences of successful cystocele repair (85.4 and 97.7%, respectively; p = 0.055). No urethral or bladder injuries or mesh erosions were reported. Both groups had comparable postoperative complications, except the greater incidence of micturition difficulty in group I than group II, during the early follow-up (12.2% vs. 0.0%; p = 0.024).Transvaginal mesh was not superior to native tissue repair. Anterior colporrhaphy and TOT may be an appropriate alternative to four-armed TOM application for concomitant correction of SUI and cystocele.

The strong therapeutic potential of CB2 receptor agonists for use as anti-inflammatory agents that lack psychiatric side effects has attracted substantial interest. We herein describe the rational design and synthesis of novel thiazole and benzothiazole derivatives and the evaluation of their binding affinity and functional activity on CB1 and CB2 receptors. The series with the general formula N-(3-pentylbenzo [d] thiazol-2(3H)-ylidene) carboxamide (compounds 6a-6d) exhibited the highest affinity and selectivity towards CB2 receptors with K(i)s in the picomolar or low nanomolar range, and selectivity indices (K-i hCB1/K-i hCB2) reaching up to 429 fold. Notably, these compounds also demonstrated an agonistic functional activity in cellular assays with EC(50)s in the low nanomolar range. More interestingly, compound 6d, the 3-(trifluoromethyl)benzamide derivative, exhibited remarkable protection against DSS-induced acute colitis in mice model. (C) 2019 Elsevier Masson SAS. All rights reserved.

Negative pressure therapy plays an important role in the healing process of different types of wounds.this study aimed to compare between modified and traditional method of vacuum wound closure for chronic wounds.Thirty participants with chronic ulcers completed the study, their ages ranged from 47 to 65 years, from Benha city, divided randomly into two groups, it was carried out from December 2017 to March 2019.The first group treated by the traditional method of vacuum assisted wound closure for 8 weeks; dressing was changed 3 times weekly, at 125 mmHg. The mode of 2 min off and 5 min on was used. The second group treated by the modified method by switching off the device at the fifth week and applying traditional dressing for one week then ended by three weeks of vacuum wound closure. Assessment was performed before and after the study. Student t-test was used for analysis.Paired t-test showed a significant improvement in wound surface area as well as volume for pre and post treatment in each group (p 0.05). On the other hand independent t-test revealed a non-significant difference between the two groups pre as well as post treatment (p 0.05).There is no significant difference between the two programs on healing of chronic ulcers.NCT03701152 - at Clinicaltrials.gov.

Detecting the cognitive profiles of learners is an important step towards personalized and adaptive learning. Electroencephalograms (EEG) have been used to detect the subject&rsquo, s emotional and cognitive states. In this paper, an approach for detecting two cognitive skills, focused attention and working memory, using EEG signals is proposed. The proposed approach consists of the following main steps: first, subjects undergo a scientifically-validated cognitive assessment test that stimulates and measures their full cognitive profile while putting on a 14-channel wearable EEG headset. Second, the scores of focused attention and working memory are extracted and encoded for a classification problem. Third, the collected EEG data are analyzed and a total of 280 time- and frequency-domain features are extracted. Fourth, several classifiers were trained to correctly classify and predict three levels (low, average, and high) of the two cognitive skills. The classification accuracies that were obtained on 86 subjects were 84% and 81% for the focused attention and working memory, respectively. In comparison with similar approaches, the obtained results indicate the generalizability and suitability of the proposed approach for the detection of these two skills. Thus, the presented approach can be used as a step towards adaptive learning where real-time adaptation is to be done according to the predicted levels of the measured cognitive skills.

Distal half leg complex wounds are usually a formidable problem that necessitates either local or free flap coverage. The aim of this study was to compare cost billing charges in free Gracilis flap (fGF) and local fasciocutaneous perforator flap (lFPF) in reconstructing complex soft tissue leg and foot defects.Thirty consecutive adult (15-year-old) patients with soft tissue defects in the leg and/or foot requiring tissue coverage with a flap in the period between 2012 and 2015 were randomly assigned (block randomization) to either an fGF or lFPF procedure. The outcome measures addressed were total billed charges costs, perioperative billed charges cost, partial or complete flap loss, length of hospital stay, inpatient postsurgical care duration, complications, operating time and number of operative scrub staff.One patient suffered from complete flap loss in each group. Reconstruction with lFPF showed total lower billed charges costs by 62% (2509 USD) (p 0.001) and perioperative billed charges cost by 54% (779 USD) (p 0.001), and shorter total hospital stay (36.5 days; p 0.001), inpatient postsurgical care duration (6.4 days; p 0.001), operating time (4.3 h; p 0.001) and fewer scrub staff (2.2 persons; p 0.001).These results suggest that neither flap is totally superior to the other; the choice should instead be based on the outcome sought and logistics. lFPF requires lower billed charges cost and resource use and saves operative time and personnel and reduces length of hospital stay. Our approach changed towards using perforator flaps in medium-sized defects, keeping the free flap option for larger defects.

Aim This study evaluated the survival outcome, pattern of failure and prognostic factors in cervix uteri cancer patients. Methods We reviewed the data of 60 patients with stages IB-IVA cancer who were treated between January 2004 and December 2010. Results Most patients (n = 50; 83%) had squamous cell carcinoma. Stage IIB was the most common presentation (n = 41; 68%). Forty-seven patients (78%) received Cisplatin concurrent with radiotherapy (CRT). The 2- and 4-year overall survival (OS) was 82% and 79%, respectively. Prolongation of the overall treatment time (OAT) for greater than 56 days, advanced stage and pretreatment hemoglobin (Hb) levels (

Background: Tamoxifen (TAM) is metabolized to the more active 4-hydroxytamoxifen by CYP2D6 enzyme. Due to the genetic polymorphisms in CYP2D6, clinical outcomes of TAM treatment vary. Novel flexible TAM analogs with altered activation pathway were synthesized and were tested for their antiproliferative action on MCF-7 cell lines and their binding affinity for ERα and ERβ. Results: All compounds showed better antiproliferative activity than TAM. Compound 3 showed 80-times more ERα binding than TAM, 900-times more selectivity toward ERα. Compound 3 was tested on the entire National Cancer Institute cancerous cell lines; results indicated a broad spectrum anticancer activity. Conclusion: The novel analogs were more potent than TAM with higher selectivity toward ERα and with potential metabolic stability toward CYP2D6.

Scalds are the most common type of burn in children, and one way to treat them is with xenografts with no topical antimicrobials in line with the recommendations of a recent review. However, this treatment has not been examined in detail. Our aim was to describe the treatment of such children when biological dressings (xenografts) were used without local antimicrobials. We reviewed the medical records of all children admitted to a Swedish National Burn Centre during the period 2010-2012 with scalds who were treated with xenografts. Percentage TBSA injured, age, length of hospital stay, number of operations, antibiotics given, duration of antibiotic treatment, and pain score during the first 3 days, application of xenografts, and clinical notes of wound infection were recorded. We studied 67 children, (43 of whom were boys), with a median (interquartile range [IQR]) age of 1 (1-2) year and median (IQR) TBSA% 6.2 (4-11). Twenty children (30%) required operation. Twelve (18%) developed a wound infection, 29 (43%) had other infections, and 26 (39%) were free from infection. The median (IQR) duration of systemic antibiotics was 10 (6-13) days. On the day that the xenografts were applied 10 of the children had a Face, Legs, Activity, Cry, and Consolability (FLACC) score between 3 and 7, and during the following 2 days, only four children scored in this range. The remaining 57 children had scores amp;lt;3 on the day that xenografts were applied and on the following 2 days. Median (IQR) length of stay/TBSA% was 0.7 (0.4-1.0). Treatment with xenografts was associated with median length of stay/TBSA% amp;lt; 1 and low pain scores. Despite a high rate of prescription of systemic antibiotics, most were for reasons other than wound infection. Funding Agencies|Department of Hand Surgery, Plastic Surgery and Burns, Linkoping University Hospital, Sweden

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including 1 H nuclear magnetic resonance (NMR) and 13 C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure-activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC50 value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC50 value of 5.95 µM. The observed IC50 values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.

Novel symmetric molecules, bearing a benzidine prolinamide core, two terminal carbamate caps of variable sizes and nature, including natural and unnatural amino acids were developed. Several terminal N-carbamate substituents of the core structure, ranging from linear methyl, ethyl and butyl groups to branching isobutyl group; and an aromatic substituent were also synthesized. Series 1 has hydrophobic AA residues, namely S and R phenylglycine and a terminal carbamate capping group, whereas Series 2 bears sulphur containing amino acids, specifically S and R methionine and the natural R methylcysteine. The novel compounds were tested for their inhibitory activity (EC50) and their cytotoxicity (CC50), using an HCV 1b (Con1) reporter replicon cell line. Compound 4 with the unnatural capping residue, bearing d -Phenylglycine amino acid residue and N-isobutyloxycarbonyl capping group, was the most active within the two series, with EC50 = 0.0067 nM. Moreover, it showed high SI50 > 14788524 and was not cytotoxic at the highest tested concentration (100 μΜ), indicating its safety profile. Compound 4 also inhibited HCV genotypes 2a, 3a and 4a. Compared to the clinically approved NS5A inhibitor Daclatasvir, compound 4 shows higher activity against genotypes 1b and 3a, as well as improved safety profile.

The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10–32 was evaluated in human hepatocellular carcinoma (HePG-2), breast cancer (MCF-7), prostate cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC50, 2.83–13.97 μM), similar to doxorubicin (IC50, 4.17–8.87 μM) and afatinib (IC50, 5.4–11.4 μM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC50, 3.06–10.5 μM), similar to doxorubicin (IC50, 4.50 μM) and afatinib (IC50, 5.4 μM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC50, 2.83–10.36 and 5.69–11.36 μM, respectively), similar to doxorubicin and afatinib (IC50 = 5.23 and 4.17, and 11.4 and 7.1 μM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC50, 7.56–12.28 μM) compared with doxorubicin (IC50, 8.87 µM) and afatinib (IC50 7.7 μM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC50, 5.31 and 10.30 μM, respectively) and compounds 18 and 25 exhibited modest IC50 values (17.09 and 32.96 μM, respectively) compared with bromosporine (IC50, 5.00 μM). Compound 17 was cytotoxic to HePG2 cells (IC50, 3.06 μM), inducing apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.

There is a continuous need to develop new antibacterial agents with non-traditional mechanisms to combat the nonstop emerging resistance to most of the antibiotics used in clinical settings. We identified novel pyrazolidinone derivatives as antibacterial hits in an in-house library screening and synthesized several derivatives in order to improve the potency and increase the polarity of the discovered hit compounds. The oxime derivative 24 exhibited promising antibacterial activity against E. coli TolC, B. subtilis and S. aureus with MIC values of 4, 10 and 20 µg/mL, respectively. The new lead compound 24 was found to exhibit a weak dual inhibitory activity against both the E. coli MurA and MurB enzymes with IC50 values of 88.1 and 79.5 µM, respectively, which could partially explain its antibacterial effect. A comparison with the previously reported, structurally related pyrazolidinediones suggested that the oxime functionality at position 4 enhanced the activity against MurA and recovered the activity against the MurB enzyme. Compound 24 can serve as a lead for further development of novel and safe antibiotics with potential broad spectrum activity.

Herein we present the synthesis and characterization of a novel chemical series of tadalafil analogues that display different pharmacological profiles. Compounds that have the 6R, 12aR configuration and terminal carboxylic acid group at the side chain arising from the piperazinedione nitrogen were potent PDE5 inhibitors, with compound 11 having almost equal potency to tadalafil and superior selectivity over PDE11, the most common off–target for tadalafil. Modifying the stereochemistry into 6S, 12aS configuration and adopting the hydroxamic acid moiety as a terminal group gave rise to compounds that only inhibited HDAC. Dual PDE5/HDAC inhibition could be achieved with compounds having 6R, 12aR configuration and hydroxamic acid moiety as a terminal group. The anticancer activity of the synthesized compounds was evaluated against a diverse number of cell lines of different origin. The compounds elicited anticancer activity against cell lines belonging to lymphoproliferative cancer as well as solid tumors. Despite the previous reports suggesting anticancer activity of PDE5 inhibitors, the growth inhibitory activity of the compounds seemed to be solely dependent on HDAC inhibition. Compound 26 (pan HDAC IC50 = 14 nM, PDE5 IC50 = 46 nM) displayed the most potent anticancer activity in the present series and was shown to induce apoptosis in Molt-4 cells. HDAC isoform selectivity testing for compound 26 showed that it is more selective for HDAC6 and 8 over HDAC1 by more than 20-fold.

A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.

Failure of plasma aldosterone suppression during fludrocortisone suppression testing (FST) or saline suppression testing (SST) confirms primary aldosteronism (PA). Aldosterone is often higher upright than recumbent in PA; upright levels are used during FST. In a pilot study (24 patients with PA), seated saline suppression testing (SSST) was more sensitive than recumbent saline suppression testing (RSST).The current validation study involved 100 patients who underwent FST, RSST, and SSST, eight before and after unilateral adrenalectomy. Of the 108 FSTs, 73 confirmed and 18 excluded PA. Four patients with inconclusive FST lateralized on adrenal venous sampling, making a total of 77 with PA.The area under the receiver operating characteristic (ROC) curve was greater for SSST than RSST (0.96 vs. 0.80; P0.01). ROC analysis predicted optimal cutoff aldosterone levels of 162 pmol/L for SSST and 106 pmol/L for RSST. At these cutoffs, SSST showed high sensitivity for PA (87%) that markedly exceeded that for RSST (38%; P0.001) but similar specificity (94 vs. 94%; not significant). SSST was more sensitive than RSST in detecting both unilateral (n = 28, 93% vs. 68%, P0.05) and bilateral (n = 40, 85% vs. 20%, P0.001) forms of PA. Only three SSST (vs. 9 RSST and 17 FST) results were inconclusive.SSST is highly sensitive and superior to RSST in identifying both unilateral and bilateral forms of PA and has a low rate of false positives and inconclusive results. It therefore offers a reliable and much less complicated and expensive alternative to FST for confirming PA.

Purpose The purpose of this study was to conduct a matched-pair analysis to determine the effect of prior lumbar spine surgery (LSS) on clinical outcomes of hip arthroscopy. Methods Data were prospectively collected on all patients undergoing hip arthroscopy during the study period from April 2008 to December 2012. Patients were excluded if they had previous hip conditions or had undergone prior hip surgery. Patients in the LSS group (history of LSS) were matched in a 1:1 ratio to a control group (no history of LSS) according to age ±5 years, gender, body mass index categories, Tonnis grade, and labral treatment. The following outcomes were recorded in each group: modified Harris Hip Score, Non-Arthritic Hip Score (NAHS), Hip Outcome Score–Sports Specific Subscale, Hip Outcome Score–Activities of Daily Living, and visual analogue scale (VAS) score for pain, patient satisfaction, and rates for revision hip arthroscopies and conversion to total hip arthroplasty (THA). Results During the study period, 1,405 hip arthroscopies were performed with 1,017 eligible for matching. A total of 873 (85.8%) patients had a minimum 2-year follow-up. Fifty-seven patients were matched in each group. Both groups demonstrated significant improvement in patient-reported outcome (PRO) and VAS scores. The LSS group had a lower mean for all preoperative PRO scores. There was no significant difference for the postoperative mean PRO score and change in the PRO score compared with the control group except for NAHS. The mean change in the NAHS demonstrated a greater magnitude of improvement in the LSS group. There was no significant difference between mean VAS scores, patient satisfaction, and rates for revision arthroscopy and conversion to THA between the groups. Conclusions Prior LSS does not adversely affect outcomes of hip arthroscopy at a minimum 2-year follow-up. These patients have lower preoperative scores but similar magnitude of improvement and revision/THA rates compared with a matched comparative group of patients without prior LSS. Level of Evidence Level II, retrospective analysis of prospectively collected data.

In our attempt to develop effective EGFR-TKIs, two series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR

Aim: Acute kidney injury (AKI) is a major health problem with poor patient prognosis. We evaluated the clinical characteristics, risk factors, associated comorbidities, and outcomes of AKI patients. Methodology: A single-center prospective observational study. The patients were admitted in Mansoura Nephrology and Dialysis Unit over a period of 1 year from January to December, 2016. Patients were diagnosed as AKI or AKI in addition to chronic kidney disease according to the creatinine criteria of KDIGO 2013. All patients were subjected to complete history taking, physical examination, and full laboratory and pelvi-abdominal ultrasound investigations. The study outcomes were all-cause hospital mortality, and recovery of renal function. Predictors of mortality were assessed using multivariate logistic regression analysis. The study was reviewed and approved by local Ethical Committee of IBR. Results: We evaluated 199 (96 males plus 103 females) aged between 18 and 88 years old. Dehydration was the commonest precipitating factor for AKI in our patients (68.8%) and Oliguria was the commonest symptom present in 47.7% of patients. Intravenous fluids were received by 79.9% of patients, 22.6% of patients received diuretics, and 33.7% received renal replacement therapy in the form of intermittent hemodialysis. Death occurred in 25 patients (13.16%) and 69 (36.32%) showed no renal recovery. Shock and sepsis were the most significant predictors of mortality. Conclusion: Community acquired AKI is a major health problem with high morbidity and mortality.

3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H-pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the proliferation of three human cancer cell lines; human liver carcinoma cell line (HepG-2), colon cancer cell line (HCT-116) and human breast cancer cell line (MCF-7) using MTT assay. The synthesized compounds were characterized on the basis of IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis results. Cytotoxicity assay results revealed that some of the compounds showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.64–7.73 μg/mL. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis-inducing effect of the most active compounds. The results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway. Molecular modeling and binding mode analysis of the most active compounds to caspase 3 active site further provide a synergistic mechanism for their pro-apoptotic effects. In order to explore the structural requirements controlling the observed cytotoxic properties, 3D pharmacophore model was generated.

A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 9 h.