Differences in management approaches for lupus nephritis within the UK.

Objectives: Outcomes of therapy for LN are often suboptimal. Guidelines offer varied options for treatment of LN and treatment strategies may differ between clinicians and regions. We aimed to assess variations in the usual practice of UK physicians who treat LN. Methods: We conducted an online survey of simulated LN cases for UK rheumatologists and nephrologists to identify treatment preferences for class IV and class V LN. Results: Of 77 respondents, 48 (62.3%) were rheumatologists and 29 (37.7%) were nephrologists. A total of 37 (48.0%) reported having a joint clinic between nephrologists and rheumatologists, 54 (70.0%) reported having a multidisciplinary team meeting for LN and 26 (33.7%) reported having a specialized lupus nurse. Of the respondents, 58 (75%) reported arranging a renal biopsy before starting the treatment. A total of 20 (69%) of the nephrologists, but only 13 (27%) rheumatologists, reported having a formal departmental protocol for treating patients with LN (P < 0.001). The first-choice treatment of class IV LN in pre-menopausal patients was MMF [41 (53.2%)], followed by CYC [15 (19.6%)], rituximab [RTX; 12 (12.5%)] or a combination of immunosuppressive drugs [9 (11.7%)] with differences between nephrologists' and rheumatologists' choices (P = 0.026). For class V LN, MMF was the preferred initial treatment, irrespective of whether proteinuria was in the nephrotic range or not. RTX was the preferred second-line therapy for non-responders. Conclusion: There was variation in the use of protocols, specialist clinic service provision, biopsies and primary and secondary treatment choices for LN reported by nephrologists and rheumatologists in the UK.

Exploring antiproliferative activities and kinase profile of ortho-substituted N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)benzamides.

Designing kinase inhibitors that bind to the substrate site of oncogenic kinases in a promising, albeit less explored, approach to kinase inhibition as it was sought to avoid the issue of untoward off-target modulations. Our previously identified compound KAC-12 with a meta-chlorophenyl substitution was an example of this approach. While it showed confirmed inhibitory activity against cancer cells, this substitution shifted the profile of affected targets away from Src/tubulin which were seen with the parent KX-01. In this paper, we synthesized compounds with ortho-substitutions, and we investigated the effect of such substitutions on their cellular and subcellular activities. The compound N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-2-(morpholine-4-carbonyl)benzamide (4) exhibited substantial activities against cell lines such HCT116 (IC50 of 0.97 µM) and IC50 HL60 (2.84 µM). Kinase profiling showed that compound 4 trended consistently with KAC-12 as it did not affect Src, but it had more impact on members of the Src family of kinases (SFK) such as Yes, Hck, Fyn, Lck, and Lyn. Both compounds exhibited profound downregulation effects on Erk1/2 but differed on others such as GSK3α/ß and C-Jun. Collectively, this study further support to the hypothesis that small structural changes might bring higher changes in their kinome profile.

The Impact of Using Carbohydrate Counting on Managing Diabetic Patients: A Review.

Carbohydrate counting (CC) is a meal planning practice for diabetic patients, focusing on tracking the amount of carbohydrates in grams consumed at meals to manage blood glucose (BG) levels. The purpose of this narrative review is to evaluate the impact of CC in helping people with diabetes manage their condition. It reveals that CC offers superior glycemic control and flexibility compared to other food planning techniques. Specifically, when applied to children and teenage patients diagnosed with type 1 diabetes mellitus (T1DM), CC demonstrates the potential for substantial improvements in metabolic control without any adverse effects on weight or increased insulin requirements. In the context of T1DM, the combination of CC and the use of automated bolus calculators (ABCs) contributes to lowering glycated hemoglobin (HbA1c) levels. Furthermore, the study highlights that CC also holds promise in the management of type 2 diabetes mellitus (T2DM). In T2DM patients, adhering to a low glycemic index (GI) diet has proven to be more effective in controlling HbA1c and fasting BG levels compared to a higher GI diet or standard dietary control. This research underscores the evolving significance of CC as a pivotal component in diabetes management, attributed to increased awareness and education among patients. CC emerges as a versatile tool that can benefit individuals with various forms of diabetes by enhancing their glycemic control and overall quality of life. The findings affirm the impact of CC in improving patient outcomes, solidifying its status as a vital strategy in the multifaceted landscape of diabetes care.

Assessment of chemokines MIP-1α and MIP-1 ßin Iraqi women with polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is reproductive, endocrine, and metabolic disorder affecting females. The pathology of PCOS is complicated and associated to chronic low-grade inflammation, this includes a disruption in pro-inflammatory factor production, leukocytosis, and endothelial cell dysfunction, also associated with high level of pro-inflammatory cytokines, chemokines and leukocyte count. In addition, PCOS is characterized by hormonal and immunological dysfunction. Inflammation of the ovary affects ovulation and induces or aggravates systemic inflammation. Macrophage inflammatory protein-1 (MIP-1), a pro-inflammatory chemokine, is crucial in the recruitment of inflammatory and immunological cells to the place of inflammation or infection, T- and B-lymphocytes, neutrophils, macrophages, mast cells, dendritic cells and natural killer cells are all capable of producing large amounts of MIP-1. The current study aimed to investigate the role of MIP-1α and MIP-1ß in Iraqi patients with PCOS and their correlation with obesity and other demographic parameters. This study included two groups, 60 women with PCOS and 30 control women, conducted during the period from October 2022 to January 2023. The diagnosis of PCOS women was based on two out of three of the following diagnostic criteria (hyperandrogenism - oligo or anovulation - polycystic ovaries). MIP-1 alpha and Beta levels were determined by ELISA. The outcomes revealed that the group with PCOS showed significant increase in the level of MIP-1α (635.28 ±20.58) than in the control women, (571.20 ±25.92), (p<0.05). Although there was an increase the level of MIP-1ß in women with PCOS (191.85 ±17.54) than in the control group (165.31 ±11.01), the difference did not reach statistical significance. In conclusion, based on our findings, that MIP-1α and MIP-1ß increased in PCOS cases, this may indicate that PCOS is low grade chronic inflammation.

Corticosteroids for managing acute pain subsequent to surgical extraction of mandibular third molars: A systematic review and meta-analysis.

BACKGROUND: Corticosteroids are used to manage pain after surgical tooth extractions. The authors assessed the effect of corticosteroids on acute postoperative pain in patients undergoing surgical tooth extractions of mandibular third molars. TYPES OF STUDIES REVIEWED: The authors conducted a systematic review and meta-analysis. The authors searched the Epistemonikos database, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and the US clinical trials registry (ClinicalTrials.gov) from inception until April 2023. Pairs of reviewers independently screened titles and abstracts, then full texts of trials were identified as potentially eligible. After duplicate data abstraction, the authors conducted random-effects meta-analyses. Risk of bias was assessed using Version 2 of the Cochrane Risk of Bias tool and certainty of the evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Forty randomized controlled trials proved eligible. The evidence suggested that corticosteroids compared with a placebo provided a trivial reduction in pain intensity measured 6 hours (mean difference, 8.79 points lower; 95% CI, 14.8 to 2.77 points lower; low certainty) and 24 hours after surgical tooth extraction (mean difference, 8.89 points lower; 95% CI, 10.71 to 7.06 points lower; very low certainty). The authors found no important difference between corticosteroids and a placebo with regard to incidence of postoperative infection (risk difference, 0%; 95% CI, -1% to 1%; low certainty) and alveolar osteitis (risk difference, 0%; 95% CI, -3% to 4%; very low certainty). PRACTICAL IMPLICATIONS: Low and very low certainty evidence suggests that there is a trivial difference regarding postoperative pain intensity and adverse effects of corticosteroids administered orally, submucosally, or intramuscularly compared with a placebo in patients undergoing third-molar extractions.

To segment or not to segment: COVID-19 detection for chest X-rays.

Artificial intelligence (AI) has been integrated into most technologies we use. One of the most promising applications in AI is medical imaging. Research demonstrates that AI has improved the performance of most medical imaging analysis systems. Consequently, AI has become a fundamental element of the state of the art with improved outcomes across a variety of medical imaging applications. Moreover, it is believed that computer vision (CV) algorithms are highly effective for image analysis. Recent advances in CV facilitate the recognition of patterns in medical images. In this manner, we investigate CV segmentation techniques for COVID-19 analysis. We use different segmentation techniques, such as k-means, U-net, and flood fill, to extract the lung region from CXRs. Afterwards, we compare the effectiveness of these three segmentation approaches when applied to CXRs. Then, we use machine learning (ML) and deep learning (DL) models to identify COVID-19 lesion molecules in both healthy and pathological lung x-rays. We evaluate our ML and DL findings in the context of CV techniques. Our results indicate that the segmentation-related CV techniques do not exhibit comparable performance to DL and ML techniques. The most optimal AI algorithm yields an accuracy range of 0.92-0.94, whereas the addition of CV algorithms leads to a reduction in accuracy to approximately the range of 0.81-0.88. In addition, we test the performance of DL models under real-world noise, such as salt and pepper noise, which negatively impacts the overall performance.

Sexual Harassment: Knowledge, Prevalence, Pattern, and Impacts Among Egyptian Female College Students.

Sexual harassment (SH) is an uprising problem worldwide, especially in Egypt. This study aims to determine the magnitude, patterns, and circumstances of SH among female students at Suez Canal University. A cross-sectional study was conducted on a representative female student sample (N = 644) from all the faculties using a self-administered anonymous questionnaire. The high prevalence of SH among college students in this study could be a consequence of the absence of knowledge about the legal framework. It mostly happened at all times of the day and night in the streets, and the least amount happened on the campus. Most of the harassers were younger than 20 years old and strangers. The majority of harassed females and surrounding people displayed negative reactions. None of the harassed females notified the authorities. The majority blamed men, and half claimed the SH act was due to the absence of religious principles. Moreover, the ignorance of the majority is with Egyptian law against SH. Both psychological and social impacts are significantly experienced by the harassed females. Thus, it is urgent to establish an institutional program (e.g., psycho-educative sessions during classes and peer training) or national awareness campaigns. Such programs and trainings aim to increase the awareness of students about the SH legal framework and how to deal with such acts, either as a victim or a witness, and how to provide the needed psychological assistance.

Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun.

Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.

Analgesics for the management of acute dental pain in the pediatric population: A systematic review and meta-analysis.

BACKGROUND: The authors assessed the clinical effectiveness of analgesics to manage acute pain after dental extractions and pain associated with irreversible pulpitis in children. TYPES OF STUDIES REVIEWED: The authors searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and US Clinical Trials registry from inception through November 2020. They included randomized controlled trials comparing any pharmacologic interventions with each other and a placebo in pediatric participants undergoing dental extractions or experiencing irreversible pulpitis. After duplicate screening and data abstraction, the authors conducted random-effects meta-analyses. They assessed risk of bias using the Cochrane Risk of Bias 2.0 tool and certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: The authors included 6 randomized controlled trials reporting 8 comparisons. Ibuprofen may reduce pain intensity compared with acetaminophen (mean difference [MD], 0.27 points; 95% CI, -0.13 to 0.68; low certainty) and a placebo (MD, -0.19 points; 95% CI, -0.58 to 0.21; low certainty). Acetaminophen may reduce pain intensity compared with a placebo (MD, -0.13 points; 95% CI, -0.52 to 0.26; low certainty). Acetaminophen and ibuprofen combined probably reduce pain intensity compared with acetaminophen alone (MD, -0.75 points; 95% CI, -1.22 to -0.27; moderate certainty) and ibuprofen alone (MD, -0.01 points; 95% CI, -0.53 to 0.51; moderate certainty). There was very low certainty evidence regarding adverse effects. PRACTICAL IMPLICATIONS: Several pharmacologic interventions alone or in combination may provide a beneficial effect when managing acute dental pain in children. There is a paucity of evidence regarding the use of analgesics to manage irreversible pulpitis.

An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of aldosterone in human serum and plasma.

OBJECTIVES: An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedure (RMP) for aldosterone quantification in human serum and plasma is presented. METHODS: The material used in this RMP was characterized by quantitative nuclear magnetic resonance (qNMR) to assure traceability to SI Units. For liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis a two-dimensional heart cut LC approach, in combination with an optimal supported liquid extraction protocol, was established for the accurate analysis of aldosterone in human serum and plasma in order to minimize matrix effects and avoid the co-elution of interferences. Assay validation was performed according to current guidelines. Selectivity and specificity were assessed using spiked serum; potential matrix effects were examined by a post column infusion experiment and the comparison of standard line slopes. An extensive protocol over 5 days was applied to determine precision, accuracy and trueness. Measurement uncertainty was evaluated according to the Guide to the Expression of Uncertainty in Measurement (GUM), for which three individual sample preparations were performed on at least two different days. RESULTS: The RMP allowed aldosterone quantification within the range of 20-1,200 pg/mL without interference from structurally-related compounds and no evidence of matrix effects. Intermediate precision was ≤4.7% and repeatability was 2.8-3.7% for all analyte concentrations. The bias ranged between -2.2 and 0.5% for all levels and matrices. Total measurement uncertainties for target value assignment (n=6) were found to be ≤2.3%; expanded uncertainties were ≤4.6% (k=2) for all levels. CONCLUSIONS: The RMP showed high analytical performance for aldosterone quantification in human serum and plasma. The traceability to SI units was established by qNMR content determination of aldosterone, which was utilized for direct calibration of the RMP. Thus, this candidate RMP is suitable for routine assay standardization and evaluation of clinical samples.

Evaluation of the use of GRADE in dentistry systematic reviews and its impact on conclusions: a protocol for a methodological study.

BACKGROUND: There is a growing body of evidence of systematic reviews (SRs) with varying degrees of methodological quality. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach allows SR authors to assess the certainty of the evidence they found and transparently relay their conclusions. As there appears to be infrequent utilization of GRADE in the field of dentistry, to identify the impact of GRADE, the aim of this study is to evaluate the use of GRADE in the dental literature and determine whether SRs that use GRADE differ from those that do not with respect to their conclusions. METHODS/DESIGN: We will search Ovid MEDLINE for SRs published from 2016 to the present. We will conduct both screening and data extraction independently and in duplicate and use pre-piloted, standardized forms for data extraction. We will determine the frequency of the use of GRADE and the varying levels of certainty in the current literature and evaluate whether GRADE is being used appropriately. We will also evaluate whether SRs not using GRADE differ from those that use GRADE with regard to methodological quality. We will also determine whether the conclusions of SRs that do not use GRADE would change had GRADE been utilized. Additionally, we will evaluate whether SRs using GRADE are more likely to formulate appropriate conclusions compared to SRs that do not use it. DISCUSSION: This study will investigate the frequency of GRADE assessments in dentistry SRs and the impact of GRADE assessments on the conclusions of a SR. It has important implications for both SR authors and users of this type of literature.

Leveraging Marine Predators Algorithm with Deep Learning for Lung and Colon Cancer Diagnosis.

Cancer is a deadly disease caused by various biochemical abnormalities and genetic diseases. Colon and lung cancer have developed as two major causes of disability and death in human beings. The histopathological detection of these malignancies is a vital element in determining the optimal solution. Timely and initial diagnosis of the sickness on either front diminishes the possibility of death. Deep learning (DL) and machine learning (ML) methods are used to hasten such cancer recognition, allowing the research community to examine more patients in a much shorter period and at a less cost. This study introduces a marine predator's algorithm with deep learning as a lung and colon cancer classification (MPADL-LC3) technique. The presented MPADL-LC3 technique aims to properly discriminate different types of lung and colon cancer on histopathological images. To accomplish this, the MPADL-LC3 technique employs CLAHE-based contrast enhancement as a pre-processing step. In addition, the MPADL-LC3 technique applies MobileNet to derive feature vector generation. Meanwhile, the MPADL-LC3 technique employs MPA as a hyperparameter optimizer. Furthermore, deep belief networks (DBN) can be applied for lung and color classification. The simulation values of the MPADL-LC3 technique were examined on benchmark datasets. The comparison study highlighted the enhanced outcomes of the MPADL-LC3 system in terms of different measures.

Reactive sputtering onto an ionic liquid, a new synthesis route for bismuth-based nanoparticles.

Metallic bismuth and Bi-oxyfluoride nanoparticles (NPs) are successfully synthesized by non-reactive and reactive sputtering of a Bi target onto 1-butyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)imide ([BMIM][TFSI]) ionic liquid (IL). Non-reactive sputtering is realized in pure Ar plasma, where isotropic, well crystallized and dispersed Bi NPs of 3-7 nm are obtained. The diameter and the size distribution of these NPs do not significantly vary with the power, gas pressure, and sputtering time; but these sputtering parameters seem to influence the NP concentration. Then, the introduction of O2 and CF4 gases in addition to Ar enables the reaction of radicals from plasma with Bi clusters at the liquid's top surface to form Bi-oxyfluoride NPs of 3-12 nm in diameter with photocatalytic activity. Hence, the reactive sputtering onto an IL is an efficient, original and promising method for synthesizing Bi-based compound NPs. Finally, we propose a mechanism based on reactions of species from plasma at the IL surface to explain the formation of Bi-compounds by reactive sputtering.

Injectable and topical local anesthetics for acute dental pain: 2 systematic reviews.

BACKGROUND: Local anesthesia is essential for pain control in dentistry. The authors assessed the comparative effect of local anesthetics on acute dental pain after tooth extraction and in patients with symptomatic irreversible pulpitis. TYPES OF STUDIES REVIEWED: The authors searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and the US Clinical Trials registry through November 21, 2020. The authors included randomized controlled trials (RCTs) comparing long- vs short-acting injectable anesthetics to reduce pain after tooth extraction (systematic review 1) and evaluated the effect of topical anesthetics in patients with symptomatic pulpitis (systematic review 2). Pairs of reviewers screened articles, abstracted data, and assessed risk of bias using a modified version of the Cochrane risk of bias 2.0 tool. The authors assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Fourteen RCTs comparing long- vs short-acting local anesthetics suggest that bupivacaine may decrease the use of rescue analgesia and may not result in additional adverse effects (low certainty evidence). Bupivacaine probably reduces the amount of analgesic consumption compared with lidocaine with epinephrine (mean difference, -1.91 doses; 95% CI, -3.35 to -0.46; moderate certainty) and mepivacaine (mean difference, -1.58 doses; 95% CI, -2.21 to -0.95; moderate certainty). Five RCTs suggest that both benzocaine 10% and 20% may increase the number of people experiencing pain reduction compared with placebo when managing acute irreversible pulpitis (low certainty). PRACTICAL IMPLICATIONS: Bupivacaine may be superior to lidocaine with epinephrine and mepivacaine with regard to time to and amount of analgesic consumption. Benzocaine may be superior to placebo in reducing pain for 20 through 30 minutes after application.

Role of fluid-phase complement system regulation in the development of hepatitis C virus-associated glomerulonephritis.

OBJECTIVES: It is not known why only some hepatitis C virus (HCV) infected patients develop glomerulonephritis (GN). Therefore, we investigated the role of soluble complement regulators in the development of HCV associated GN. METHODS: Patients with HCV associated GN who were admitted to our nephrology unit between July 2016 and July 2018 were recruited to the study (group 1). Two other age and sex matched groups were studied as control groups: patients with HCV without GN (group 2) and healthy HCV negative volunteers (group 3). There were 26 participants in each of the three groups at the end of the recruitment period. An assay of serum fluid-phase complement regulators was performed using enzyme linked immunosorbent assay technique. Three complement single nucleotide polymorphisms (SNPs) were analyzed using real time polymerase chain reaction (Taqman; thermo fisher scientific): rs2230199 and rs1047286 for complement 3 (C3) and rs800292 for complement factor H (CFH). RESULTS: Serum levels of complement 4 binding protein (C4BP) were significantly lower in group 1 (median 70 ng/ml) than in groups 2 (median 88.8 ng/ml) and 3 (median 82.8 ng/ml) with p value of 0.007. The minor allele (allele A) of rs800292 for CFH was significantly higher in group 2 and group 3 (G 54% and A 46%) than in group 1 (G 73% and A 27%), p = 0.04. CONCLUSIONS: Low C4BP levels are associated with GN in HCV infected patients. In addition, rs800292 SNP in CFH protects against GN in patients with HCV.

Efficacy of secondary vs primary closure techniques for the prevention of postoperative complications after impacted mandibular third molar extractions: A systematic review update and meta-analysis.

BACKGROUND: The aim of this systematic review was to determine whether secondary closure (SC) or primary closure (PC) is better at preventing postoperative complications after impacted mandibular third-molar extraction. TYPES OF STUDIES REVIEWED: The authors sought randomized controlled trials comparing the effects of PC and SC on pain, swelling, trismus, infection, and bleeding after impacted mandibular third-molar extraction. Screening, data extraction, and risk of bias assessments were conducted independently and in duplicate. The reviewers pooled results across studies using a random-effects meta-analysis and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: This review identified 785 unique citations and included 40 trials. Compared with PC, SC was found to have trivial benefits for pain at day 7 and trismus within 1 week (moderate certainty). The incidence of infection and bleeding did not differ importantly between techniques (moderate certainty). However, SC is probably associated with less swelling on day 1 (standardized mean difference, -0.98; 95% CI, -1.22 to -0.73; moderate certainty) and day 3 (standardized mean difference, -0.87; 95% CI, -1.16 to -0.59; moderate certainty). There was very low certainty evidence for pain on days 1 and 3 and low certainty evidence for swelling on day 7. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Clinicians choosing between closure techniques should be aware that SC probably imparts an important benefit only for swelling at days 1 and 3. There seems to be a trivial difference between the techniques in other outcomes.

SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases.

Tirbanibulin (KX2-391, KX-01), a dual non-ATP (substrate site) Src kinase and tubulin-polymerization inhibitor, demonstrated a universal anti-cancer activity for variety of cancer types. The notion that KX2-391 is a highly selective Src kinase inhibitor have been challenged by recent reports on the activities of this drug against FLT3-ITD mutations in some leukemic cell lines. Therefore, we hypothesized that analogues of KX2-391 may inhibit oncogenic kinases other than Src. A set of 4-aroylaminophenyl-N-benzylacetamides were synthesized and found to be more active against leukemia cell lines compared to solid tumor cell lines. N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-4-chlorobenzamide (4e) exhibited activities at IC50 0.96 µM, 1.62 µM, 1.90 µM and 4.23 µM against NB4, HL60, MV4-11 and K562 leukemia cell lines, respectively. We found that underlying mechanisms of 4e did not include tubulin polymerization or Src inhibition. Such results interestingly suggested that scaffold-hopping of KX2-391 may change the two main underlying cytotoxic mechanisms (Src and tubulin). Kinase profiling using two methods revealed that 4e significantly reduces the activities of some other potent oncogenic kinases like the MAPK member ERK1/2 (>99%) and it also greatly upregulates the pro-apoptotic c-Jun kinase (84%). This research also underscores the importance of thorough investigation of total kinase activities as part of the structure-activity relationship studies.

Managing acute presentations of atheromatous renal artery stenosis.

BACKGROUND: Atherosclerotic renovascular disease (ARVD) often follows an asymptomatic chronic course which may be undetected for many years. However, there are certain critical acute presentations associated with ARVD and these require a high index of suspicion for underlying high-grade RAS (renal artery stenosis) to improve patient outcomes. These acute presentations, which include decompensated heart failure syndromes, accelerated hypertension, rapidly declining renal function, and acute kidney injury (AKI), are usually associated with bilateral high-grade RAS (> 70% stenosis), or high-grade RAS in a solitary functioning kidney in which case the contralateral kidney is supplied by a vessel demonstrating renal artery occlusion (RAO). These presentations are typically underrepresented in large, randomized control trials which to date have been largely negative in terms of the conferred benefit of revascularization. CASE PRESENTATION: Here we describe 9 individual patients with 3 classical presentations including accelerated phase hypertension, heart failure syndromes, AKI and a fourth category of patients who suffered recurrent presentations. We describe their response to renal revascularization. The predominant presentation was that consistent with ischaemic nephropathy all of whom had a positive outcome with revascularization. CONCLUSION: A high index of suspicion is required for the diagnosis of RAS in these instances so that timely revascularization can be undertaken to restore or preserve renal function and reduce the incidence of hospital admissions for heart failure syndromes.

Ruthenium(II) carbon monoxide releasing molecules: Structural perspective, antimicrobial and anti-inflammatory properties.

Carbon monoxide has recently emerged to promote tissue regeneration, enhance the innate immune system, and have anti-inflammatory and antibacterial properties. While the first generation Ru(II) carbonyl prodrugs (CORM-2 and CORM-3) displayed several beneficial biological effects, a search in the literature shows that little work has been done to address the drawbacks of CORM-2/-3, exploring other CO triggered methods for the next generation Ru(CO)2II based compounds and examining their valuable biological impact. We present a summary of most work related to Ru(II) carbon monoxide-releasing molecules, protein bioconjugation, and antibacterial and anti-inflammatory properties.

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in adults. NAFLD progresses from benign liver fat accumulation to liver inflammation and cirrhosis, and ultimately leads to liver failure. Although several rodent models have been established for studying NAFLD, they have limitations that include cost, speed of disease development, key dissimilarities, and poor amenability to pharmacological screens. Here, we present a novel 2-hit zebrafish model to replicate aspects of NAFLD pathogenesis. We fed zebrafish larvae a high-fat diet (HFD) to drive liver fat accumulation (first hit). Next, we exacerbated liver-specific inflammation using a transgenic line (fabp10-CETI-PIC3) that induces the expression of proinflammatory cytokines following induction with doxycycline (second hit). These hits promoted fat accumulation and liver inflammation, as demonstrated by the high expression of inflammatory cytokines, macrophage infiltration, stress induction, and hepatic lipid droplet accumulation. Furthermore, zebrafish in this paradigm showed deranged glucose metabolism. To validate a small-molecule screening approach, we treated HFD-fed fish with pioglitazone, a drug shown to be beneficial for NAFLD in humans, and measured a sharp reduction in liver lipid accumulation. These results demonstrate new utility for zebrafish in modeling early NAFLD pathogenesis and demonstrate their feasibility for in vivo screening of new pharmacological interventions.