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Marwa S Hamza,1 Samia A Shouman,2 Raafat Abdelfattah,3 Heba S Moussa,4 Mervat M Omran2 1Clinical Pharmacy Practice Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, Egypt; 2Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 3Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt; 4Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, EgyptCorrespondence: Marwa S Hamza, Clinical Pharmacy Practice Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, Egypt, Email marwa.hamza@bue.edu.egBackground: Imatinib is used to treat chronic myelogenous leukemia (CML). Variations in imatinib pharmacokinetics have been linked to genetic variations. That has an impact on imatinib response and adverse effects. Therefore, the aim of the study was to study bone pain as an adverse effect that occurs with imatinib and to investigate the risk factors for bone pain.Methods: The relationship between the peak and trough plasma concentrations of imatinib with bone pain as one of the most frequently occurring adverse effects was examined. Multiple linear regression analysis and binary logistic regression analysis were used to measure the impact of various patients’ characteristics on both peak and trough imatinib concentrations and the risk of the occurrence of imatinib-induced bone pain.Results: As a side effect of imatinib, approximately 15% of patients with CML who were taking it experienced bone pain. This side effect was linked to the imatinib peak and trough plasma levels. Imatinib trough concentration was also linked to gender and the gene SLCO1B3-334T > G (TT). There were significant associations between peak concentrations and gender as well as patient weight.Conclusion: Higher peak and trough plasma concentrations of imatinib are linked with the risk of the occurrence of bone pain as a side effect of imatinib. Monitoring plasma concentrations of imatinib is useful to predict the bone pain of imatinib and to support quality of life in patients with CML.Keywords: imatinib, tyrosine kinase inhibitor, chronic myelogenous leukemia, trough plasma concentration, bone pain

Osama A Badary,1,2 Marwa S Hamza,1 Rajiv Tikamdas1 1Clinical Pharmacy Practice Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; 2Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, EgyptCorrespondence: Osama A BadaryClinical Pharmacy Practice Department, Faculty of Pharmacy, The British University in Egypt, P.O. Box 43, El-Sherouk City, Cairo, 11837, EgyptTel +201064112110Email osama.badary@bue.edu.egAbstract: COVID-19 has caused a major global health crisis, as excessive inflammation, oxidation, and exaggerated immune response in some sufferers can lead to a condition known as cytokine storm, which may progress to acute respiratory distress syndrome (ARDs), which can be fatal. So far, few effective drugs have emerged to assist in the treatment of patients with COVID-19, though some herbal medicine candidates may assist in the fight against COVID-19 deaths. Thymoquinone (TQ), the main active ingredient of black seed oil, possesses antioxidant, anti-inflammatory, antiviral, antimicrobial, immunomodulatory and anticoagulant activities. TQ also increases the activity and number of cytokine suppressors, lymphocytes, natural killer cells, and macrophages, and it has demonstrated antiviral potential against a number of viruses, including murine cytomegalovirus, Epstein-Barr virus, hepatitis C virus, human immunodeficiency virus, and other coronaviruses. Recently, TQ has demonstrated notable antiviral activity against a SARSCoV-2 strain isolated from Egyptian patients and, interestingly, molecular docking studies have also shown that TQ could potentially inhibit COVID-19 development through binding to the receptor-binding domain on the spike and envelope proteins of SARS-CoV-2, which may hinder virus entry into the host cell and inhibit its ion channel and pore forming activity. Other studies have shown that TQ may have an inhibitory effect on SARS CoV2 proteases, which could diminish viral replication, and it has also demonstrated good antagonism to angiotensin-converting enzyme 2 receptors, allowing it to interfere with virus uptake into the host cell. Several studies have also noted its potential protective capability against numerous chronic diseases and conditions, including diabetes, hypertension, dyslipidemia, asthma, renal dysfunction and malignancy. TQ has recently been tested in clinical trials for the treatment of several different diseases, and this review thus aims to highlight the potential therapeutic effects of TQ in the context of the COVID-19 pandemic.Keywords: thymoquinone, COVID-19, natural, therapeutic benefits

African eggplant (Solanum aethiopicum L.) is one of the most common traditional vegetables in Tanzania and Uganda, but its productivity is severely affected by wilt diseases caused by a number of pathogens. Plant stem and root samples were collected in several fields from many neighboring diseased and healthy plants of the Gilo group in Tanzania and from the Shum group in Uganda to identify putative pathogens causing wilt on African eggplants. Through amplicon sequencing of sampled diseased and healthy tissues, we identified putative causal pathogens for the wilt symptoms. Wilting of S. aethiopicum in Uganda is most likely caused by the bacterial pathogen Ralstonia solanacearum whereas, in Tanzania, wilt is most likely caused by the fungal pathogen Macrophomina phaseolina, infecting roots. Infection of stems by Fusarium solani may also contribute to the wilt symptoms in Tanzania. Further artificial inoculation under controlled conditions confirmed that M. phaseolina can cause typical wilting symptoms on S. aethiopcium genotypes. The discovery of different putative causal agents of wilt in the crop demonstrates the need for site specific etiological analysis of wilt before developing and implementing effective control methods. Further research is needed to confirm the results and develop appropriate management measures against specific wilt pathogens.

Chronic Myeloid Leukemia (CML) requires consistent medication adherence to Imatinib (IM) for optimal outcomes, however, adherence to oral chemotherapy is challenging. This observational study explores the relationship between patient knowledge, motivation, and adherence to IM therapy, and their collective impact on clinical outcomes. A prospective, observational study was conducted with 101 CML patients. The 6-Item Morisky Medication Adherence Scale (MMAS-6) was used to assess adherence, motivation, and knowledge levels. The study found that high motivation was significantly associated with lower BCR-ABL expression ( p  = 0.025). Patients with high knowledge and motivation had a 71% favorable response rate, compared to 0% in those with low knowledge and motivation ( p  = 0.01). As conclusion both patient motivation and knowledge are crucial for favorable treatment outcomes in CML. High levels of both significantly correlate with better clinical responses. Tailored interventions to enhance patient knowledge and motivation are essential.

Background: Imatinib treatment for certain cancers can lead to elevated creatine kinase (CK) levels, potentially indicating muscle injury, and ongoing research aims to understand the correlation between imatinib levels and creatine kinase to assess its impact on treatment response., Methods: This single-center observational study involved 76 chronic myeloid leukemia (CML) patients receiving imatinib treatment, focusing on evaluating drug and metabolite levels using liquid chromatography-mass spectrometry (LC-MS-MS) instrumentation. Serum CK and creatine kinase-MB (CK-MB) levels were assessed using Colorimetric kits., Results: CK and CK-MB levels were measured, CK showed a median value of 211.5 IU/l and CK-MB showed a median value of 4.4 IU/l. Comparing low and high CK groups, significant differences were found in peak and trough plasma concentrations of imatinib and its metabolites. Correlations between CK levels and pharmacokinetic parameters were explored, with notable associations identified. Binary logistic regression revealed predictors influencing the therapeutic response to imatinib and categorized expected CK levels into high or low, with peak levels of imatinib emerging as a significant predictor for CK level categorization., Conclusion: The study highlights the link between imatinib's pharmacokinetics and elevated CK levels, indicating a possible correlation between specific metabolites and improved treatment response. Individualized monitoring of CK levels and imatinib pharmacokinetics could enhance care for CML patients., (© 2024. The Author(s).)

Urinary bladder cancer (UBC) holds a potentially profound social burden and affects over 573,278 new cases annually. The disease's primary risk factors include occupational tobacco smoke exposure and inherited genetic susceptibility. Over the past 30 years, a number of treatment modalities have emerged, including cisplatin, a platinum molecule that has demonstrated effectiveness against UBC. Nevertheless, it has severe dose-limiting side effects, such as nephrotoxicity, among others. Since intracellular accumulation of platinum anticancer drugs is necessary for cytotoxicity, decreased uptake or enhanced efflux are the root causes of platinum resistance and response failure. Evidence suggests that genetic variations in any transporter involved in the entry or efflux of platinum drugs alter their kinetics and, to a significant extent, determine patients' responses to them. This review aims to consolidate and describe the major transporters and their polymorphic variants in relation to cisplatin-induced toxicities and resistance in UBC patients. We concluded that the efflux transporters ABCB1, ABCC2, SLC25A21, ATP7A, and the uptake transporter OCT2, as well as the organic anion uptake transporters OAT1 and OAT2, are linked to cisplatin accumulation, toxicity, and resistance in urinary bladder cancer patients. While suppressing the CTR1 gene's expression reduced cisplatin-induced nephrotoxicity and ototoxicity, inhibiting the expression of the MATE1 and MATE2-K genes has been shown to increase cisplatin's nephrotoxicity and resistance. The roles of ABCC5, ABCA8, ABCC10, ABCB10, ABCG1, ATP7B, ABCG2, and mitochondrial SLC25A10 in platinum-receiving urinary bladder cancer patients should be the subject of further investigation., (© 2023. The Author(s).)

Roles of platelets during infections surpass the classical thrombus function and are now known to modulate innate immune cells. Leukocyte-platelet aggregations and activation-induced secretome are among factors recently gaining interest but little is known about their interplay with severity and mortality during the course of SARS-Cov-2 infection. The aim of the present work is to follow platelets' bioenergetics, redox balance, and calcium homeostasis as regulators of leukocyte-platelet interactions in a cohort of COVID-19 patients with variable clinical severity and mortality outcomes. We investigated COVID-19 infection-related changes in platelet counts, activation, morphology (by flow cytometry and electron microscopy), bioenergetics (by Seahorse analyzer), mitochondria function (by high resolution respirometry), intracellular calcium (by flow cytometry), reactive oxygen species (ROS, by flow cytometry), and leukocyte-platelet aggregates (by flow cytometry) in non-intensive care unit (ICU) hospitalized COVID-19 patients (Non-ICU, n=15), ICU-survivors of severe COVID-19 (ICU-S, n=35), non-survivors of severe COVID-19 (ICU-NS, n=60) relative to control subjects (n=31). Additionally, molecular studies were carried out to follow gene and protein expressions of mitochondrial electron transport chain complexes (ETC) in representative samples of isolated platelets from the studied groups. Our results revealed that COVID-19 infection leads to global metabolic depression especially in severe patients despite the lack of significant impacts on levels of mitochondrial ETC genes and proteins. We also report that severe patients' platelets exhibit hyperpolarized mitochondria and significantly lowered intracellular calcium, concomitantly with increased aggregations with neutrophil. These changes were associated with increased populations of giant platelets and morphological transformations usually correlated with platelets activation and inflammatory signatures, but with impaired exocytosis. Our data suggest that hyperactive platelets with impaired exocytosis may be integral parts in the pathophysiology dictating severity and mortality in COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yasseen, Elkhodiry, El-Messiery, El-sayed, Elbenhawi, Kamel, Gad, Zidan, Hamza, Al-ansary, Abdel-Rahman and Ali.)

Background: Vitamin D deficiency is a common side effect of imatinib mesylate (IM) therapy. Transporter polypeptides involved in the disposition of IM may be required for maintenance of adequate vitamin D concentrations., Objective: The aim of the present work is to study the association between the plasma concentrations of IM and plasma 25-hydroxyvitamin (25[OH]) D3 with transporter genotypes in patients with chronic myelogenous leukemia., Methods: A total of 77 adult patients with chronic myelogenous leukemia treated with IM participated in this study. Peak and trough plasma IM and 25(OH) vitamin D3 concentrations were measured and compared to the results of single nucleotide polymorphisms of the efflux transporting gene ABCB1-1236 C>T and the uptake transporting gene OATP1B3-334 T>G. Multiple linear regressions were used to examine the associations between 25(OH) vitamin D3 concentrations and a number of patient characteristics, including responses to therapy. Binary logistic regression analysis was used to predict odd ratios for the clinical response to IM., Results: Plasma 25(OH) vitamin D3 concentration quartile values were: 25%, 8.2 ng/mL; 50%, 9.8 ng/mL; and 75%, 12 ng/mL. High IM peak concentration, being OATP1B3-334 T>G (TT), and/ or ABCB1-1236 C>T (CT) are associated with lower concentrations of 25(OH) vitamin D3. Moreover, IM peak concentration, IM trough concentration, and plasma concentration of 25(OH) vitamin D3 were associated with the clinical response to IM., Conclusions: vitamin D, IM concentration, as well as the genotype of OATP1B3-334 T>G, had an influence on the response of patients with chronic myelogenous leukemia., Competing Interests: The authors have indicated that they have no conflicts of interest regarding the content of this article., (© 2022 The Authors.)

Background: Clinical pharmacists have a vital role during COVID-19 pandemic in mitigating medication errors, particularly prescribing errors in hospitals. That is owing to the fact that prescribing errors during the COVID-19 pandemic has increased., Aim: This study aimed to evaluate the impact of the clinical pharmacist on the rate of prescribing errors on COVID-19 patients in a governmental hospital., Methods: The study was a pre-post study conducted from March 2020 till September 2020. It included the pre-education phase P0; a retrospective phase where all the prescriptions for COVID-19 patients were revised by the clinical pharmacy team and prescription errors were extracted. Followed by a one-month period; the clinical pharmacy team prepared educational materials in the form of posters and flyers covering all prescribing errors detected to be delivered to physicians. Then, the post-education phase P1; all prescriptions were monitored by the clinical pharmacy team to assess the rate and types of prescribing errors and the data extracted was compared to that from pre-education phase., Results: The number of prescribing errors in P0 phase was 1054 while it was only 148 in P1 Phase. The clinical pharmacy team implemented education phase helped to significantly reduce the prescribing errors from 14.7/1000 patient-days in the P0 phase to 2.56/1000 patient-days in the P1 phase (p-value <0.001)., Conclusion: The clinical pharmacist significantly reduced the rate of prescribing errors in patients with COVID-19 which emphasizes the great role of clinical pharmacists' interventions in the optimization of prescribing in these stressful conditions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Mass vaccination is the most effective strategy against the spread of the COVID-19 pandemic. However, concerns about the vaccine's safety and effectiveness remain a huge obstacle to vaccine acceptance. The aim of the present study was to explore different COVID-19 vaccine outcomes, including the development of adverse events and/or COVID-19 infection following COVID-19 vaccination. A cross-sectional study was conducted by distributing an online survey targeting staff and students at the British university in Egypt. A total of 637 participants fully completed the survey. Of these, 609 (95.6%) participants received the COVID-19 vaccine. Only 12.6% of the total vaccinated participants reported COVID-19 infection after vaccination. Of these, only 2.8% reported having severe symptoms while 9.9% reported having no or mild symptoms. The most common side effects reported after the first vs. second dose were headache (36.3% vs. 14.6%), tiredness and fatigue (26.9% vs. 10.7), and fever (25.6% vs. 6.7%). In conclusion, the present study explored different COVID-19 vaccine outcomes where the overall incidence of side effects is higher after the first dose than after the second dose. There is a relationship between COVID-19 vaccines' side effects and gastrointestinal disorders, gender, and the type of COVID-19 vaccine. Post-vaccination symptoms were more frequently reported in women compared to men and more frequent with viral vector vaccines compared to other types. The effectiveness of different types of COVID-19 vaccines was confirmed by the lower incidence rate of post-vaccination COVID-19 infection.

Pediatric populations from lower-income countries may experience a higher incidence of zinc deficiency, which may cause physical and neurological dysfunctions. This case control study aims to assess different levels of zinc between malnourished and well-nourished children. Our study included 108 participants, all children less than 12 years of age. Out of the 108, 54 were malnourished children (cases), while 54 were well nourished (control group) and were screened for zinc deficiencies. Zinc deficiencies were 4 times more common in malnourished cases than in controls (OR: 3.89 95% CI: 1.1-14.9) with median value of zinc in cases being 91.69 and that of controls was 117.6. Our findings indicate significant deficiencies in malnourished children as compared to well-nourished children. Additionally, our findings support literature surveyed that suggest dietary changes alone would not be able to replenish zinc levels in children., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Ulipristal acetate (UPA) is effective in the treatment of uterine fibroids. However, its clinical use is hampered by the development of pathologic progesterone receptor modulator-associated endometrial changes (PAECs). The current study was designed to test the hypothesis that UPA-induced PAECs are associated with deranged expression of some metabolic genes. In addition, metformin can mitigate UPA-induced PAECs through modulating the expression of these genes. In the present study, twenty-eight female non-pregnant, nulligravid Wistar rats were treated with UPA (0.1 mg/kg/day, intragastric) and/or metformin (50 mg/kg/day, intragastric) for 8 weeks. Our results demonstrated that co-treatment with metformin significantly reduced UPA-induced PAECs. In addition, co-treatment with metformin and UPA was associated with significant increase in the Bax and significant reduction in Bcl-2, PCNA, Cyclin-D1and ER-α as compared to treatment with UPA alone. Furthermore, treatment with UPA alone was associated with deranged expression of 3-phosphoglycerate dehydrogenase (3-PHGDH), glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT), fatty acid synthase (FAS) and CD36. Most importantly, co-treatment with metformin markedly reduced UPA-induced altered expression of these metabolic genes in endometrial tissues. In conclusion, UPA-induced PAECs are associated with altered expression of genes involved in cell proliferation, apoptosis, estrogen receptor, glucose metabolism and lipid metabolism. Co-treatment with metformin abrogated UPA-induced PAECs most likely through the modulation of the expression of these genes.

Serum miRNAs (miRs) have gained consideration as encouraging molecular markers for cancer diagnosis and prediction of prognosis. The authors aimed to identify the exact role of miR-17-5p, miR-125b, and miR-221 among glioblastoma multiforme (GBM) patients before and after standard treatment, and correlate their expression with survival pattern. The study included 25 GBM patients and 20 healthy controls. Serum miR-17-5p, miR-125b, and miR-221 expression were analyzed before and after treatment using quantitative real-time polymerase chain reaction (qPCR). The diagnostic efficacy for the tested miRs was evaluated using the receiver operating characteristic (ROC) curve, and the relation of miRs expression versus clinical criteria for GBM was assessed. Patients' survival patterns were examined versus miRs expression levels. A significant difference was reported between miRs expression among the enrolled individuals. Both miR-17-5p and miR-221 reported significant elevations in GBM patients who: are above 60 years old, underwent biopsy resection, have a non-frontal lesion, with tumor size above 5 cm, and with performance status equals 2 according to the Eastern Cooperative Oncology Group (ECOG) Performance Status. With regard to miR-125b, a significant difference was detected according to surgery strategy, primary lesion of the tumor, and ECOG status. MiRs levels were significantly decreased for GBM patients after treatment. Survival patterns demonstrated an increase in miR-17-5p, miR-125b, and miR-221 in GBM patients with worse progression-free survival and among those with worse overall survival. Detection of serum miR-17-5p, miR-125b, and miR-221 aids in the prediction of prognosis and response to treatment strategy for GBM patients.

Objective: We aimed to assess the incidence, management, and visual outcome of acute endophthalmitis in patients following intravitreal bevacizumab injection in a tertiary care setup. It was a prospective and single-center database study., Patients and Methods: Patients receiving intravitreal bevacizumab injections for various retinal vascular diseases from January 2019 to September 2020. The study was carried out at the Institute of Ophthalmology, Mayo Hospital, Lahore over a period of 21 months. Preformed bevacizumab injections were administered intravitreally on patients of various retinal vascular diseases under strict aseptic measures and by following the standard guidelines. The patients were put on follow-ups for a duration of four weeks to see any signs of acute endophthalmitis., Results: A total of 3051 injections were administered in 1104 eyes of 743 patients during the above-mentioned study period. The incidence of endophthalmitis was found to be 0.0328% (1/3051). The patient, who developed endophthalmitis, was treated with topical and intravitreal antibiotics followed by vitrectomy that resulted in clinically significant improvement in vision., Conclusion: Incidence of acute endophthalmitis following intravitreal bevacizumab injection was low and could be prevented by taking strict aseptic measures during administration., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ahmed et al.)

Extraordinary actions have been implemented in an effort to control the rapid spread of the ongoing COVID-19 epidemic in Egypt. People's adherence to control measures is influenced by their knowledge, attitudes and practices towards the disease. Therefore, in the present study we assessed pharmacy senior students' knowledge, attitudes and practices towards the COVID-19 pandemic. An online questionnaire was created and it consisted of 12 questions testing their knowledge about COVID-19 clinical characteristics, transmission routes and prevention and control steps. Among senior pharmacy students (n = 238), 70% were females and 63% were living in greater Cairo. Their main source of information included social media (70%), published articles (48%) and television (48%). The overall correct knowledge score was 83%. Most of the students displayed a good COVID-19 knowledge level (72.5% of the students). The students were least informed when trying to answer questions about hyper-coagulation, as a major cause for death in patients with severe COVID-19, and about the timings on the necessity to wear masks. Assessment of students' attitudes and practices towards COVID-19 reflected that 87% of them were confident that health care teams and scientists could win the fight against the virus. In addition, 72% of students agreed that COVID-19 will be controlled successfully. The greater the students' knowledge, the more confident they felt that COVID-19 will be controlled successfully (OR 2.2, 95% confidence interval [CI] 1.03-4.72). Good behavioral practice towards COVID-19 control was confirmed when 87% of students answered that they didn't go out to any crowded place. Females were 3.6 times (95% confidence interval [CI] 1.03-3.11) more likely to avoid going out than males. Bad behavioral practice became evident when approximately 50% of students admitted that they did not wear masks when they left their house. Therefore, more efforts should be taken to protect future pharmacists from this pandemic.

Recently, experimental studies demonstrated that 2-methoxyestradiol (2ME2) ameliorates high fat diet (HFD)-induced obesity and restores insulin sensitivity. However, the mechanisms underlying these effects are unveiled yet. The current study was undertaken to test the hypothesis that 2ME2 exerts its effects by modulating adipose tissue macrophages (ATMs) accumulation, polarization and immunophenotypes. The experiment was carried out in males Wistar rats (n = 28) for 13 consecutive weeks. In HFD-fed group; body weight, glucose intolerance, serum insulin, HOMA-IR, lipid profile and adipose tissue (AT) weight were significantly higher compared to normal standard diet (NSD)- fed rats. However, treatment of HFD-fed rats with 2ME2 (200 μg/kg/day; i.p. from the beginning of the 9th week) resulted in significant enhancements in all these parameters as compared to HFD-fed rats. Treatment with 2ME2 was associated with a significant reduction in macrophage infiltration in the AT, shifting macrophage polarization towards M2 phenotype as indicated by significant decrease in the expression of pro-inflammatory M1 macrophages markers (IL-6, IL-1β, CD11c and iNOS) and concurrent significant increase in the M2 anti-inflammatory macrophage markers (Arginase 1 and IL-10). 2ME2 ameliorates HFD-induced obesity and glucose intolerance through inhibition of ATM infiltration in AT and shifting macrophage polarization from pro-inflammatory M1 to M2 anti-inflammatory phenotypes., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Leaves from Eugenia uniflora , the red Brazilian cherry, have a high content of flavonoids that possess several biological effects such as anti-inflammatory, antioxidant, and antidiabetic activities. However, their influence on carbon tetrachloride (CCl 4 )-induced acute liver injury in rats has not been investigated. In the current study, a bioguided fractionation assay revealed that the ethyl acetate fraction (EAF) of Eugenia uniflora is the safest and most active fraction. LC-MS analysis of the ethyl acetate fraction revealed 22 secondary metabolites, mainly myricetin and quercetin derivatives. EAF did not show toxicity up to 2000 mg/kg, and exhibited antioxidant activities in vitro in DPPH assay with IC 50 of 3.35 µg/mL. Additionally, EAF exhibited substantial antioxidant activities in vivo by counteracting the oxidative damage of the prooxidant juglone [80 µM] in Caenorhabditis elegans model organism and increased its survival rate in a dose-dependent fashion through the DAF-16/Foxo pathway. Furthermore, the hepatoprotective activity of EAF (200 mg/kg against carbon tetrachloride (CCl 4 ) intoxicated male Wistar rats was assessed. EAF significantly inhibited CCl 4 -induced elevation of alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TB), total cholesterol (TC), and triglycerides (TG), in the blood serum and prevented lipid peroxidation and restored superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissues. The observed hepatoprotective effects of EAF, which were supported by histopathological observations as pretreatment with EAF, effectively attenuated the CCl 4 -induced histopathological changes. In conclusion, EAF of Eugenia uniflora leaves has substantial hepatoprotective activities against CCl 4 induced acute liver injury in rats due to its antioxidant activity.

Purpose: We aimed to assess normal values of hand grip strength in preschool children and to determine their correlations with anthropometric measurements., Methods: According to (Indira and Rajeswari, 2015) a pilot study was performed before the current study in order to confirm the variation in values of grip strength in age ranged from 3-6 years old. Therefore, ten children from each age group was assigned and it showed a significant changes in the measurements of grip strength corresponding to the age. Thus, it was important to assign them to three groups based on age so the first group from 3 to 4 years old, the second group from 4 to 5 years old, the third group from 5 to 6 years old., Results: The study included 636 normal preschool-age children. Grip strengths with the dominant hand were 26.87 ± 6.77 kPa, 29.78 ± 8.43 kPa, and 38.04 ± 8.55 kPa in the 3-4, 4-5, and 5-6 years age groups, respectively. With the non-dominant hand, grip strengths were 25.03 ± 7.19 kPa, 28.13 ± 8.43 kPa, and 33.74 ± 8.14 kPa, respectively. In the 3-4 years group, there were negative significant correlations between grip strength of the dominant hand and forearm circumference (FC) or hand circumference (HC). However, we found a positive non-significant correlation with hand length (HL). Grip strength of the non-dominant hand showed a negative significant correlation with FC, a positive non-significant correlation with HC, and a positive significant correlation with HL. Grip strength of both dominant and non-dominant hands in the 4-5 years group showed moderately positive significant correlations with all anthropometric measurements. Grip strength of both dominant and non-dominant hands in the 5-6 years group showed weak positive significant correlations with FC and moderate positive significant correlations with HC and HL., Conclusion: This study established normal values of grip strength and demonstrated positive significant correlations between grip strength and FC, HC, and HL with increasing age in preschool children., (© 2020 The Authors.)

Venous thromboembolism (VTE) is a major health problem in patients with cancer. Cancer augments thrombosis and causes cancer-associated thrombosis (CAT) and vice versa thrombosis amplifies cancer progression, termed thrombosis-associated cancer (TAC). Risk factors that lead to CAT and TAC include cancer type, chemotherapy, radiotherapy, hormonal therapy, anti-angiogenesis therapy, surgery, or supportive therapy with hematopoietic growth factors. There are some other factors that have an effect on CAT and TAC such as tissue factor, neutrophil extracellular traps (NETs) released in response to cancer, cancer procoagulant, and cytokines. Oncogenes, estrogen hormone, and thyroid hormone with its integrin αvβ3 receptor promote angiogenesis. Lastly, patient-related factors can play a role in development of thrombosis in cancer. Low-molecular-weight heparin and direct oral anticoagulants (DOACs) are used in VTE prophylaxis and treatment rather than vitamin K antagonist. Now, there are new directions for potential management of VTE in patients with cancer such as euthyroid, blockade of thyroid hormone receptor on integrin αvβ3, sulfated non-anticoagulant heparin, inhibition of NETs and stratifying low and high-risk patients with significant bleeding problems with DOACs.

Objectives: Multiple myeloma (MM) is a malignant disorder characterized by proliferation of a single clone of plasma cells derived from β-cells in the bone marrow. It is the second most common adult hematological malignancy, and it is the most common cancer with skeletal components as its primary site. The purpose of the retrospective study was to assess the hematological profile, different biochemical parameters, and the serum electrophoresis patterns of patients consistent with clinical symptoms of multiple myeloma., Materials and Methods: A retrospective study of 99 patients diagnosed with multiple myeloma (MM) was carried out at the Hematology Department of Benghazi Medical Center (BMC) in Benghazi, Libya from January 2010 to March 2017. Information on the laboratory features was obtained at presentation (before treatment) and analyzed., Results: Of the 99 study detected cases of multiple myeloma at diagnosis, 14% were younger than 45 years and 35% were 70 years or older. The mean age was 61 years, of which 42 (42.4%) were males and 57 (57.6%) were females. Anemia was seen in roughly half of the diagnosed cases, most of which was normocytic normochromic anemia. High erythrocyte sedimentation rate (ESR) was seen in 65.3% of cases and increased neutrophil-to-lymphocyte ratio (NLR) was seen in 29.7%. Other abnormal serum levels with regard to the cases are as follows: hyperproteinemia in 30%, low albumin/globulin (A/G) ratio in 54.2%, hypercalcemia in 11.3%, serum creatinine level of >2.0 mg/dL in 27.2% cases, and increased β2-microglobulin in 67%. Serum protein electrophoresis revealed a localized band in 70.8% of patients. Monoclonal bands were seen in 44 cases (95.7%) and a bi-clonal pattern in two cases (4.3%), 78% of M-band showed migration to γ-region of electrophoretogram and 18% to β-region. Hypogammaglobulinemia was detected in 32.8% and hypergammaglobulinemia was detected in 49.2%. Of the hypergammaglobulinemia, 18.1% showed polyclonal gammaglobulinemia. Bence Jones protein was positive in 50% cases. IgG was the commonest type, followed by IgA then light chain. In 26.5% of cases, the only diagnosis was multiple myeloma. Light chain multiple myeloma patients had high α2 globulin concentration and normal A/G ratio. Apart from the diagnosis of multiple myeloma, a number of cases had varying diagnoses including the following: 4% non-secretory myeloma, 2% amyloidosis with nephrotic syndrome, 2% liver cirrhosis, and 18.2% renal failure. Most patients presented in stage III., Conclusions: The presence of anemia, high ESR, and low A/G ratio in elderly patients should alert the clinician to investigate along the lines of multiple myeloma. In this study, unfortunately, the laboratory investigations were insufficient for diagnosing this disease in most patients. Most patients were diagnosed at stage III. Absence of paraprotein in the blood does not exclude multiple myeloma. It was further observed that most of the patients presented with significant renal damage, which attributed to hyperuricemia, hypercalcemia, or high NLR. Multiple causes of renal failure occur in myeloma and are often present at the time of diagnosis., Competing Interests: The authors have declared that no competing interests exist.

The greater genomic conservation between humans and non-human primates (NHP) enables target validation studies for developing of therapeutic strategies for human diseases. Together with predicting activity and potential adverse clinical signs, the inclusion of NHP testing bequeaths to efficacy models for dose titration and pharmacodynamic effects. We have used lipid nanoparticle encapsulated siRNA to silence ApoB in the liver and assessed the phenotypic effects on serum lipids with various levels of hepatic ApoB mRNA knockdown in healthy lean cynomolgus monkeys. ApoB siRNA dosed animals demonstrated significant reductions of hepatic ApoB mRNA and serum APOB protein, with a substantial lowering of plasma lipid levels without obvious signs of toxicity. Microarray based assessment of ApoB siRNA mediated effects revealed a number of differentially expressed genes which mapped onto biological pathways and processes related to lipid and cholesterol metabolism. Furthermore, we identified potential targets and cellular effects that could be studied for therapeutic benchmarking of APOB mediated effects. The network of ApoB regulated genes should be of significance for the understanding and development of novel hypercholesterolemia therapies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Numerous studies have demonstrated that autophagy plays a vital role in maintaining cellular homeostasis. Interestingly, several anticancer agents were found to exert their anticancer effects by triggering autophagy. Emerging data suggest that autophagy represents a novel mechanism that can be exploited for therapeutic benefit. Pharmacologically active natural compounds such as those from marine, terrestrial plants and animals represent a promising resource for novel anticancer drugs. There are several prominent examples from the past proving the success of natural products and derivatives exhibiting anticancer activity. Helenalin, a sesquiterpene lactone has been demonstrated to have potent anti-inflammatory and antitumor activity. Albeit previous studies demonstrating helenalin's multi modal action on cellular proliferative and apoptosis, the mechanisms underlying its action are largely unexplained., Methods: To deduce the mechanistic action of helenalin, cancer cells were treated with the drug at various concentrations and time intervals. Using western blot, FACS analysis, overexpression and knockdown studies, cellular signaling pathways were interrogated focusing on apoptosis and autophagy markers., Results: We show here that helenalin induces sub-G1 arrest, apoptosis, caspase cleavage and increases the levels of the autophagic markers. Suppression of caspase cleavage by the pan caspase inhibitor, Z-VAD-fmk, suppressed induction of LC3-B and Atg12 and reduced autophagic cell death, indicating caspase activity was essential for autophagic cell death induced by helenalin. Additionally, helenalin suppressed NF-κB p65 expression in a dose and time dependent manner. Exogenous overexpression of p65 was accompanied by reduced levels of cell death whereas siRNA mediated suppression led to augmented levels of caspase cleavage, autophagic cell death markers and increased cell death., Conclusions: Taken together, these results show that helenalin mediated autophagic cell death entails inhibition of NF-κB p65, thus providing a promising approach for the treatment of cancers with aberrant activation of the NF-κB pathway.

An essential oil extract, derived from the rhizome of Curcuma wenyujin (CWE), possesses antioxidative, antimicrobial, and anti-inflammatory properties. However, it remains unknown how exactly CWE inhibits tumor growth. In this study, using human cervical cancer HeLa cells, the authors postulated that CWE has the ability to inhibit tumor growth. The study shows that CWE dose-dependently suppressed colony formation and inhibited the proliferation of HeLa cells through blockade of cell cycle progression at G1 phase and apoptosis. CWE-induced G1 arrest was associated with retinoblastoma protein dephosphorylation and reduced amounts of cyclins D1 and D3, and cyclin-dependent kinase 4 and 6 proteins. CWE treatment resulted in apoptosis in HeLa cells as evidenced by morphological changes, caspase activation and PARP cleavage, which can be reversed by a pan-caspase inhibitor. It was observed that CWE treatment activated the mitochondrial apoptotic pathway indicated by a decrease in Mcl-1 and Bcl-xL levels, resulting in mitochondrial membrane potential loss and caspases 9 activation. CWE-treated cells displayed reduced PTEN, AKT, and STAT3 phosphorylation and downregulation of NFkappaB signaling, providing a mechanism for the G1 arrest and apoptosis observed. Furthermore, CWE inhibited tumor growth of HeLa in a xenograft mouse tumor model, suggesting that CWE inhibited tumorigenesis by inhibiting cell proliferation and inducing apoptosis. These findings are the first to reveal the molecular basis for the anticervical cancer action of CWE. The results suggest that CWE could be developed as a drug for the management of cervical cancer.

Kruppel-like factor 4 (KLF4) belongs to a family of evolutionarily conserved zinc finger-containing transcription factors. It has been shown to mediate self renewal and pluripotency, regulate adipogenesis and play a critical role in monocyte differentiation. KLF4 is also highly expressed in squamous cell carcinomas and in 70% of all primary human breast cancers, suggesting a putative role for KLF4 as being an oncogene and as an antiapoptotic factor. However, the mechanism of this regulation remains unclear. Here, we show that KLF4 is induced during histone deacetylase inhibitor treatment, and regulates the extrinsic apoptosis pathway by inhibiting caspase cleavage. In addition, KLF4 binds to the p57(Kip2) promoter and transcriptionally upregulates its expression, which in turn inhibits the stress activated protein kinase cascade and c-Jun phosphorylation. Our findings indicate that in cancer cells that express high levels of KLF4 may be refractory to HDACi treatment. Results of our study demonstrate an unexpected antiapoptotic function of KLF4, and suggest an important cell fate determinant following histone deacetylase inhibitor induced apoptosis.

Objective: The purpose of this open-label study was to assess the effectiveness and tolerability of levetiracetam (LEV) in the treatment of patients with lower lumbar radiculopathy diagnosed by clinical presentation, physical examination, and electrodiagnostics., Design: Open-label, forced titration, prospective cohort intent-to-treat analysis., Setting: Major teaching hospital., Patients: Participants were recruited from the university pain clinic and through referrals from the community. Subjects were eligible to participate if they (1) were older than 18 years, (2) had leg pain greater than back pain, (3) had been symptomatic for 6 months and <5 years, (3) had a baseline visual analog scale of at least 6 on the 0-10 scale, (4) had undergone lumbar spine magnetic resonance imaging within the last 12 months that showed no surgically correctable etiology for their radicular symptoms, and (5) had undergone electrodiagnostics that was positive for lumbar radiculopathy (L4, L5, or S1 nerve roots). Twenty-six patients were enrolled, and 24 (92.3%) completed the study., Interventions: Patients initially received LEV 500 mg twice a day for 2 weeks. Dosages were then increased to 750 mg twice day for 2 weeks, and then to 1500 mg twice a day for the remainder of the study. Patients were observed for 8 weeks after reaching the maximum dose., Main Outcome Measurements: Treatment effectiveness was assessed with the use of biweekly brief pain inventory and patient global assessment scales. Frequency and severity of adverse events were recorded., Results: The mean biweekly worst and average pain scores decreased from 7.17 and 6.27 at baseline to 4.2 and 3.9, respectively, at week 12 (P < or = .001). Improvements were reported in general activity, ability to walk, mood, and relationship with people. Side effects consisted of sedation/drowsiness (46%), gastrointestinal upset (23%), headache (19%), blurred vision (15%), weakness/fatigue (11%), and dyscoordination (11%)., Conclusions: This study showed that LEV might be a well-tolerated and effective treatment for lumbar radiculopathy. A large randomized placebo-controlled trial is recommended and comparative studies with alternative agents should be sought.

Background: The pathophysiology of obesity and type 2 diabetes mellitus is associated with abnormalities in endocrine signaling in adipose tissue and one of the key signaling affectors operative in these disorders is the nuclear hormone transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma has pleiotropic functions affecting a wide range of fundamental biological processes including the regulation of genes that modulate insulin sensitivity, adipocyte differentiation, inflammation and atherosclerosis. To date, only a limited number of direct targets for PPARgamma have been identified through research using the well established pre-adipogenic cell line, 3T3-L1. In order to obtain a genome-wide view of PPARgamma binding sites, we applied the pair end-tagging technology (ChIP-PET) to map PPARgamma binding sites in 3T3-L1 preadipocyte cells., Methodology/principal Findings: Coupling gene expression profile analysis with ChIP-PET, we identified in a genome-wide manner over 7700 DNA binding sites of the transcription factor PPARgamma and its heterodimeric partner RXR during the course of adipocyte differentiation. Our validation studies prove that the identified sites are bona fide binding sites for both PPARgamma and RXR and that they are functionally capable of driving PPARgamma specific transcription. Our results strongly indicate that PPARgamma is the predominant heterodimerization partner for RXR during late stages of adipocyte differentiation. Additionally, we find that PPARgamma/RXR association is enriched within the proximity of the 5' region of the transcription start site and this association is significantly associated with transcriptional up-regulation of genes involved in fatty acid and lipid metabolism confirming the role of PPARgamma as the master transcriptional regulator of adipogenesis. Evolutionary conservation analysis of these binding sites is greater when adjacent to up-regulated genes than down-regulated genes, suggesting the primordial function of PPARgamma/RXR is in the induction of genes. Our functional validations resulted in identifying novel PPARgamma direct targets that have not been previously reported to promote adipogenic differentiation., Conclusions/significance: We have identified in a genome-wide manner the binding sites of PPARgamma and RXR during the course of adipogenic differentiation in 3T3L1 cells, and provide an important resource for the study of PPARgamma function in the context of adipocyte differentiation.

Although Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interference technology, we show that cells deficient in KLF5 have increased sensitivity to DNA damage, regardless of p53 status. Both p53 and p53-dependent factors are unaffected by KLF5 depletion. Instead, the apoptotic phenotype consequent to damage is associated with reduced bad phosphorylation, and downregulation of Pim1. Consistently, transfection of wild-type Pim1 is sufficient to rescue this phenotype. Previous data have shown a number of putative Sp1-binding consensus sequences on the Pim1 promoter. Remarkably, chromatin immunoprecipitation studies show that KLF5 binds to the Pim1 promoter, and that binding increases soon after damage. These results identify a novel, p53-independent apoptotic pathway through which KLF5 functions in response to DNA damage. Therapeutic deregulation of this pathway could be used to modulate chemosensitivity.

A sensitive and highly selective spectrophotometric method is described for the determination of cyanide. It is based on a reaction of cyanide with aquacyanocobyrinic acid heptamethyl ester (ACCbs) reagent (orange color) at pH 9.5 to give dicyanocobester (DCCbs) (violet color). The increase of the absorption bands of the reaction product at 368 and 580nm and the decrease of the reagent band at 353nm are linearly proportional to the cyanide concentration. The method is used in static mode for determining cyanide over the concentration range 0.04-1.20mugml(-1) with a detection limit of 0.02mugml(-1) and for hydrodynamic analysis of 0.4-5.2mugml(-1) cyanide. Application for batch and flow injection monitoring of cyanide in electroplating wastewater samples gives results agree within+/-1.2% with those obtained by the standard potentiometry using the cyanide ion selective electrode. The method is practically free from interferences by PO(4)(3-), NO(3)(-), NO(2)(-), SO(4)(2-), F(-), Cl(-), Br(-), I(-), S(2-) and SCN(-) ions and gives results with average recoveries of 97.6-99.2%. Advantages offered by using ACCbs as a chromogen for cyanide assay are: (i) high selectivity and sensitivity of the coordination site of the reagent towards cyanide ion; (ii) fast reaction, since legation takes place at the axial position of the reagent; (iii) good solubility and stability of the reagent in aqueous solutions over a wide pH range; (iv) high stability of the reagent (ACCbs) and the colored complex product (DCCbs) and (v) possible absorbance measurements at three different wavelengths.

Substitution reactions of the complexes [Pd(bpma)(H2O)]2+, [Pd(bpma)Cl]+, [Pd(dien)(H2O)]2+ and [Pd(dien)Cl]+, where bpma = bis(2-pyridylmethyl)amine and dien = diethylentriamine or 1,5-diamino-3-azapentane, with some nitrogen-donor ligands such as triazole, pyrazole, pyrimidine, pyrazine and pyridazine, were studied in an aqueous 0.10 M NaClO4 at pH 2.8 using variable-temperature and -pressure stopped-flow spectrophotometry. The second-order rate constants indicate that the Pd(II) complexes of bpma, viz. [Pd(bpma)(H2O)]2+ and [Pd(bpma)Cl]+, are more reactive than the complexes of dien, viz. [Pd(dien)(H2O)]2+ and [Pd(dien)Cl]+. Also, the aqua complexes, [Pd(bpma)(H2O)]2+ and [Pd(dien)(H2O)]2+, are much more reactive than the corresponding chloro complexes. The most reactive nucleophile of the five-membered rings is triazole and for the six-membered rings the most reactive one is pyridazine. Activation parameters were determined for all reactions and the negative entropies and volumes of activation (Delta S++, Delta V++) support an associative ligand substitution mechanism. The crystal structure of [Pd(bpma)(H2O)](ClO4)2.2H2O was determined by X-ray diffraction. Crystals are monoclinic with the space group P2(1)/c. The coordination geometry of [Pd(bpma)(H2O)]2+ is distorted square-planar. The Pd-N (central) bond distance, 1.958(5) A, is shorter than the other two Pd-N distances, 2.007(5) and 2.009(5) A. The Pd-O distance is 2.043(5) A.

A novel spectrophotometric assay method for batch and flow injection determination of sulfite in beverages is described. The method involves a reaction with diaquacobyrinic acid heptamethyl ester (diaquacobester, DACbs) in acetate buffer of pH 3 to form a highly stable sulfite cobester complex (SO3Cbs). In the absence of sulfite, the reagent displays three absorption maxima at 349, 409 and 525 nm. Addition of sulfite is associated with the development of a new absorption band at 313 nm, an increase in the intensity of the band at 425 nm and a decrease in the absorbance of the bands at 349 and 525 nm. Variations of the absorptions at 313, 349, 425 and 525 nm are linearly proportional to sulfite concentrations over the range of 0.05-25 microg ml(-1)with a detection limit of 0.01-0.2 microg ml(-1). Negligible interferences are caused by most common ions. Validation of the method according to the quality assurance standards shows suitability for quality control assessment of sulfite in complex matrices without prior treatment. The method has the advantages of high selectivity, good sensitivity, fast reaction, high stability of the reagent and reaction product and absorbance measurements at four different wavelengths in the same run. The method is successfully applied to determine the sulfite contents of some beverages. The results compare fairly well with data obtained using the standard method.

A detailed kinetic study of the substitution behavior of the seven-coordinate [Fe(dapsox)(L)2]ClO4 complex (H(2)dapsox = 2,6-diacetylpyridine-bis(semioxamazide), L = solvent or its deprotonated form) with thiocyanate as a function of the thiocyanate concentration, temperature, and pressure was undertaken in protic (EtOH and acidified EtOH and MeOH) and aprotic (DMSO) organic solvents. The lability and substitution mechanism depend strongly on the selected solvent (i.e., on solvolytic and protolytic processes). In the case of alcoholic solutions, substitution of both solvent molecules by thiocyanate could be observed, whereas in DMSO only one substitution step occurred. For both substitution steps, [Fe(dapsox)(L)2]ClO4 shows similar mechanistic behavior in methanol and ethanol, which is best reflected by the values of the activation volumes (MeOH DeltaV(I) = +15.0 +/- 0.3 cm(3) mol(-1), DeltaV(II) = +12.0 +/- 0.2 cm(3) mol(-1); EtOH DeltaV(I) = +15.8 +/- 0.7 cm(3) mol(-1), DeltaV(II) = +11.1 +/- 0.5 cm(3) mol(-1)). On the basis of the reported activation parameters, a dissociative (D) mechanism for the first substitution step and a D or dissociative interchange (I(d)) mechanism for the second substitution step are suggested for the reaction in MeOH and EtOH. This is consistent with the predominant existence of alcoxo [Fe(dapsox)(ROH)(OR)] species in alcoholic solutions. In comparison, the activation parameters for the substitution of the aqua-hydroxo [Fe(dapsox)(H2O)(OH)] complex by thiocyanate at pH 5.1 in MES were determined to be DeltaH = 72 +/- 3 kJ mol(-1), DeltaS = +38 +/- 11 J K(-1) mol(-1), and DeltaV = -3.0 +/- 0.1 cm(3) mol(-1), and the operation of a dissociative interchange mechanism was suggested, taking the effect of pressure on the employed buffer into account. The addition of triflic acid to the alcoholic solutions ([HOTf] = 10(-3) and 10(-2) M to MeOH and EtOH, respectively) resulted in a drastic changeover in mechanism for the first substitution step, for which an associative interchange (Ia) mechanism is suggested, on the basis of the activation parameters obtained for both the forward and reverse reactions and the corresponding volume profile. The second substitution step remained to proceed through an I(d) or D mechanism (acidified MeOH DeltaV(II) = +9.2 +/- 0.2 cm(3) mol(-1); acidified EtOH DeltaV(II) = +10.2 +/- 0.2 cm(3) mol(-1)). The first substitution reaction in DMSO was found to be slowed by several orders of magnitude and to follow an associative interchange mechanism (DeltaS = -50 +/- 9 J K(-1) mol(-1), DeltaV(I) = -1.0 +/- 0.5 cm(3) mol(-1)), making DMSO a suitable solvent for monitoring substitution processes that are extremely fast in aqueous solution.

The interaction of [Ru(III)(edta)(H(2)O)](-) with a series of selected thiols having extra functional groups was investigated potentiometrically and kinetically. The pK(a) values of the uncoordinated carboxylic acid group and coordinated water molecule are 3.12 and 7.41, respectively, in aqueous solution at 25 degrees C and 0.1 M ionic strength. The formation constants of the complexes were determined in the pH range 3-9, and the concentration distribution of the various complex species was evaluated as a function of pH. The effect of dioxane on the pK(a) values of [Ru(III)(Hedta)(H(2)O)] and the formation constants of the corresponding thiol complexes is presented. The study also provides mechanistic information on the reaction of [Ru(III)(edta)(H(2)O)](-) with the thiols. The low values of DeltaH(not equal) and negative values of DeltaS(not equal) and DeltaV(not equal) for the substitution reactions of [Ru(III)(edta)(H(2)O)](-) clearly support the associative character of the substitution process.

After receiving a continuous spinal anesthetic for labor following an inadvertent dural puncture with a 17-gauge epidural needle, a morbidly obese parturient underwent post-partum tubal ligation 12 h after vaginal delivery. The patient received a total of 2 mL of 0.75% hyperbaric bupivacaine for the surgery. In response to moderate hypertension the patient received intravenous labetalol hydrochloride 20 mg. She subsequently was inadvertently administered approximately 15 mg of labetalol through the spinal catheter. The spinal catheter was removed immediately after the procedure. She suffered no apparent adverse neurologic effects.

Ligand substitution reactions of the vitamin B12 analog cyanoimidazolylcobamide, CN(Im)Cbl, with cyanide were studied. Cyanide substitutes imidazole (Im) in the alpha-position more slowly than it substitutes dimethylbenzimidazole in cyanocobalamin (vitamin B12). The kinetics of the displacement of Im by CN- showed saturation behaviour at high cyanide concentration; the limiting rate constant was found to be 0.0264 s(-1) at 25 degrees C and is characterized by the activation parameters: DeltaH(not =) = 111 +/- 2 kJ mol(-1), DeltaS(not =) = +97 +/- 6 J K(-1) mol(-1), and DeltaV(not =) = +9.3 +/- 0.3 cm3 mol(-1). These parameters are interpreted in terms of an I(d) mechanism. The equilibrium constant for the reaction of CN(Im)Cbl with CN- was found to be 861 +/- 75 M(-1), which is significantly less than that obtained for the reaction of cyanocobalamin with CN- (viz. 10(4) M(-1)). pKbase-off for the base-on/base-off equilibrium was determined spectrophotometrically and found to be 0.99 +/- 0.05, which is about 0.9 pH units higher than that obtained previously in the case of cyanocobalamin. In addition, the kinetics of the base-on/base-off reaction was studied using a pH-jump technique and the data obtained revealed evidence for an acid catalyzed reaction path. The results obtained in this study are discussed in reference to those reported previously for cyanocobalamin.

The kinetics of axial water substitution by azoles (pyrazole and 1,2,4-triazole) in three different cobaloximes, viz.trans-[Co(Hdmg)(2)(R)H(2)O] where Hdmg = dimethylglyoximate, R = PhCH(2), Et and CF(3)CH(2), were studied as a function of azole concentration, temperature and pressure in aqueous solution. The second order rate constants for the substitution of water in trans-[Co(Hdmg)(2)(R)H(2)O] for R = Et at pH 6.0, 25 degrees C and I= 0.1 M (NaClO(4)), were found to be 1309 and 1200 M(-1) s(-1) for pyrazole (Pz) and 1,2,4-triazole (Tz), respectively, and those obtained for R = PhCH(2) were found to be 755 and 691 M(-1) s(-1), respectively. The second order rate constants in the case of R = CF(3)CH(2) were found to be 0.358 and 0.348 M(-1) s(-1) for Pz and Tz, respectively. The relative order of reactivity for the different alkyls being Et > PhCH(2) > CF(3)CH(2). The activation parameters (DeltaH([not equal]), DeltaS([not equal]) and DeltaV([not equal])) obtained for these reactions were found to be in the range of 65-87 kJ mol(-1), 24-47 J mol(-1) K(-1) and 2.5-7.7 cm(3) mol(-1), respectively. These data suggest that an I(d) substitution mechanism operates where the azoles participate in the transition state.

alpha-, beta-, and gamma-Herpesviruses encode putative viral protein kinases. The herpes simplex virus UL13, varicella-zoster virus ORF47, and Epstein-Barr virus BGLF4 genes all show protein kinase domains in their protein sequences. Mutational analysis of these herpesviruses demonstrated that the viral kinase is important for optimal virus growth. Previous studies have shown that ORF36 of Kaposi's sarcoma herpesvirus (KSHV) has protein kinase activity and is autophosphorylated on serine. The gene for ORF36 is expressed during lytic growth of the virus and has been classified as a late gene. Inspection of the ORF36 sequence indicated potential motifs that could be involved in activation of cellular transcription factors. To analyze the function of ORF36, the cDNA for this viral gene was tagged with the FLAG epitope and inserted into an expression vector for mammalian cells. Transfection experiments in 293T and SLK cells demonstrated that expression of ORF36 resulted in phosphorylation of the c-Jun N-terminal kinase. Autophosphorylation of ORF36 is important for JNK activation because a mutation in the predicted catalytic domain of ORF36 blocked its ability to phosphorylate JNK. Western blot analysis, using phosphospecific antibodies, revealed that mitogen-activated kinases MKK4 and MKK7 were phosphorylated by ORF36 but not by the kinase-negative mutant. Binding experiments in transfected cells also demonstrated that both the wild type and kinase-negative mutant of ORF36 form a complex with JNK, MKK4, and MKK7. In addition, using a tetracycline-inducible Rta BCBL-1 cell line (TREx BCBL1-Rta), JNK was phosphorylated during lytic replication, and inhibition of JNK activation blocked late viral gene expression but not early viral gene expression. In summary, these studies demonstrate that KSHV ORF36 activates the JNK pathway; thus this cell signaling pathway may function in the KSHV life cycle by regulating viral and/or cellular transcription.

The kinetics of axial water substitution by cysteine in six different cobaloximes, viz.trans-RCo(Hdmg)(2)H(2)O, where Hdmg = dimethylglyoximate, R = cyclo-C(5)H(9) (c-P), CH(3)CH(2) (Et), CH(3) (Me), C(6)H(5)CH(2) (Bz), C(6)H(5) (Ph) and CF(3)CH(2), were studied as a function of cysteine concentration, temperature and pressure. It was found that cysteine substitutes the coordinated H(2)O molecule trans to the alkyl group with second order rate constants that follow the order of reactivity: c-P > Et > Bz > Me > Ph > CF(3)CH(2). Rate and activation parameters (Deltan H(++), Delta S(++) and Delta V(++)) enable the formulation of a reaction mechanism that can account for the substitution behaviour of the investigated alkylcobaloximes. In particular, a gradual mechanistic changeover from I(d) to I is observed along the series of R groups from c-P to CF(3)CH(2).

This Perspective reports the development of mechanistic insight over the past 6 years, on the substitution behaviour of cobalamins that contain a single Co-C bond. The effect of the alkyl group, located in the trans position, on the thermodynamic, kinetic and ground state trans effect, was studied in detail. The substitution reactions of different alkylcobalamins with CN- were investigated, the apparent mechanistic discrepancy reported for the co-enzyme B12 was resolved and a logical explanation could be offered. In addition, a complete picture of the effect of pressure on the UV-Vis spectra of different base-on and base-off cobalamins is presented, which clearly shows the role of the alkyl group in controlling the equilibrium between five- and six-coordinate species, and the possible participation of such species in the studied ligand substitution reactions. The kinetics of the base-on/base-off equilibration was studied for the first time using a pH-jump technique. All in all the novel mechanistic information adds to the understanding of the profound effect that a single metal-carbon bond can have on the reactivity of such Co(III) complexes.

A detailed mechanistic study of the substitution behavior of a 3d metal heptacoordinate complex, with a rare pentagonal-bipyramidal structure, was undertaken to resolve the solution chemistry of this system. The kinetics of the complex-formation reaction of [Fe(dapsox)(H(2)O)(2)]ClO(4) (H(2)dapsox = 2,6-diacetylpyridine-bis(semioxamazide)) with thiocyanate was studied as a function of thiocyanate concentration, pH, temperature, and pressure. The reaction proceeds in two steps, which are both base-catalyzed due to the formation of an aqua-hydroxo complex (pK(a1) = 5.78 +/- 0.04 and pK(a2) = 9.45 +/- 0.06 at 25 degrees C). Thiocyanate ions displace the first coordinated water molecule in a fast step, followed by a slower reaction in which the second thiocyanate ion coordinates trans to the N-bonded thiocyanate. At 25 degrees C and pH <4.5, only the first reaction step can be observed, and the kinetic parameters (pH 2.5: k(f(I)) = 2.6 +/- 0.1 M(-1) s(-1), DeltaH(#)(f(I)) = 62 +/- 3 kJ mol(-1), DeltaS(#)(f(I)) = -30 +/- 10 J K(-1) mol(-1), and DeltaV(#)(f(I)) = -2.5 +/- 0.2 cm(3) mol(-1)) suggest the operation of an I(a) mechanism. In the pH range 2.5 to 5.2 this reaction step involves the participation of both the diaqua and aqua-hydroxo complexes, for which the complex-formation rate constants were found to be 2.19 +/- 0.06 and 1172 +/- 22 M(-1) s(-1) at 25 degrees C, respectively. The more labile aqua-hydroxo complex is suggested to follow an I(d) or D substitution mechanism on the basis of the reported kinetic data. At pH > or =4.5, the second substitution step also can be monitored (pH 5.5 and 25 degrees C: k(f(II)) = 21.1 +/- 0.5 M(-1) s(-1), DeltaH(#)(f(II)) = 60 +/- 2 kJ mol(-1), DeltaS(#)(f(II)) = -19 +/- 6 J K(-1) mol(-1), and DeltaV(#)(f(II)) = +8.8 +/- 0.3 cm(3) mol(-1)), for which an I(d) or D mechanism is suggested. The results are discussed in terms of known structural parameters and in comparison to relevant structural and kinetic data from the literature.

Ligand substitution equilibria of different alkylcobalamins (RCbl, R = Me, CH(2)Br, CH(2)CF(3), CHF(2), CF(3)) with cyanide have been studied. It was found that CN(-) first substitutes the 5,6-dimethylbenzimidazole (Bzm) moiety in the alpha-position, followed by substitution of the alkyl group in the beta-position trans to Bzm. The formation constants K(CN) for the 1:1 cyanide adducts (R(CN)Cbl) were found to be 0.38 +/- 0.03, 0.43 +/- 0.03, and 123 +/- 9 M(-1) for R = Me, CH(2)Br, and CF(3), respectively. In the case of R = CH(2)CF(3), the 1:1 adduct decomposes in the dark with CN(-) to give (CN)(2)Cbl. The unfavorable formation constants for R = Me and CH(2)Br indicate the requirement of very high cyanide concentrations to produce the 1:1 complex, which cause the kinetics of the displacement of Bzm to be too fast to follow kinetically. The kinetics of the displacement of Bzm by CN(-) could be followed for R = CH(2)CF(3) and CF(3) to form CF(3)CH(2)(CN)Cbl and CF(3)(CN)Cbl, respectively, in the rate-determining step. Both reactions show saturation kinetics at high cyanide concentration, and the limiting rate constants are characterized by the activation parameters: R = CH(2)CF(3), DeltaH = 71 +/- 1 kJ mol(-1), DeltaS = -25 +/- 4 J K(-1) mol(-1), and DeltaV = +8.9 +/- 1.0 cm(3) mol(-1); R = CF(3), DeltaH = 77 +/- 3 kJ mol(-1), DeltaS = +44 +/- 11 J K(-1) mol(-1), and DeltaV = +14.8 +/- 0.8 cm(3) mol(-1), respectively. These parameters are interpreted in terms of an I(d) and D mechanism for R = CH(2)CF(3) and CF(3), respectively. The results of the study enable the formulation of a general mechanism that can account for the substitution behavior of all investigated alkylcobalamins including coenzyme B(12).

Background: Cannabinoid receptor agonists reverse nausea and vomiting produced by chemotherapy and radiation therapy in animals and humans but have not been tested against opioid-induced emesis. This study tests the hypothesis that cannabinoid receptor agonists will prevent opioid-induced vomiting., Methods: Twelve male ferrets were used. They weighed 1.2-1.6 kg at the beginning and 1.8-2.3 kg at the end of the experiments. All drugs were injected subcutaneously. WIN55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was administered 25 min before morphine. Retches and vomits were counted at 5-min intervals for 30 min after morphine injection., Results: Retching and vomiting responses increased with increasing morphine doses up to 1.0 mg/kg, above which the responses decreased. Previous administration of naloxone prevented morphine-induced retching and vomiting. WIN55,212-2 dose-dependently reduced retching and vomiting. The ED50 was 0.05 mg/kg for retches and 0.03 mg/kg for vomits. At 0.13 mg/kg, retching decreased by 76% and vomiting by 92%. AM251, a CB1 receptor-selective antagonist, blocked the antiemetic actions of WIN55,212-2, but AM630, a CB2 receptor-selective antagonist, did not., Conclusions: These results demonstrate that WIN55,212-2 prevents opioid-induced vomiting and suggest that the antiemetic activity of WIN55,212-2 occurs at CB1 receptors. This is consistent with findings that CB1 receptors are the predominant cannabinoid receptors in the central nervous system and that antiemetic effects of cannabinoids appear to be centrally mediated.

The ligand substitution reactions of trans-[CoIII(en)2(Me)H2O]2+, a simple model for coenzyme B12, were studied for cyanide and imidazole as entering nucleophiles. It was found that these nucleophiles displace the coordinated water molecule trans to the methyl group and form the six-coordinate complex trans-[Co(en)2(Me)L]. The complex-formation constants for cyanide and imidazole were found to be (8.3 +/- 0.7) x 10(4) and 24.5 +/- 2.2 M-1 at 10 and 12 degrees C, respectively. The second-order rate constants for the substitution of water were found to be (3.3 +/- 0.1) x 10(3) and 198 +/- 13 M-1 s-1 at 25 degrees C for cyanide and imidazole, respectively. From temperature and pressure dependence studies, the activation parameters delta H++, delta S++, and delta V++ for the reaction of trans-[CoIII(en)2(Me)H2O]2+ with cyanide were found to be 50 +/- 4 kJ mol-1, 0 +/- 16 J K-1 mol-1, and +7.0 +/- 0.6 cm3 mol-1, respectively, compared to 53 +/- 2 kJ mol-1, -22 +/- 7 J K-1 mol-1, and +4.7 +/- 0.1 cm3 mol-1 for the reaction with imidazole. On the basis of reported activation volumes, these reactions follow a dissociative mechanism in which the entering nucleophile could be weakly bound in the transition state.

Rhesus macaques infected with simian immunodeficiency virus (SIV) containing either a large nef deletion (SIVmac239Delta(152)nef) or interleukin-2 in place of nef developed high virus loads and progressed to simian AIDS. Viruses recovered from both juvenile and neonatal macaques with disease produced a novel truncated Nef protein, tNef. Viruses recovered from juvenile macaques infected with serially passaged virus expressing tNef exhibited a pathogenic phenotype. These findings demonstrated strong selective pressure to restore expression of a truncated Nef protein, and this reversion was linked to increased pathogenic potential in live attenuated SIV vaccines.

The reaction of coenzyme B(12) (adenosylcobalamin) with cyanide has been reinvestigated in detail using spectroscopic and kinetic techniques. It has been shown that this reaction proceeds in one kinetically observable step, contradicting previous findings, with rate-determining attack of the first cyanide (k = (7.4 +/- 0.1) x 10(-3) M(-1) s(-1), 25.0 degrees C, I = 1.0 M (NaClO(4))). The activation parameters were found to be DeltaH() = 53.0 +/- 0.6 kJ mol(-1), DeltaS() = -127 +/- 3 J mol(-1) K(-1) and DeltaV() = -10.0 +/- 0.4 cm(3) mol(-1), suggesting an associative displacement mechanism. It is postulated that attack of the first cyanide occurs at the beta-(5'-deoxy-5'-adenosyl) site rather than at the alpha-dimethylbenzimidazole site.

The groundwater resources of the El-Qusier-Safaga area on the Red Sea coastal zone have still to be utilised fully for social and economic development. In the present study, an inventory of recharge sources and quality of groundwater in different water bearing formations is made to assist in management of these vital resources. From a hydrochemical point of view, the origin of salinity in the five investigated aquifers are mainly dissolution of terrestrial minerals, leaching of soilsvia floods or ion exchanges processes. Stable isotope data clarify the interaction between different aquifers and indicate that the source of recharge is mainly meteoric water originating from palaeowater of the Pleistocene pluvial period, and from local precipitation as well as some marine water. Evaluation of the groundwater quality for domestic, irrigation and industrial purposes is discussed.

Chemical and isotopic investigations indicate that the recharge source for the groundwater in the Tahta district, adjacent to the Nile, is mainly from the Nile water seeping from irrigation channels. The water's chemical type is sodium bicarbonate, with values of oxygen-18 and deuterium close to that of Nile water. Another minor source of recharge to the far west of the Nile bank is palaeowater. This water's chemical type is sodium sulphate and sodium chloride. The change of water quality in some groundwater samples could be due to the extensive use of fertilizers to improve soil characteristics in new reclamation projects. In addition, these wells are slightly depleted in oxygen-18, deuterium and tritium. Recommendations for the periodic monitoring of groundwater quality for proper use are given.