Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid-Induced AKI.

SIGNIFICANCE STATEMENT: Patients with AKI suffer a staggering mortality rate of approximately 30%. Fibroblast growth factor 23 (FGF23) and phosphate (P i ) rise rapidly after the onset of AKI and have both been independently associated with ensuing morbidity and mortality. This study demonstrates that dietary P i restriction markedly diminished the early rise in plasma FGF23 and prevented the rise in plasma P i , parathyroid hormone, and calcitriol in mice with folic acid-induced AKI (FA-AKI). Furthermore, the study provides evidence for P i -sensitive osseous Fgf23 mRNA expression and reveals that P i restriction mitigated calciprotein particles (CPPs) formation, inflammation, acidosis, cardiac electrical disturbances, and mortality in mice with FA-AKI. These findings suggest that P i restriction may have a prophylactic potential in patients at risk for AKI. BACKGROUND: In AKI, plasma FGF23 and P i rise rapidly and are independently associated with disease severity and outcome. METHODS: The effects of normal (NP) and low (LP) dietary P i were investigated in mice with FA-AKI after 3, 24, and 48 hours and 14 days. RESULTS: After 24 hours of AKI, the LP diet curbed the rise in plasma FGF23 and prevented that of parathyroid hormone and calcitriol as well as of osseous but not splenic or thymic Fgf23 mRNA expression. The absence of Pth prevented the rise in calcitriol and reduced the elevation of FGF23 in FA-AKI with the NP diet. Furthermore, the LP diet attenuated the rise in renal and plasma IL-6 and mitigated the decline in renal α -Klotho. After 48 hours, the LP diet further dampened renal IL-6 expression and resulted in lower urinary neutrophil gelatinase-associated lipocalin. In addition, the LP diet prevented the increased formation of CPPs. Fourteen days after AKI induction, the LP diet group maintained less elevated plasma FGF23 levels and had greater survival than the NP diet group. This was associated with prevention of metabolic acidosis, hypocalcemia, hyperkalemia, and cardiac electrical disturbances. CONCLUSIONS: This study reveals P i -sensitive FGF23 expression in the bone but not in the thymus or spleen in FA-AKI and demonstrates that P i restriction mitigates CPP formation, inflammation, acidosis, and mortality in this model. These results suggest that dietary P i restriction could have prophylactic potential in patients at risk for AKI.

A novel method for automated crystal visualization and quantification in murine folic acid-induced acute kidney injury.

Folic acid (FA)-induced acute kidney injury (FA-AKI) is an increasingly prevalent rodent disease model involving the injection of a high dose of FA that culminates in renal FA crystal deposition and injury. However, the literature characterizing the FA-AKI model is sparse and dated in part due to the absence of a well-described methodology for the visualization and quantification of renal FA crystals. Using widely available materials and tools, we developed a straightforward and crystal-preserving histological protocol that can be coupled with automated imaging for renal FA crystal visualization and generated an automated macro for downstream crystal content quantification. The applicability of the method was demonstrated by characterizing the model in male and female C57BL6/JRj mice after 3 and 30 h of FA treatment. Kidneys from both sexes and timepoints showed a bimodal distribution of FA crystal deposition in the cortical and medullary regions while, compared with males, females exhibited higher renal FA crystal content at the 30-h timepoint accompanied by greater kidney weight and higher plasma urea. Despite comparable plasma phosphate concentrations, FA-AKI resulted in a substantially more elevated plasma intact fibroblast growth factor 23 (FGF23) in females, reflected by a similar pattern in osseous Fgf23 mRNA expression. Therefore, the presented method constitutes a valuable tool for the quantification of renal FA crystals, which can aid the mechanistic characterization of the FA-AKI model and serves as a means to control for confounding changes in FA crystallization when using the model for investigating early and prophylactic AKI therapeutic interventions.NEW & NOTEWORTHY Here, we describe a novel method for the visualization and quantification of renal folic acid (FA) crystals in the rodent FA-induced acute kidney injury (FA-AKI) model. The protocol involves a straightforward histological approach followed by fully automated imaging and quantification steps. Applicability was confirmed by showing that the FA-AKI model is sex-dependent. The method can serve as a tool to aid in characterizing FA-AKI and to control for studies investigating prophylactic therapeutic avenues using FA-AKI.

On finding natural antibiotics based on TCM formulae.

CONTEXT: Novel kinds of antibiotics are needed to combat the emergence of antibacterial resistance. Natural products (NPs) have shown potential as antibiotic candidates. Current experimental methods are not yet capable of exploring the massive, redundant, and noise-involved chemical space of NPs. In silico approaches are needed to select NPs as antibiotic candidates. OBJECTIVE: This study screens out NPs with antibacterial efficacy guided by both TCM and modern medicine and constructed a dataset aiming to serve the new antibiotic design. METHOD: A knowledge-based network is proposed in this study involving NPs, herbs, the concepts of TCM, and the treatment protocols (or etiologies) of infectious in modern medicine. Using this network, the NPs candidates are screened out and compose the dataset. Feature selection of machine learning approaches is conducted to evaluate the constructed dataset and statistically validate the im- portance of all NPs candidates for different antibiotics by a classification task. RESULTS: The extensive experiments prove the constructed dataset reaches a convincing classification performance with a 0.9421 weighted accuracy, 0.9324 recall, and 0.9409 precision. The further visu- alizations of sample importance prove the comprehensive evaluation for model interpretation based on medical value considerations.

Design, synthesis, biological evaluation, and in silico studies of 2-aminobenzothiazole derivatives as potent PI3Kα inhibitors.

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC50 value of 6.34 µM and compound 8m displayed an IC50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC50 = 10.25 µM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamics simulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally.

Cooperative Power-Domain NOMA Systems: An Overview.

Interference has been a key roadblock against the effectively deployment of applications for end-users in wireless networks including fifth-generation (5G) and beyond fifth-generation (B5G) networks. Protocols and standards for various communication types have been established and utilised by the community in the last few years. However, interference remains a key challenge, preventing end-users from receiving the quality of service (QoS) expected for many 5G applications. The increased need for better data rates and more exposure to multimedia information lead to a non-orthogonal multiple access (NOMA) scheme that aims to enhance spectral efficiency and link additional applications employing successive interference cancellation and superposition coding mechanisms. Recent work suggests that the NOMA scheme performs better when combined with suitable wireless technologies specifically by incorporating antenna diversity including massive multiple-input multiple-output architecture, data rate fairness, energy efficiency, cooperative relaying, beamforming and equalization, network coding, and space-time coding. In this paper, we discuss several cooperative NOMA systems operating under the decode-and-forward and amplify-and-forward protocols. The paper provides an overview of power-domain NOMA-based cooperative communication, and also provides an outlook of future research directions of this area.

Beamforming Using Exact Evaluation of Leakage and Ergodic Capacity of MU-MIMO System.

Closed-form evaluation of key performance indicators (KPIs) of telecommunication networks help perform mathematical analysis under several network configurations. This paper deals with a recent mathematical approach of indefinite quadratic forms to propose simple albeit exact closed-form expressions of the expectation of two significant logarithmic functions. These functions formulate KPIs which include the ergodic capacity and leakage rate of multi-user multiple-input multiple-output (MU-MIMO) systems in Rayleigh fading channels. Our closed-form expressions are generic in nature and they characterize several network configurations under statistical channel state information availability. As a demonstrative example of the proposed characterization, the derived expressions are used in the statistical transmit beamformer design in a broadcast MU-MIMO system to portray promising diversity gains using standalone or joint maximization techniques of the ergodic capacity and leakage rate. The results presented are validated by Monte Carlo simulations.

Overview of Explainable Artificial Intelligence for Prognostic and Health Management of Industrial Assets Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Surveys on explainable artificial intelligence (XAI) are related to biology, clinical trials, fintech management, medicine, neurorobotics, and psychology, among others. Prognostics and health management (PHM) is the discipline that links the studies of failure mechanisms to system lifecycle management. There is a need, which is still absent, to produce an analytical compilation of PHM-XAI works. In this paper, we use preferred reporting items for systematic reviews and meta-analyses (PRISMA) to present a state of the art on XAI applied to PHM of industrial assets. This work provides an overview of the trend of XAI in PHM and answers the question of accuracy versus explainability, considering the extent of human involvement, explanation assessment, and uncertainty quantification in this topic. Research articles associated with the subject, since 2015 to 2021, were selected from five databases following the PRISMA methodology, several of them related to sensors. The data were extracted from selected articles and examined obtaining diverse findings that were synthesized as follows. First, while the discipline is still young, the analysis indicates a growing acceptance of XAI in PHM. Second, XAI offers dual advantages, where it is assimilated as a tool to execute PHM tasks and explain diagnostic and anomaly detection activities, implying a real need for XAI in PHM. Third, the review shows that PHM-XAI papers provide interesting results, suggesting that the PHM performance is unaffected by the XAI. Fourth, human role, evaluation metrics, and uncertainty management are areas requiring further attention by the PHM community. Adequate assessment metrics to cater to PHM needs are requested. Finally, most case studies featured in the considered articles are based on real industrial data, and some of them are related to sensors, showing that the available PHM-XAI blends solve real-world challenges, increasing the confidence in the artificial intelligence models' adoption in the industry.

Performance Analysis and Beamforming Design of a Secure Cooperative MISO-NOMA Network.

This paper studies the cell-edge user's performance of a secure multiple-input single-output non-orthogonal multiple-access (MISO-NOMA) system under the Rayleigh fading channel in the presence of an eavesdropper. We suppose a worst-case scenario that an eavesdropper has ideal user detection ability. In particular, we suggest an optimization-based beamforming scheme with MISO-NOMA to improve the security and outage probability of a cell-edge user while maintaining the quality of service of the near-user and degrading the performance of the eavesdropper. To this end, power allocation coefficients are adjusted with the help of target data rates of both the users by utilizing a simultaneous wireless information and power transfer with time switching/power splitting protocol, where the near-user is used to forward the information to cell-edge user. The analytical results demonstrate that our beamformer analysis can achieve reduced outage probability of cell-edge user in the presence of the eavesdropper. Moreover, the provided simulation results validate our theoretical analysis and show that our approach improves the overall performance of a two-user cooperative MISO-NOMA system.

Geochemical and mineralogical assessment of sedimentary limestone mine waste and potential for mineral carbonation.

This paper attempts to evaluate the mineralogical and chemical composition of sedimentary limestone mine waste alongside its mineral carbonation potential. The limestone mine wastes were recovered as the waste materials after mining and crushing processes and were analyzed for mineral, major and trace metal elements. The major mineral composition discovered was calcite (CaCO3) and dolomite [CaMg(CO3)2], alongside other minerals such as bustamite [(Ca,Mn)SiO3] and akermanite (Ca2MgSi2O7). Calcium oxide constituted the greatest composition of major oxide components of between 72 and 82%. The presence of CaO facilitated the transformation of carbon dioxide into carbonate form, suggesting potential mineral carbonation of the mine waste material. Geochemical assessment indicated that mean metal(loid) concentrations were found in the order of Al > Fe > Sr > Pb > Mn > Zn > As > Cd > Cu > Ni > Cr > Co in which Cd, Pb and As exceeded some regulatory guideline values. Ecological risk assessment demonstrated that the mine wastes were majorly influenced by Cd as being classified having moderate risk. Geochemical indices depicted that Cd was moderately accumulated and highly enriched in some of the mine waste deposited areas. In conclusion, the limestone mine waste material has the potential for sequestering CO2; however, the presence of some trace metals could be another important aspect that needs to be considered. Therefore, it has been shown that limestone mine waste can be regarded as a valuable feedstock for mineral carbonation process. Despite this, the presence of metal(loid) elements should be of another concern to minimize potential ecological implication due to recovery of this waste material.

Burkholderia pseudomallei pathogenesis and survival in different niches.

Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a disease of the tropics with high clinical mortality rates. To date, no vaccines are approved for melioidosis and current treatment relies on antibiotics. Conversely, common misdiagnosis and high pathogenicity of Bp hamper efforts to fight melioidosis. This bacterium can be isolated from a wide range of niches such as waterlogged fields, stagnant water bodies, salt water bodies and from human and animal clinical specimens. Although extensive studies have been undertaken to elucidate pathogenesis mechanisms of Bp, little is known about how a harmless soil bacterium adapts to different environmental conditions, in particular, the shift to a human host to become a highly virulent pathogen. The bacterium has a large genome encoding an armory of factors that assist the pathogen in surviving under stressful conditions and assuming its role as a deadly intracellular pathogen. This review presents an overview of what is currently known about how the pathogen adapts to different environments. With in-depth understanding of Bp adaptation and survival, more effective therapies for melioidosis can be developed by targeting related genes or proteins that play a major role in the bacteria's survival.

Octyl gallate triggers dysfunctional mitochondria leading to ROS driven membrane damage and metabolic inflexibility along with attenuated virulence in Candida albicans.

Recently the high incidence of worldwide Candida infections has substantially increased. The growing problem about toxicity of antifungal drugs and multidrug resistance aggravates the need for the development of new effective strategies. Natural compounds in this context represent promising alternatives having potential to be exploited for improving human health. The present study was therefore designed to evaluate the antifungal effect of a naturally occurring phenolic, octyl gallate (OG), on Candida albicans and to investigate the underlying mechanisms involved. We demonstrated that OG at 25 µg/ml could effectively inhibit C. albicans. Mechanistic insights revealed that OG affects mitochondrial functioning as Candida cells exposed to OG did not grow on non-fermentable carbon sources. Dysfunctional mitochondria triggered generation of reactive oxygen species (ROS), which led to membrane damage mediated by lipid peroxidation. We explored that OG inhibited glucose-induced reduction in external pH and causes decrement in ergosterol levels by 45%. Furthermore, OG impedes the metabolic flexibility of C. albicans by inhibiting the glyoxylate enzyme isocitrate lyase, which was also confirmed by docking analysis. Additionally, OG affected virulence traits such as morphological transition and cell adherence. Furthermore, we depicted that OG not only prevented biofilm formation but eliminates the preformed biofilms. In vivo studies with Caenorhabditis elegans nematode model confirmed that OG could enhance the survival of C. elegans after infection with Candida. Toxicity assay using red blood cells showed only 27.5% haemolytic activity. Taken together, OG is a potent inhibitor of C. albicans that warrants further structural optimization and pharmacological investigations.

Synthesis of metronidazole based thiazolidinone analogs as promising antiamoebic agents.

Metronidazole and its derivatives are widely used for the treatment of amoebiasis. However, metronidazole is considered as the standard drug but it has many side effects. The present study describes the synthesis of a series of metronidazole based thiazolidinone analogs via Knoevenagel condensation of 4-[2-(2-methyl-5-nitro-1H-imidazole-1-yl)ethoxy]benzaldehyde 1 with various thiazolidinone derivatives 2-14 to get the new scaffold (15-27) having better activity and lesser toxicity. Six compounds have shown better efficacy and lesser cytotoxicity than the standard drug metronidazole towards HM1: IMSS strain of Entamoeba histolytica. These compounds may combat the problem of drug resistance and might be effective in identifying potential alternatives for future drug discovery against EhOASS.

Foaming properties, wettability alteration and interfacial tension reduction by saponin extracted from soapnut (Sapindus Mukorossi) at room and reservoir conditions.

In this study, a natural surfactant, saponin was isolated from soapnut (Sapindus Mukorossi). The extracted surfactant was characterized by Fourier-transform infrared spectroscopy (FTIR) analysis. The effectiveness of the isolated surfactant as EOR agent was evaluated from foam generation/stabilization properties, wettability alteration of the rock surfaces, as well as oil-water interfacial tension (IFT) reduction characteristics. The performance of the extracted saponin was compared with that of a commercial saponin and sodium dodecyl sulfate (SDS). The foaming properties of the saponin with carbon dioxide (CO2) was characterized using Teclis Foamscan instrument at room condition and 60 °C. The IFT and contact angles at room conditions and reservoir conditions were measured using KRUSS Drop Shape Analyzer (DSA 25 and DSA 100) via pendant drop and sessile drop techniques respectively. The foamability of the saponin-stabilized foam was good at ambient condition and 60 °C. Moreover, the time taken for almost 100% liquid drainage was higher in saponin-stabilized foam than the SDS-stabilized foam. The optimum concentration for attaining maximum foam stability decreased from 0.4 wt% at room temperature to 0.1 wt% at 60 °C. Signifying that the quantity of the surfactant to be used in foam generation could reduce at high temperature. The isolated saponin exhibited relatively good interfacial activities individually and in synergistic interaction with silicon dioxide (SiO2) nanoparticles at reservoir conditions. Precisely, at 8 MPa and 80 °C, the crude-oil water IFT was reduced from 23.24 mN/m to 1.59 mN/m (about 93.2%) by 0.2 wt% saponin concentration. The IFT was further reduced to 0.87 mN/m (about 96.3%) by a mixed system of 0.5 wt% saponin and 0.05 wt% SiO2 nanoparticles concentration. Increasing IFT with increasing temperature were observed at very high temperature due to phase separation resulting from clouding phenomenon. However, the clouding temperature increased with 0.1 wt% saponin concentration, and in presence of SiO2 nanoparticles (0.05 wt% and 0.1 wt%). The study suggests that the extracted saponin could be considered as supplementary alternative to conventional EOR surfactants.

Medico-legal autopsies of homicidal deaths: A five-year retrospective study in Hospital Sungai Buloh.

INTRODUCTION: Homicide is the act of killing one human being by another, encompassing death as a result of criminal act including justifiable homicide such as judicial killing and self-defence. This study aimed to ascertain the epidemiology and patterns of injury of homicide victims. MATERIALS AND METHODS: We reviewed records of medico-legal autopsy cases performed at the Department of Forensic Medicine, Hospital Sungai Buloh, for a period of five years, from January 2012 until December 2016. Subjects' demographic data such as age, gender, nationality, ethnicity and cause of death were recorded. RESULTS: A total of 122 homicide cases were documented. 90% of the victims were 18 to 65 years old. Males contributed 80% of the subjects. An alarming 42% of the subjects comprised of non-Malaysians. Indonesian subjects contributed one-third of the non-citizen category, followed by Bangladeshis at 20.4%. Other nationalities were Burmese, Nepalese, Pakistani, Vietnamese and unspecified. Among Malaysians, 50% of the subjects were Indians, followed by Malay (31.5%) and Chinese (17.8%). Sharp and blunt force traumas were the most common injuries found, contributing 33% and 32% respectively. Asphyxiation and firearm injuries recorded an almost similar frequency, contributing 25% in combination. Other patterns included combined sharp and blunt objects (4.9%) and burns (3%). CONCLUSIONS: A large number of immigrants in the country have significantly increased the forensic casework. Sharp and blunt objects continue to be the weapon of choice due to its easy accessibility. As domestic violence including fatal spousal and child abuse continue to rise, in-depth study in the area is warranted.

Novel 9-(2-(1-arylethylidene)hydrazinyl)acridine derivatives: Target Topoisomerase 1 and growth inhibition of HeLa cancer cells.

A series of 9-(2-(1-arylethylidene)hydrazinyl)acridine and its analogs were designed, synthesized and evaluated for biological activities. Various biochemical assays were performed to determine the free radical scavenging capacity of synthesized compounds (4a-4j). Anticancer activity of these compounds was assessed against two different human cancer cell lines viz cervical cancer cells (HeLa) and liver cancer cells (HepG2) as well as normal human embryonic kidney cell line (HEK 293). Compounds 4b, 4d and 4e showed potential anti-proliferative effects on HeLa cells. Based on results obtained from antioxidant and cytotoxicity studies, 4b, 4d and 4e were further studied in detail for different biological activities. 4b, 4d and 4e reduced the cell growth, inhibited metastatic activity and declined the potential of cell migration in HeLa cell lines. Topoisomerase1 (Top1) treated with compounds 4b, 4d and 4e exhibited inhibition of Top1 and prevented DNA replication. Molecular docking results validate that interaction of compounds 4b, 4d and 4e with Top1-DNA complex, which might be accountable for their inhibitory effects. Further it was concluded that compounds 4b, 4d and 4e arrests the cells at S phase and consequently induces cell death through DNA damage in HeLa cells.

The Proposed Future Infrastructure Model for Basic Occupational Health Services in Malaysia.

The objectives of occupational health services (OHS) are to create a healthy and safe working environment, prevent work-related diseases, optimise employees' functional capacity and promote health. According to the literature, global accessibility to OHS has not shown much improvement and even worsened in certain countries. The main challenges come from the small and medium enterprises (SMEs). To respond to these global challenges, the basic occupational health services (BOHS) guideline was published under the purview of the World Health Organization and the International Labour Organization. The guideline describes BOHS as part of the infrastructure called the occupational safety and health system, an essential element that ensures the high service coverage and sustainability of the programme. The BOHS guideline was introduced in Malaysia by the Department of Occupational Safety and Health with a focus on SMEs, but its accessibility is low. A gap analysis was conducted between the current BOHS in Malaysia and the published international guideline. The important challenges identified that contributes to the low BOHS accessibility in Malaysia is the weakness in the BOHS infrastructure and OHS system provision. The proposed BOHS infrastructure model is meant to increase accessibility and to provide fair and equitable health services for Malaysians.

Bursal transcriptome profiling of different inbred chicken lines reveals key differentially expressed genes at 3 days post-infection with very virulent infectious bursal disease virus.

Infectious bursal disease is a highly contagious disease in the poultry industry and causes immunosuppression in chickens. Genome-wide regulations of immune response genes of inbred chickens with different genetic backgrounds, following very virulent infectious bursal disease virus (vvIBDV) infection are poorly characterized. Therefore, this study aims to analyse the bursal tissue transcriptome of six inbred chicken lines 6, 7, 15, N, O and P following infection with vvIBDV strain UK661 using strand-specific next-generation sequencing, by highlighting important genes and pathways involved in the infected chicken during peak infection at 3 days post-infection. All infected chickens succumbed to the infection without major variations among the different lines. However, based on the viral loads and bursal lesion scoring, lines P and 6 can be considered as the most susceptible lines, while lines 15 and N were regarded as the least affected lines. Transcriptome profiling of the bursa identified 4588 genes to be differentially expressed, with 2985 upregulated and 1642 downregulated genes, in which these genes were commonly or uniquely detected in all or several infected lines. Genes that were upregulated are primarily pro-inflammatory cytokines, chemokines and IFN-related. Various genes that are associated with B-cell functions and genes related to apoptosis were downregulated, together with the genes involved in p53 signalling. In conclusion, bursal transcriptome profiles of different inbred lines showed differential expressions of pro-inflammatory cytokines and chemokines, Th1 cytokines, JAK-STAT signalling genes, MAPK signalling genes, and their related pathways following vvIBDV infection.

Monoterpenoid perillyl alcohol impairs metabolic flexibility of Candida albicans by inhibiting glyoxylate cycle.

The metabolic pathway such as glyoxylate cycle (GC) enables Candida albicans, to survive under glucose deficient conditions prevalent in the hostile niche. Thus its key enzymes (Isocitrate lyase; ICL and malate synthase; MLS) represent attractive targets against C. albicans. We have previously reported the antifungal potential of a natural monoterpenoid perillyl alcohol (PA). The present study uncovers additional role of PA as a potent GC inhibitor. We explored that PA phenocopied ICL1 deletion mutant and were hypersensitive under low carbon utilizing conditions. The effect of PA on GC was substantiated by molecular docking analyses, which reveals the in-silico binding affinity of PA with ICL and MLS and explored that PA binds to the active sites of both proteins with better binding energy in comparison to their known inhibitors 3-nitropropionate and bromopyruvate respectively. Enzyme kinetics by Lineweaver-Burk plot unravels that PA inhibits ICL and MLS enzymes in competitive and non-competitive manner respectively. Moreover, semi-quantitative RT-PCR indicated that PA inhibits ICL1 and MLS1 mRNA expressions. Lastly, we demonstrated the antifungal efficacy of PA by enhanced survival of Caenorhabditis elegans model and less hemolytic activity (10.6%) on human blood cells. Further studies are warranted for PA to be considered as viable drug candidate.

Intraoperative Parathyroid Hormone Levels at 5 min Can Identify Multigland Disease.

BACKGROUND: Intraoperative parathyroid hormone (IOPTH) monitoring is crucial in the treatment of primary hyperparathyroidism (PHPT). Often, the 5 min IOPTH levels fall, but not by the requisite 50 %. In such cases, the surgeon must decide whether to wait for additional levels or to continue exploration. This study aimed to evaluate the 5 min drop in IOPTH for distinguishing single adenomas (SA) from multigland disease. METHODS: A retrospective analysis of a prospectively collected database was performed on PHPT patients who underwent initial curative parathyroidectomy between 2001 and 2013. Those with familial disease and those taking lithium or undergoing concomitant thyroidectomy were excluded from the analysis. For cases of double adenomas (DA) or hyperplasia (HA), the IOPTH values indicating additional glands were analyzed. RESULTS: The inclusion criteria were met by 1021 patients: 817 patients with SA (82.2 %), 99 patients with DA (10 %), and 78 with HA (7.9 %). The SA patients exhibited a 56.6 ± 4.9 % decline in IOPTH at 5 min compared with 21.3 ± 4.5 % of the DA patients and 22.5 ± 4.3 % of the HA patients (p < 0.01). Post hoc comparisons showed that the 5 min decrease in the SA group was significantly greater than in either the DA group or the HA group (p < 0.01). A 5 min percentage decline of 35 % best distinguished SA from multiglandular disease (85.3 vs. 24.9 %). CONCLUSION: The data suggest that when IOPTH level does not drop by at least 35 % at 5 min after excision, the surgeon should consider further exploration rather than wait for additional levels.

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives.

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5-14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC50 values (0.14-1.26µM) lower than the standard drug metronidazole (IC50 1.80µM). All nine compounds exhibited antimalarial activity (IC50 range: 1.42-19.62µM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC50 range: 14.67-81.24µM) than quinine (IC50: 275.6±16.46µM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.