Small Molecules as LIM Kinase Inhibitors.

LIMK1 and LIMK2 are involved in the regulation of cellular functions that depend on the dynamics of actin cytoskeleton. Disregulation of LIM kinases has been associated with diseases, such as tumor progression and metastasis, viral infection, and ocular diseases. Motivated by this, numerous studies have been carried out to discover small organic molecules capable of inhibiting LIM kinase effectively and selectively. In this review, a comprehensive survey of small organic molecules for LIM kinase inhibitors is reported, together with SAR study results, and the synthesis of these inhibitors.

Evaluation of home medication review for patients with type 2 diabetes mellitus by community pharmacists: a randomised controlled trial.

BACKGROUND: Successful diabetes treatment requires commitment and understanding of disease management by the patients. OBJECTIVE: This trial aimed to evaluate the programme effectiveness of home medication review by community pharmacists (HMR-CP) in optimising diabetes care and reducing medication wastage. METHODS: A randomised controlled trial was conducted on 166 patients with Type 2 Diabetes Mellitus (T2DM) who were randomly assigned to the intervention or control groups. The intervention group received HMR-CP at 0-month, 3-month, and 6-month. The primary outcome was haemoglobin A1c (HbA1c) while clinical outcomes, anthropometric data, and humanistic outcomes were the secondary outcomes. For the intervention group, drug-related problems (DRP) were classified according to the Pharmaceutical Care Network Europe Foundation (PCNE). Medication adherence was determined based on the Pill Counting Adherence Ratio (PCAR). The cost of medication wastage was calculated based on the total missed dose by the T2DM patients multiplied by the cost of medication. General linear model and generalised estimating equations were used to compare data across the different time-points within and between the groups, respectively. RESULTS: No significant difference was observed in the demographic and anthropometric data at baseline between the two groups except for fasting blood glucose (FBG). There was a significant reduction in the HbA1c (-0.91%) and FBG (-1.62mmol/L) over the study period (p<0.05). A similar observation was noted in diastolic blood pressure (DBP) and total cholesterol (TC) but not in high-density lipoprotein (HDL), and anthropometric parameters. Both utility value and Michigan Diabetes Knowledge Test (MDKT) scores increased significantly over time. As for the intervention group, significant changes in PCAR (p<0.001) and the number of DRP (p<0.001) were noted. CONCLUSIONS: HMR-CP significantly improved the glycaemic control, QoL, medication adherence, and knowledge of T2DM patients as well as reduced the number of DRP and cost of medication wastage. However, the impact of HMR-CP on certain clinical and anthropometric parameters remains inconclusive and further investigation is warranted.

CT of blunt splenic injuries: what the trauma team wants to know from the radiologist.

Splenic injury is commonly encountered in severe blunt abdominal trauma. Technological improvements and the increasing availability of both diagnostic computed tomography (CT) and therapeutic splenic artery embolisation (SAE) are key factors in defining the high success rate of modern-day non-operative management (NOM) for blunt splenic injuries (BSIs). The Association for Surgery for Trauma (AAST) Organ Injury Scale (OIS) is commonly used by both radiologists and clinicians to stratify injury severity, traditionally based on the degree of parenchymal disruption seen on CT, and guide management. Its recent 2018 update takes splenic vascular injuries (i.e., active bleed, pseudoaneurysm, and traumatic arteriovenous fistulae) into consideration, the presence of which will indicate at least a grade IV (i.e., high-grade) injury. This is a reflection of the paradigm shift towards spleen conservation with regular use of SAE as the current standard of treatment. Prompted by the latest AAST OIS revision, which represents a more complete and current grading system, we present the spectrum of pertinent CT findings that the diagnostic radiologist should accurately identify and convey to the multidisciplinary trauma team (including the interventional radiologist). This review divides imaging findings based on the AAST OIS definitions and categorises them into (1) parenchymal and (2) vascular injuries. Features that may help in the detection of subtle BSIs are also described. Lastly, it touches on the key changes made to the new AAST OIS, substantiated by case illustrations.

Prevalence and Risk Factors for Cardiac and Liver Iron Overload in Adults with Thalassemia in Malaysia.

We explored the severity and risk factors for cardiac and liver iron overload (IOL) in 69 thalassemia patients who underwent T2* magnetic resonance imaging (T2* MRI) in a Malaysian tertiary hospital from 2011 to 2015. Fifty-three patients (76.8%) had transfusion-dependent thalassemia (TDT) and 16 (23.2%) had non transfusion-dependent thalassemia (NTDT). Median serum ferritin prior to T2* MRI was 3848.0 µg/L (TDT) and 3971.0 µg/L (NTDT). Cardiac IOL was present in 16 (30.2%) TDT patients and two (12.5%) NTDT patients, in whom severe cardiac IOL defined as T2* <10 ms affected six (11.3%) TDT patients. Liver IOL was present in 51 (96.2%) TDT and 16 (100%) NTDT patients, 37 (69.8%) TDT and 13 (81.3%) NTDT patients were in the most severe category (>15 mgFe/gm dry weight). Serum ferritin showed a significantly strong negative correlation with liver T2* in both TDT (rs = -0.507, p = 0.001) and NTDT (r = -0.762, p = 0.002) but no correlation to cardiac T2* in TDT (r = -0.252, p = 0.099) as well as NTDT (r = -0.457, p = 0.100). For the TDT group, regression analysis showed that cardiac IOL was more severe in males (p = 0.022) and liver IOL was more severe in the Malay ethnic group (p = 0.028) and those with higher serum ferritin levels (p = 0.030). The high prevalence of IOL in our study and the poor correlation between serum ferritin and cardiac T2* underline the need to routinely screen thalassemia patients using T2* MRI to enable the early detection of cardiac IOL.

Identification of Novel Sesamol Dimers with Unusual Methylenedioxy Ring-Opening Skeleton and Evaluation of Their Antioxidant and Cytotoxic Activities.

BACKGROUND: Sesamol is a widely used antioxidant for the food and pharmaceutical industries. The oxidation products of this compound may be accumulated in foods or ingested. Little is known about its effect on human health. OBJECTIVE: It is of great interest to identify the oxidation products of sesamol that may be beneficial to humans. This study was undertaken to identify the oxidation products of sesamol and investigate their antioxidant and cytotoxic activities. MATERIALS AND METHODS: Using the ferricyanide oxidation approach, four oxidation products of sesamol (2, 3, 20 & 21) have been identified. Structural elucidation of these compounds was established on the basis of their detailed NMR spectroscopic analysis, mass spectrometry and x-ray crystallography. Additionally, a formation mechanism of compound 20 was proposed based on high-resolution mass spectrometry-fragmentation method. The antioxidant activities of these compounds were determined by the DPPH, FRAP, and ABTS assays. The in vitro antiproliferative activity of these compounds was evaluated against a panel of human cancer cell lines as well as non-cancerous cells. RESULTS: Two oxidation products of sesamol were found to contain an unusual methylenedioxy ring-opening skeleton, as evidenced by spectroscopic and x-ray crystallographic data. Among all compounds, 20 displayed impressive antiproliferative activities against a panel of human cancer cell lines yet remained non-toxic to noncancerous cells. The antioxidant activities of compound 20 are significantly weaker than sesamol as determined by the DPPH, FRAP, and ABTS assays. CONCLUSION: The oxidation products of sesamol could be a valuable source of bioactive molecules. Compound 20 may be used as a potential lead molecule for cancer studies.

Simulation of Multispecies Desmoplastic Cancer Growth via a Fully Adaptive Non-linear Full Multigrid Algorithm.

A fully adaptive non-linear full multigrid (FMG) algorithm is implemented to computationally simulate a model of multispecies desmoplastic tumor growth in three spatial dimensions. The algorithm solves a thermodynamic mixture model employing a diffuse interface approach with Cahn-Hilliard-type fourth-order equations that are coupled, non-linear, and numerically stiff. The tumor model includes extracellular matrix (ECM) as a major component with elastic energy contribution in its chemical potential term. Blood and lymphatic vasculatures are simulated via continuum representations. The model employs advection-reaction-diffusion partial differential equations (PDEs) for the cell, ECM, and vascular components, and reaction-diffusion PDEs for the elements diffusing from the vessels. This study provides the details of the numerical solution obtained by applying the fully adaptive non-linear FMG algorithm with finite difference method to solve this complex system of PDEs. The results indicate that this type of computational model can simulate the extracellular matrix-rich desmoplastic tumor microenvironment typical of fibrotic tumors, such as pancreatic adenocarcinoma.

A qualitative exploration of hypertensive patients' perception towards quality use of medication and hypertension management at the community level

Objective: This study aimed to explore hypertensive patients’ perspectives on quality use of medication and issues related to hypertension management at the community level in Malaysia. Methods: Focus groups discussion was employed in this qualitative study. A total of 17 hypertensive patients were purposively recruited. Three focus group discussions with semi-structured interview were carried out at Flat Desa Wawasan, Penang. All the conversations were audio recorded, transcribed verbatim and thematically analysed. Results: Three major themes were developed, including medication adherence among hypertensive patients, self-management of hypertension and patients’ knowledge towards hypertension. Poor medication adherence was found and different strategies were taken to overcome the barriers towards adherence. Use of herbal and traditional therapies was perceived as alternative method in controlling blood pressure instead of taking antihypertensive medication. The participants were found to have poor knowledge on side effect and mechanism of action of hypertensive medication. Conclusions: The misconception about the side effect of antihypertensive medication has led to poor adherence among the participants. Lack of knowledge on targeted blood pressure level has led to poor blood pressure monitoring among the participants. Health awareness program and counselling from health care professional should be advocated among the hypertensive patients in addressing the above gaps (AU)

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Model of vascular desmoplastic multispecies tumor growth.

We present a three-dimensional nonlinear tumor growth model composed of heterogeneous cell types in a multicomponent-multispecies system, including viable, dead, healthy host, and extra-cellular matrix (ECM) tissue species. The model includes the capability for abnormal ECM dynamics noted in tumor development, as exemplified by pancreatic ductal adenocarcinoma, including dense desmoplasia typically characterized by a significant increase of interstitial connective tissue. An elastic energy is implemented to provide elasticity to the connective tissue. Cancer-associated fibroblasts (myofibroblasts) are modeled as key contributors to this ECM remodeling. The tumor growth is driven by growth factors released by these stromal cells as well as by oxygen and glucose provided by blood vasculature which along with lymphatics are stimulated to proliferate in and around the tumor based on pro-angiogenic factors released by hypoxic tissue regions. Cellular metabolic processes are simulated, including respiration and glycolysis with lactate fermentation. The bicarbonate buffering system is included for cellular pH regulation. This model system may be of use to simulate the complex interactions between tumor and stromal cells as well as the associated ECM and vascular remodeling that typically characterize malignant cancers notorious for poor therapeutic response.

A qualitative exploration of hypertensive patients' perception towards quality use of medication and hypertension management at the community level.

OBJECTIVE: This study aimed to explore hypertensive patients' perspectives on quality use of medication and issues related to hypertension management at the community level in Malaysia. METHODS: Focus groups discussion was employed in this qualitative study. A total of 17 hypertensive patients were purposively recruited. Three focus group discussions with semi-structured interview were carried out at Flat Desa Wawasan, Penang. All the conversations were audio recorded, transcribed verbatim and thematically analysed. RESULTS: Three major themes were developed, including medication adherence among hypertensive patients, self-management of hypertension and patients' knowledge towards hypertension. Poor medication adherence was found and different strategies were taken to overcome the barriers towards adherence. Use of herbal and traditional therapies was perceived as alternative method in controlling blood pressure instead of taking antihypertensive medication. The participants were found to have poor knowledge on side effect and mechanism of action of hypertensive medication. CONCLUSIONS: The misconception about the side effect of antihypertensive medication has led to poor adherence among the participants. Lack of knowledge on targeted blood pressure level has led to poor blood pressure monitoring among the participants. Health awareness program and counselling from health care professional should be advocated among the hypertensive patients in addressing the above gaps.

Disseminated extracranial metastatic meningioma.

Meningiomas are usually low-grade, solitary lesions that rarely metastasize. In this group of central nervous system tumours, the higher grade subtypes are notorious for resistance to conventional chemo-radiation therapies. Recent studies have shown efficacy in the use of bevacizumab in patients with recurrent and, or progressive anaplastic meningioma. The authors report a case of a young patient with recurrent anaplastic meningioma who despite being treated with bevacizumab, progressed with disease dissemination to multiple extracranial sites. Although the majority of meningiomas are amendable to treatment, the higher grade subtypes remain therapeutically challenging. The unexpected resistance to anti-angiogenic therapy in this patient adds another layer of complexity to an elusive subset of a supposedly benign disease. This patient report reflects the need for in-depth studies, molecular characterization and overall, better disease understanding in order to improve prognosis for affected patients.

[(11)C]Ascorbic and [(11)C]dehydroascorbic acid, an endogenous redox pair for sensing reactive oxygen species using positron emission tomography.

Here we report the radiosynthesis of an endogenous redox pair, [(11)C]ascorbic acid ([(11)C]VitC) and [(11)C]dehydroascorbic acid ([(11)C]DHA), the reduced and oxidized forms of vitamin C, and their application to ROS sensing. These results provide the basis for in vivo detection of ROS using positron emission tomography (PET).

A Review of Pharmacological Treatment Options for Lung Cancer: Emphasis on Novel Nanotherapeutics and Associated Toxicity.

Lung cancer remains a leading cause of death. Current treatment options are generally ineffective, highlighting the dire need for novel approaches. While numerous biologically-active chemotherapeutics have been discovered in the last two decades, biological barriers including minimal water solubility, stability, and cellular resistance hinder in vivo effectiveness. To overcome these limitations, nanoparticles have been designed to deliver chemotherapeutics selectively to cancerous tissue while minimizing pharmacokinetics hindrance. Numerous studies are underway analyzing the efficacy of nanoparticles in drug delivery, theranostic applications, and photothermal therapy. However, while nanoparticles have shown efficacy in treating some cancers, their potential toxicity and lack of targeting may hinder clinical potential. With the aim to help sort through these issues, we conduct a review to describe recent applications of nanotherapeutics for the treatment and diagnosis of lung cancer. We first provide a detailed background of statistics, etiology, histological classification, staging, diagnosis, and current treatment options. This is followed by a description of current applications of nanotherapeutics, focusing primarily on results published during the past five years. The potential toxicity associated with nanoparticles is evaluated, revealing inconclusive information which highlights the need for further studies. Lastly, recent advances in mathematical modeling and computational simulation have shown potential in predicting tumor response to nanotherapeutics. Thus, although nanoparticles have shown promise in treating lung cancer, further multi-disciplinary studies to quantify optimal dosages and assess possible toxicity are still needed. To this end, nanotherapeutic options currently in clinical trials offer hope to help address some of these critical issues.

Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy.

The aims of this study were to investigate mechanisms of action involved in H2AX phosphorylation by DNA interstrand crosslinking (ICL) agents and determine whether gammaH2AX could be a suitable pharmacological marker for identifying potential ICL cellular chemosensitivity. In normal human fibroblasts, after treatment with nitrogen mustard (HN2) or cisplatin, the peak gammaH2AX response was detected 2-3 h after the peak of DNA ICLs measured using the comet assay, a validated method for detecting ICLs in vitro or in clinical samples. Detection of gammaH2AX foci by immunofluorescence microscopy could be routinely detected with 6-10 times lower concentrations of both drugs compared to detection of ICLs using the comet assay. A major pathway for repairing DNA ICLs is the initial unhooking of the ICL by the ERCC1-XPF endonuclease followed by homologous recombination. HN2 or cisplatin-induced gammaH2AX foci persisted significantly longer in both, ERCC1 or XRCC3 (homologous recombination) defective Chinese hamster cells that are highly sensitive to cell killing by ICL agents compared to wild type or ionising radiation sensitive XRCC5 cells. An advantage of using gammaH2AX immunofluorescence over the comet assay is that it appears to detect ICL chemosensitivity in both ERCC1 and HR defective cells. With HN2 and cisplatin, gammaH2AX foci also persisted in chemosensitive human ovarian cancer cells (A2780) compared to chemoresistant (A2780cisR) cells. These results show that gammaH2AX can act as a highly sensitive and general marker of DNA damage induced by HN2 or cisplatin and shows promise for predicting potential cellular chemosensitivity to ICL agents.

Initial evaluation of 18F-fluorothymidine (FLT) PET/CT scanning for primary pancreatic cancer.

PURPOSE: The aim of this study was to evaluate the potential of (18)F-fluorothymidine (FLT) PET/CT for imaging pancreatic adenocarcinoma. METHODS: This was a pilot study of five patients (four males, one female) with newly diagnosed and previously untreated pancreatic adenocarcinoma. Patients underwent FLT PET/CT, (18)F-fluorodeoxyglucose (FDG) PET/CT, and contrast-enhanced CT scanning before treatment. The presence of cancer was confirmed by histopathological analysis at the time of scanning in all five patients. The degree of FLT and FDG uptake at the primary tumor site was assessed using visual interpretation and semi-quantitative SUV analyses. RESULTS: The primary tumor size ranged from 2.5 x 2.8 cm to 3.5 x 7.0 cm. The SUV of FLT uptake within the primary tumor ranged from 2.1 to 3.1. Using visual interpretation, the primary cancer could be detected from background activity in two of five patients (40%) on FLT PET/CT. By comparison, FDG uptake was higher in each patient with a SUV range of 3.4 to 10.8, and the primary cancer could be detected from background in all five patients (100%). CONCLUSIONS: In this pilot study of five patients with primary pancreatic adenocarcinoma, FLT PET/CT scanning showed poor lesion detectability and relatively low levels of radiotracer uptake in the primary tumor.

Scenario of a dirty bomb in an urban environment and acute management of radiation poisoning and injuries.

In the new security environment, there is a clear and present danger of terrorists using non-conventional weapons to inflict maximum psychological and economic damage on their targets. This article examines two scenarios of radiation contamination and injury, one accidental in nature leading to environmental contamination, and another of deliberate intent resulting in injury and death. This article also discusses the management of injury from radiological dispersion devices or dirty bombs, with emphasis on the immediate aftermath as well as strategy recommendations.

The rate of cellular hydrogen peroxide removal shows dependency on GSH: mathematical insight into in vivo H2O2 and GPx concentrations.

Although its concentration is generally not known, glutathione peroxidase-1 (GPx-1) is a key enzyme in the removal of hydrogen peroxide (H2O2) in biological systems. Extrapolating from kinetic results obtained in vitro using dilute, homogenous buffered solutions, it is generally accepted that the rate of elimination of H2O2 in vivo by GPx is independent of glutathione concentration (GSH). To examine this doctrine, a mathematical analysis of a kinetic model for the removal of H2O2 by GPx was undertaken to determine how the reaction species (H2O2, GSH, and GPx-1) influence the rate of removal of H2O2. Using both the traditional kinetic rate law approximation (classical model) and the generalized kinetic expression, the results show that the rate of removal of H2O2 increases with initial GPx(r), as expected, but is a function of both GPx(r) and GSH when the initial GPx(r) is less than H2O2. This simulation is supported by the biological observations of Li et al. Using genetically altered human glioma cells in in vitro cell culture and in an in vivo tumour model, they inferred that the rate of removal of H2O2 was a direct function of GPx activity x GSH (effective GPx activity). The predicted cellular average GPx(r) and H2O2 for their study are approximately GPx(r) < or =1 microm and H2O2 approximately 5 microm based on available rate constants and an estimation of GSH. It was also found that results from the accepted kinetic rate law approximation significantly deviated from those obtained from the more generalized model in many cases that may be of physiological importance.

Diversity of Archaea in marine sediments from Skan Bay, Alaska, including cultivated methanogens, and description of Methanogenium boonei sp. nov.

Methanogenesis in cold marine sediments is a globally important process leading to methane hydrate deposits, cold seeps, physical instability of sediment, and atmospheric methane emissions. We employed a multidisciplinary approach that combined culture-dependent and -independent analyses with geochemical measurements in the sediments of Skan Bay, Alaska (53 degrees N, 167 degrees W), to investigate methanogenesis there. Cultivation-independent analyses of the archaeal community revealed that uncultivated microbes of the kingdoms Euryarchaeota and Crenarchaeota are present at Skan Bay and that methanogens constituted a small proportion of the archaeal community. Methanogens were cultivated from depths of 0 to 60 cm in the sediments, and several strains related to the orders Methanomicrobiales and Methanosarcinales were isolated. Isolates were psychrotolerant marine-adapted strains and included an aceticlastic methanogen, strain AK-6, as well as three strains of CO(2)-reducing methanogens: AK-3, AK7, and AK-8. The phylogenetic positions and physiological characteristics of these strains are described. We propose a new species, Methanogenium boonei, with strain AK-7 as the type strain.

A new paradigm: manganese superoxide dismutase influences the production of H2O2 in cells and thereby their biological state.

The principal source of hydrogen peroxide in mitochondria is thought to be from the dismutation of superoxide via the enzyme manganese superoxide dismutase (MnSOD). However, the nature of the effect of SOD on the cellular production of H(2)O(2) is not widely appreciated. The current paradigm is that the presence of SOD results in a lower level of H(2)O(2) because it would prevent the non-enzymatic reactions of superoxide that form H(2)O(2). The goal of this work was to: a) demonstrate that SOD can increase the flux of H(2)O(2), and b) use kinetic modelling to determine what kinetic and thermodynamic conditions result in SOD increasing the flux of H(2)O(2). We examined two biological sources of superoxide production (xanthine oxidase and coenzyme Q semiquinone, CoQ(*-) that have different thermodynamic and kinetic properties. We found that SOD could change the rate of formation of H(2)O(2) in cases where equilibrium-specific reactions form superoxide with an equilibrium constant (K) less than 1. An example is the formation of superoxide in the electron transport chain (ETC) of the mitochondria by the reaction of ubisemiquinone radical with dioxygen. We measured the rate of release of H(2)O(2) into culture medium from cells with differing levels of MnSOD. We found that the higher the level of SOD, the greater the rate of accumulation of H(2)O(2). Results with kinetic modelling were consistent with this observation; the steady-state level of H(2)O(2) increases if K<1, for example CoQ(*-)+O(2)-->CoQ+O(2)(*-). However, when K>1, e.g. xanthine oxidase forming O(2)(*-), SOD does not affect the steady state-level of H(2)O(2). Thus, the current paradigm that SOD will lower the flux of H(2)O(2) does not hold for the ETC. These observations indicate that MnSOD contributes to the flux of H(2)O(2) in cells and thereby is involved in establishing the cellular redox environment and thus the biological state of the cell.

A Link-Level Simulator of the cdma2000 Reverse-Link Physical Layer.

The cdma2000 system is an evolutionary enhancement of the IS-95 standards which support 3G services defined by the International Telecommunications Union (ITU). cdma2000 comes in two phases: 1XRTT and 3XRTT (1X and 3X indicates the number of 1.25 MHz wide radio carrier channels used and RTT stands for Radio Transmission Technology). The cdma2000 1XRTT, which operates within a 1.25 MHz bandwidth, can be utilized in existing IS-95 CDMA channels as it uses the same bandwidth, while 3XRTT requires the commitment of 5 MHz bandwidth to support higher data rates. This paper describes a software model implementation of the cdma2000 reverse link and its application for evaluating the effect of rake receiver design parameters on the system performance under various multipath fading conditions. The cdma2000 models were developed at the National Institute of Standards and Technology (NIST), using SPW (Signal Processing Worksystem) commercial software tools. The model has been developed in a generic manner that includes all the reverse link six radio configurations and their corresponding data rates, according to cdma2000 specifications. After briefly reviewing the traffic channel characteristics of the cdma2000 reverse link (subscriber to base station), the paper discusses the rake receiver implementation including an ideal rake receiver. It then evaluates the performance of each receiver for a Spreading Rate 3 (3XRTT) operation, which is considered as a true "3G" cdma2000 technology. These evaluations are based on the vehicular IMT-2000 (International Mobile Telecommunication 2000) channel model using the link budget defined in cdma2000 specifications for the reverse link.