Review of Modeling Methodologies for Managing Water Distribution Security.

Water distribution systems are vulnerable to hazards that threaten water delivery, water quality, and physical and cybernetic infrastructure. Water utilities and managers are responsible for assessing and preparing for these hazards, and researchers have developed a range of computational frameworks to explore and identify strategies for what-if scenarios. This manuscript conducts a review of the literature to report on the state of the art in modeling methodologies that have been developed to support the security of water distribution systems. First, the major activities outlined in the emergency management framework are reviewed; the activities include risk assessment, mitigation, emergency preparedness, response, and recovery. Simulation approaches and prototype software tools are reviewed that have been developed by government agencies and researchers for assessing and mitigating four threat modes, including contamination events, physical destruction, interconnected infrastructure cascading failures, and cybernetic attacks. Modeling tools are mapped to emergency management activities, and an analysis of the research is conducted to group studies based on methodologies that are used and developed to support emergency management activities. Recommendations are made for research needs that will contribute to the enhancement of the security of water distribution systems.

Association of dietary patterns and risk of cardiovascular disease events in the MASHAD cohort study.

BACKGROUND: Cardiovascular disease (CVD) is the principal cause of mortality and disability in Iranian adults. We aimed to evaluate the relationship between dietary patterns and CVD incidence in a large sample of adults in northeastern Iran. METHODS: The present study comprised a prospective study of 5706 CVD-free men and women aged 35-65 years who participated in a cohort study. All of the participants were followed up for a 6-year period. Dietary patterns were derived from a 65-item validated food frequency questionnaire and the factor analysis method was used to determine dietary patterns. RESULTS: We identified two major dietary patterns: (i) a Balanced dietary pattern (a high intake of green leafy vegetables, other vegetables, fruits, dairy products, red meats, poultry, seafoods, legumes and nuts, as well as a low intake of sugar) and (ii) a Western dietary pattern (a high intake of sugar, tea, egg, snacks, fast foods, potato, carbonated beverages, pickled foods, organs meat and butter) by factor analysis. The hazard ratio (HR) and 95% confidence intervals (CIs) of total CVD in the highest versus lowest tertiles of the Balanced pattern were 1.29 (95% CI = 0.67-2.47; P = 0.44). The HR and 95% CIs of CVD in the highest versus lowest tertiles of Western pattern were 2.21 (95% CI = 1.08-4.45; P = 0.03). CONCLUSIONS: During the 6-year follow-up, we found that adherence to a Balanced dietary pattern was not significantly associated with CVD events. However, adherence to a Western dietary pattern was associated with a significantly increased risk of CVD events and its associated risk.

Cellulitis: An unusual manifestation of Neisseria meningitidis infection.

INTRODUCTION: Neisseria meningitidis infections often cause severe meningitis as well as bacteraemia. However, cellulitis in meningococcal diseases have rarely been described. Here, we report a case of right lower limb cellulitis caused by N. meningitidis. CASE REPORT: A 69-year-old woman presented with fever and lower limb swelling. She had diabetes mellitus, hypertension, dyslipidaemia and a history of surgical resection of vulvar carcinoma. N. meningitidis was isolated from her blood culture. DISCUSSION: This report provides additional evidence in support of N. meningitidis as a cause of cellulitis.

Post-transplantation Presentation of ANCA-associated Vasculitis: Granulomatosis with Polyangitis.

Granulomatosis with polyangitis (GPA) is characterized by necrotizing granulomatosis of the upper and lower respiratory tract and glomerulonephritis. If GPA does not respond to appropriate management, it might result in end-stage renal disease, which may remit the disease severity. The overall impression is that immunosuppression following renal transplantation would further subside the vasculitis. However, several studies have shown that systemic vasculitis recur in 25% of patients following renal transplantation. This may indicate the perplexing nature of the immune system. One of the key factors in prevention of relapse of GPA is following up of patients by careful immunosuppressive dose adjustment and regular measurement of biomarkers for vasculitis. Herein, we describe an interesting case of biopsy-proven GPA who had a complex long history of several post-transplantation relapses in different organs with anti-neutrophil cytoplasmic antibodies seroconversion. This case emphasizes that vasculitis in particular GPA can mimic various diseases depending on which vessels and organs are affected by the inflammation and is one of the reversible causes of failure of transplanted kidney. Bearing the diagnosis in mind as one of the potential differential diagnoses of failure of renal transplantation will lead to early diagnosis and treatment of recurrent GPA.

Characterization of three layer depth of interaction PET detectors for small animal imaging.

High sensitivity and spatial resolution are two main parameters of each small animal imaging system. Multi-layers phoswich detectors have been developed to measure the depth of interaction and to improve system spatial resolution. In the past, efforts have been made to develop these kinds of detectors with different crystal materials and lengths. In this work, three layers phoswich detectors based on GE Healthcare eXplore VISTA PET scanner geometry composing LYSO, GSO and BGO scintillators with different crystal orders and lengths were investigated to find the optimum case with the highest sensitivity and uniform spatial resolution. All simulations were performed using the Monte Carlo simulation tool, the Geant4 Application for Tomographic Emission (GATE). In order to validate GATE simulation package, the GE eXplore VISTA small animal PET system was modeled and output results were compared with the experimental data. The length of each of the three layers varied, while the total length (LYSO + GSO + BGO) was fixed at 15 mm. The order of these crystal layers was also changed, so that totally we have considered 55 × 6 = 330 different configurations. Using three layer phoswich detector, a 25%-68% improvement in the sensitivity at central slice was found compared to the dual layer VISTA PET scanner, dependent on different detector configurations. In this study, among all posible configurations, detector length permutations with higher efficiency values (12 × 6 = 72 cases) were choosen to evaluate spatial resolution. The radial and tangential spatial resolutions were markedly improved for all studied different detector configurations compared to the VISTA PET scanner. Among all the possible selected detector configurations, LYSO (4 mm) + GSO (4 mm) + BGO (7 mm) and BGO (5 mm) + LYSO (5 mm) + GSO (5 mm) cases gave the best DOI radial and tangential resolutions for an energy threshold of 250 keV, respectively. In the LYSO (4 mm) + GSO (4 mm) + BGO (7 mm) scanner configuration, the radial resolution was kept below 1.154 mm, over 25 mm field of view (FOV). The tangential resolution variations were minimized to less than 1.029 mm, over 25 mm FOV, using the BGO (5 mm) + LYSO (5 mm) + GSO (5 mm) detector type. As a result, our new designed three layers phoswich detectors with excellent DOI resolution will lead to small animal PET scanners with higher sensitivity and uniform spatial resolution across the FOV.

Fluorescence microscopy image noise reduction using a stochastically-connected random field model.

Fluorescence microscopy is an essential part of a biologist's toolkit, allowing assaying of many parameters like subcellular localization of proteins, changes in cytoskeletal dynamics, protein-protein interactions, and the concentration of specific cellular ions. A fundamental challenge with using fluorescence microscopy is the presence of noise. This study introduces a novel approach to reducing noise in fluorescence microscopy images. The noise reduction problem is posed as a Maximum A Posteriori estimation problem, and solved using a novel random field model called stochastically-connected random field (SRF), which combines random graph and field theory. Experimental results using synthetic and real fluorescence microscopy data show the proposed approach achieving strong noise reduction performance when compared to several other noise reduction algorithms, using quantitative metrics. The proposed SRF approach was able to achieve strong performance in terms of signal-to-noise ratio in the synthetic results, high signal to noise ratio and contrast to noise ratio in the real fluorescence microscopy data results, and was able to maintain cell structure and subtle details while reducing background and intra-cellular noise.

Evaluation of miR-146a expression level in macrophages exposed to Candida glabrata.

BACKGROUND AND PURPOSE: MicroRNAs are small non-coding RNAs with 19-24 nucleotides in length. Up- or down-regulation of many miRNAs has been shown by stimulation of Toll-like receptors (TLRs) in the innate immune system. Up-regulation of miR-146a has been reported by both TLR and heat-killed Candida albicans. In this study, we aimed to evaluate the expression of miR-146a in cultured monocyte-derived macrophages (MDMs) infected by Candida glabrata at 12, 24, and 48 hours. MATERIALS AND METHODS: miR-146a expression was evaluated by qRT-real time polymerase chain reaction (PCR) at three time points in C. glabrata-infected MDMs. The data was analyzed using repeated measures ANOVA. RESULTS: miR-146a expression was down-regulated in infected MDMs compared to the control group (P<0.018). The expression of miR-146a was at its highest level at 48 h, as compared to 12 and 24 h (P<0.018) .The differences between the experimental group compared to the control group were statistically significant (P<0.018). CONCLUSION: These results suggest that miR-146a can be involved in regulating macrophage function following TLR stimulation in C.glabrata-infected MDMs.

Pregnancy outcomes with a primary complaint of perception of reduced fetal movements.

Reduced fetal movement is a worrisome common complaint, not only for mothers but also for the attending medical personnel. The aim of this study was to analyse the pregnancy outcomes of women who presented primarily with reduced fetal movements (RFM). A retrospective study was performed based on patients' perception alone. Obstetric, past medical history, current presentation and outcomes of pregnancy were analysed. A total of 230 case notes were reviewed, with the majority being primigravidae. Less than half (48.7%) of the women had spontaneous labour, 45.7% had induction and 5.6% had elective caesarean section. There were no maternal complications in 97.4% (n = 224) of them. About 0.9% (n = 2) and 1.7% (n = 4) had primary postpartum haemorrhage and extended perineal tear, respectively. Although there was no major neonatal mortality and morbidity, until a randomised trial with a significant sample is conducted in the management of RFM, careful selections for elective delivery or conservative management would prevent untoward complications.

Outcome of molar pregnancies in Malaysia: a tertiary centre experience.

Gestational trophoblastic disease (GTD) is a common problem among Asian ethnics. A total of 102 women with molar pregnancies between 1 January 2005 and 31 December 2010, were analysed. The aim of the study was to determine the outcome of all molar pregnancies in our institution. The local incidence of molar pregnancy was 2.6 per 1,000 deliveries. A total of 48 women (47.1%) had complete hydatidiform mole and another 54 (52.9%) had partial mole. The mean age of the women with molar pregnancies was 32.0 ± 7.9 years. The mean gestational age at initial diagnosis was 11 weeks ± 3 days. The majority (97 women, 95.1%) had symptoms of vaginal bleeding and 18 (17.6%) women had a uterus larger than dates. A total of 48 (47.1%) women had ultrasound scan findings of 'snow-storm' appearance. None of the women with uncomplicated molar pregnancy had evidence of relapse following one undetectable serum ß-hCG level. Four out of the 102 women (3.9%) developed persistent trophoblastic disease before attaining one undetectable serum ß-hCG level. All four women required single agent methotrexate and they remained in remission. The prognosis for uncomplicated molar pregnancy is good. Establishment of a National Trophoblastic Centre is recommended to maintain optimal outcome.

An integrated Shannon's Entropy-TOPSIS methodology for environmental risk assessment of Helleh protected area in Iran.

This study aims to use integrated Shannon's Entropy-TOPSIS methodology for environmental risk assessment of the Helleh protected area in Iran. In this research, first, with regard to field visits, interview with natives of the area, and investigation of the environment of the study area, the risks existing in the region were identified. Then, for final identification of the risks, the Delphi method was applied. Analysis and prioritization of risks of the area of Helleh were performed by multi-criteria decision-making methods of Shannon's Entropy and the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS). In this research, risks were assessed by three criteria of severity, probability of occurrence, and vulnerability. Twenty six of the risks were identified which were specified in two groups, natural events and environmental risks. The environmental ones were classified into four groups: physicochemical, biological, social-economic, and cultural. Results of the research showed that the construction of the Rayis-Ali-Delvari Dam at the upper part of the study area threatens the wetland. Water supply for the dam 75 km away from the area with concession of 0.9999 holds the first priority of risk-generating factors. Of the managerial workable solutions suggested controlling the risks, the stopping of the pumping of water from the wetland and observation of hunting season length and permissible type and number of hunting in the area can be mentioned.

Recurrent uric acid stones.

A 46-year-old female had a history of recurrent uric acid stone formation, but the reason why uric acid precipitated in her urine was not obvious, because the rate of urate excretion was not high, urine volume was not low, and the pH in her 24-h urine was not low enough. In his discussion of the case, Professor McCance provided new insights into the pathophysiology of uric acid stone formation. He illustrated that measuring the pH in a 24-h urine might obscure the fact that the urine pH was low enough to cause uric acid to precipitate during most of the day. Because he found a low rate of excretion of NH(4)(+) relative to that of sulphate anions, as well as a high rate of citrate excretion, he speculated that the low urine pH would be due to a more alkaline pH in proximal convoluted tubule cells. He went on to suspect that there was a problem in our understanding of the function of renal medullary NH(3) shunt pathway, and he suggested that its major function might be to ensure a urine pH close to 6.0 throughout the day, to minimize the likelihood of forming uric acid kidney stones.

Anorexia nervosa and chronic renal insufficiency: a prescription for disaster.

Our imaginary consultant, Professor McCance, is asked to explain the basis for four major acute electrolyte abnormalities in a young woman with long-standing anorexia nervosa. She has a severe degree of hypokalaemia (2.0 mmol/l) with renal potassium wasting, a contracted extracellular fluid volume with renal NaCl wasting, hyponatraemia (118 mmol/l) while excreting hypoosmolar urine, and metabolic acidosis with a normal plasma anion gap (pH 7.20, bicarbonate 9 mmol/l). McCance begins his discussion by considering the basis for hypokalaemia, as this electrolyte disorder is potentially life-threatening. Its pathophysiology is linked to the other major findings, using principles of integrative physiology together with a deductive and quantitative analysis. Nevertheless, to reach his final diagnosis, he requires information about newer molecular discoveries. Not only is he able to suggest a likely diagnosis, but he also devises a novel long-term plan for therapy.

How to select optimal maintenance intravenous fluid therapy.

Hyponatraemia is the commonest electrolyte abnormality in hospitalized patients. If the plasma sodium concentration (P(Na)) declines to approximately 120 mM in <48 h, brain cell swelling might result in herniation, with devastating consequences. The volume and/or the composition of fluids used for intravenous therapy often contribute to the development of acute hyponatraemia. Our hypothesis is that the traditional calculation of the daily loss of insensible water overestimates this parameter, leading to an excessive daily recommended requirement for water. We offer suggestions to minimize the risk of iatrogenic hyponatraemia.

A conceptual approach to the patient with metabolic acidosis. Application to a patient with diabetic ketoacidosis.

We shall illustrate that management of patients with an acid-base disorder could be improved if the acid-base analysis was based on a better understanding of basic concepts of physiology. Three concepts of acid-base physiology and their clinical implications are emphasized in a patient with diabetic ketoacidosis. First, when an acid is produced from neutral precursors in the body, there is a net increase in the number of hydrogen ions (H(+)) and new anions. The corollary is that H(+) will be removed when the accompanying anion is metabolized to a neutral end-product or is excreted in the urine with H(+) or ammonium (NH(4)(+)). Second, buffering of H(+) is beneficial if H(+) are removed by bicarbonate rather than being able to bind to proteins. This latter function depends on having a low tissue PCO(2), due to a combination of hyperventilation plus an adequate blood flow rate to vital organs. Third, the kidneys add new bicarbonate to the body when NH(4)(+) is excreted with chloride ions.

New bis(SATE) prodrug of AZT 5'-monophosphate: in vitro anti-HIV activity, stability, and potential oral absorption.

The in vitro anti-HIV activity, stability, and potential for oral absorption of a phosphotriester derivative of AZT (zidovudine; 3'-azido-2',3'-deoxythymidine) bearing a new esterase-labile S-acyl-2-thioethyl (SATE) group as transient phosphate protection are reported. The biolabile protection is characterized by the presence of a hydroxyl function in the acyl chain. In accordance with previously reported data in the bis(SATE) prodrug series, the present results demonstrate that the studied bis(hydroxytBuSATE)phosphotriester exerts its biological effects via intracellular delivery of the 5'-monophosphate of AZT. The hydroxyl function confers a high resistance against esterase hydrolysis, and the studied prodrug is able to cross the Caco-2 cell monolayers in intact form, suggesting that its further development as a possible anti-HIV pronucleotide candidate is warranted.

Species-dependent and site-specific intestinal metabolism of ester prodrugs.

In order to select a species for drug absorption studies of ester prodrugs and to identify a possible absorption window with low esterase activity and hence increased absorption of the ester prodrug, the esterase activity was investigated in homogenates from various intestinal segments of different species. p-Nitrophenyl acetate and tenofovir disoproxil [bis(POC)-PMPA] were used as substrates for esterases. p-Nitrophenyl acetate is a model substrate for esterase activity, while tenofovir disoproxil (fumarate salt) is an ester prodrug of the potent antiviral nucleoside phosphonate analogue tenofovir. As esterase-mediated degradation during transepithelial transport may be a limiting factor for its oral absorption, targeting the prodrug to a region of the intestine with lower esterase activity may lead to an increase in oral absorption of the prodrug. The results obtained with p-nitrophenyl acetate and tenofovir disoproxil showed both a site-specific (duodenum > or = jejunum > ileum > or = colon) and species-dependent (rat > man > pig) degradation in intestinal homogenates. Degradation of tenofovir disoproxil in homogenates from Caco-2 monolayers (0.016+/-0.003 nmol. s(-1). mg protein(-1)) was low compared to its degradation in homogenates from human ileum (0.177+/-0.052 nmol. s(-1). mg protein(-1)). Rat ileum appears to be a suitable model to evaluate the influence of esterase activity on the oral absorption of the ester prodrug, as the degradation rate for tenofovir disoproxil (0.245+/-0.054 nmol. s(-1). mg protein(-1)) in rat ileum was similar to degradation in human ileum. The results also suggest that colon targeting may be a useful strategy to reduce the esterase-mediated degradation of ester prodrugs, hence resulting in a possible increase in their oral absorption.

Evaluation of the potential of ion pair formation to improve the oral absorption of two potent antiviral compounds, AMD3100 and PMPA.

9-(2-phosphonyomethoxypropyl)adenine (PMPA) and AMD3100 are highly potent and selective antiretroviral agents. Since PMPA is negatively charged and AMD3100 positively charged at physiological pH, their transepithelial transport and their potential for oral drug delivery is very low. In this study, ion pair formation was evaluated as a possible strategy to enhance transepithelial transport of PMPA and AMD3100. Positively charged counter ions such as t-hexyl-, t-heptyl-, t-octylammonium bromide and dodecyl-, tetradecyl-, hexadecyltrimethylammonium bromide were used to form ion pairs with PMPA, while sodium taurodeoxycholate (in vitro experiments) and sodium taurocholate (in vivo experiments) were used as counter ions for AMD3100. The effect of counter ions on transepithelial transport of PMPA (1 mM) and AMD3100 (1 mM) was investigated by measuring the flux across Caco-2 monolayers. An enhancement in drug transport could be observed at a concentration of 2 mM of hexadecyltrimethylammonium bromide (counter ion for PMPA) and 10 mM of sodium taurodeoxycholate (counter ion for AMD3100), but at the concentrations used, the absorption enhancing effect could be attributed to a reduction of the integrity of the monolayers. When AMD3100 transport was tested at a concentration of 200 microM, no flux was observed, even in the presence of relatively high concentrations of counter ion (20 times the concentration of AMD3100). Results obtained from partitioning studies of the drugs in the presence or absence of counter ion revealed that competition by other ions was responsible for the absence of an effect: when pure water was used as the aqueous phase, a reduction up to 24.4+/-1.4% and 17.0+/-1.3% of the initial aqueous concentration was observed for PMPA and AMD3100, respectively; however, as soon as other ions were present in the aqueous phase, the effect of the counter ion was diminished (25-50 mOsm) or completely abolished (270-305 mOsm). The absorption enhancing effect of counter ions was also studied in vivo: pharmacokinetic studies in rabbits showed that the oral bioavailability of AMD3100 in the presence of 4 equivalents of taurocholic acid remained very low and was only 3.2-fold better (i.e. 3.6%) in comparison to pure AMD3100. In view of the results obtained in the Caco-2 system, this absorption enhancement can be attributed to an effect on monolayer integrity rather than to the potential to form ion pairs. We can conclude that the formation of ion pairs may not be very efficient as a strategy to enhance transepithelial transport of charged hydrophilic compounds, as competition by other ions may abolish the beneficial effect of counter ions.

Synthesis of new fluorescent nucleoside analogues and application to the study of human deoxycytidine kinase.

We have determined the affinity of human deoxycytidine kinase with respect to new fluorescent N-methylanthraniloyl cytidine derivatives or non fluorescent enantiomeric cytidine analogues. New results regarding the enantioselectivity and the mechanism of the enzyme are presented.

A comparison of the enantioselectivities of human deoxycytidine kinase and human cytidine deaminase.

The stereoselectivities of recombinant human deoxycytidine kinase (EC 2.7.1.74) (dCK) and of recombinant human cytidine deaminase (EC 3.5.4.5) (CDA) were investigated with respect to a series of cytidine analogs, most of them having the unnatural L-stereochemistry. The enantioselectivity of dCK was always low and generally favored the L-enantiomers in the case of beta-2',3'-dideoxycytidine (beta-ddC), 5-fluoro-beta-2',3'-dideoxycytidine (beta-FddC) and beta-cytidine (beta-riboC). Concerning beta-2'-deoxycytidine, dCK showed a preference for the D-enantiomer. All other examined beta-L-cytidine analogs, [1-beta-L-lyxofuranosyl cytosine (beta-L-lyxoC), l-beta-L-xylofuranosyl cytosine (beta-L-xyloC), and 5-fluoro-1-beta-L-xylofuranosyl cytosine (beta-L-Fxylo C)], were substrates of dCK regardless of the nature of the pentose. None of the studied alpha-L-anomers (alpha-L-riboC, alpha-L-araC, alpha-L-lyxoC, or alpha-L-xyloC) was a substrate of dCK. Contrasting with the relaxed enantioselectivity of dCK, CDA had a strict requirement for D-cytidine analogs since none of the already listed beta-L- or alpha-L analogs was a substrate or an inhibitor of the enzyme. The conjunction of the preceding stereochemical properties of dCK and CDA confers to L-cytidine analogs important potentialities in antiviral and anticancer therapies.

Study of the substrate-binding properties of bovine liver adenosine kinase and inhibition by fluorescent nucleoside analogues.

Adenosine kinase (AK) catalyzes the phosphorylation of adenosine to AMP with ATP as phosphate donor. Intrinsic fluorescence of bovine liver AK was shown previously to be a sensitive probe to quantify the binding of substrates to the enzyme [Elaloui, A., Divita, G., Maury, G., Imbach, J.-L. & Goody, R. S. (1994) Eur. J Biochem. 221, 839-846]. AK contains two catalytic, sites: a high-affinity site, which binds adenosine and AMP selectively; and a site for ATP and ADP. In the present work, these two sites were characterized by combining the quenching of protein fluorescence induced by the binding of the ligands and the fluorescence enhancement observed upon binding of the N-methylanthraniloyl-derivated nucleotides or adenosine. A new fluorescent analog of adenosine, 5'-N-methylanthraniloyl-adenosine, was synthesized and shown to bind selectively to the high-affinity adenosine-binding site with an affinity similar to that of adenosine (Kd 1 microM). In contrast, 2'(3')-N-methylanthraniloyl derivatives of ATP, adenosine (5')tetraphospho(5')adenosine (Ap4A), and adenosine (5')pentaphospho(5')adenosine (Ap5A), bind to the enzyme at the ATP site. Methylantraniloyl derivatives of ATP and adenosine were used as tools for selective characterization of a series of adenosine analogues. The bisubstrate inhibitors Ap4A and Ap5A bind to the ATP site with high affinity and apparently not to the adenosine site, thus acting more as ATP analogues than true bisubstrate ligands. The binding properties of a series of adenosine analogues were strongly dependent on the structural modifications on adenosine. The analogues modified at positions 2' or 3' show similar affinities for AK as that of adenosine, whereas adenosine analogues modified at the base present a relatively low affinity for the enzyme.