Monitoring of malaria parasite resistance to chloroquine and sulphadoxine-pyrimethamine in the Solomon Islands by DNA microarray technology.

BACKGROUND: Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI). The analysis of single nucleotide polymorphisms (SNPs) in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ) resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP) resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives. METHODS: The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection. RESULTS: The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39. CONCLUSION: This work provides the first insight into drug resistance markers of P. falciparum in the SI. The obtained results indicated the presence of a very homogenous P. falciparum population circulating in the community. Although CQ+SP could still clear most infections, seven fixed mutations associated with CQ resistance and two fixed mutations related to SP resistance were observed. Whether the absence of mutations in pfATPase6 indicates the efficacy of artemisinin derivatives remains to be proven.

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

How critical is timing for the diagnosis of influenza in general practice?

QUESTIONS UNDER STUDY: The diagnostic significance of clinical symptoms/signs of influenza has mainly been assessed in the context of controlled studies with stringent inclusion criteria. There was a need to extend the evaluation of these predictors not only in the context of general practice but also according to the duration of symptoms and to the dynamics of the epidemic. PRINCIPLES: A prospective study conducted in the Medical Outpatient Clinic in the winter season 1999-2000. Patients with influenza-like syndrome were included, as long as the primary care physician envisaged the diagnosis of influenza. The physician administered a questionnaire, a throat swab was performed and a culture acquired to document the diagnosis of influenza. RESULTS: 201 patients were included in the study. 52% were culture positive for influenza. By univariate analysis, temperature >37.8 degrees C (OR 4.2; 95% CI 2.3-7.7), duration of symptoms <48 hours (OR 3.2; 1.8-5.7), cough (OR 3.2; 1-10.4) and myalgia (OR 2.8; 1.0-7.5) were associated with a diagnosis of influenza. In a multivariable logistic analysis, the best model predicting influenza was the association of a duration of symptom <48 hours, medical attendance at the beginning of the epidemic (weeks 49-50), fever >37.8 and cough, with a sensitivity of 79%, specificity of 69%, positive predictive value of 67%, negative predictive value of 73% and an area under the ROC curve of 0.74. CONCLUSIONS: Besides relevant symptoms and signs, the physician should also consider the duration of symptoms and the epidemiological context (start, peak or end of the epidemic) in his appraisal, since both parameters considerably modify the value of the clinical predictors when assessing the probability of a patient having influenza.

Using transcription modules to identify expression clusters perturbed in Williams-Beuren syndrome.

The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes.

Five essays on bankruptcy

Chapter 2 Bankruptcy Initiation In The New Era of Chapter 11 2.1 Abstract The bankruptcy act of 1978 placed corporate managers (as debtor in possession) in control of the bankruptcy process. Between 2000 and 2001 managers apparently lost this control to secured creditors. This study examines financial ratios of firms filing for bankruptcy between 1993 and 2004 and tests the hypothesis that the change from manager to creditor control created or exacerbated the managerial (and dominant creditor) incentive to delay bankruptcy filing. We find a clear deterioration in the financial conditions of firms filing after 2001. This is consistent with managers (or creditors who control them) delaying filing for bankruptcy. We also observe patterns of operating losses and liquidations that suggest adverse economic consequences from such delay. Chapter 3 Bankruptcy Resolution: Priority of Claims with the Secured Creditor in Control 3.1 Abstract We present new evidence on the violation of priority of claims in bankruptcy using a sample of 222 firms that tiled for Chapter 11 bankruptcy over the 1993-2004 period. Our study reveals a dramatic reduction in the violations of priority of claims compared to research on prior periods. These results are consistent with changes in both court practices and laws transferring power to the secured creditors over our sample period. We also find an increase in the time from the date of a bankruptcy filing to reaching plan confirmation where priority is not violated. Chapter 4 Bankruptcy Resolution: Speed, APR Violations and Delaware 4.1 Abstract We analyze speed of bankruptcy resolution on a sample of 294 US firms filing for bankruptcy in the 1993-2004 period. We find strong association between type of Chapter II filing and speed of bankruptcy resolution. We also find that violations to the absolute priority rule reduce the time from bankruptcy filing to plan confirmation. This is consistent with the hypothesis that creditors are willing to grant concessions in exchange for faster bankruptcy resolution. Furthermore, after controlling for the type of filing and violations to the absolute priority rule, we do not find any difference in the duration of the bankruptcy process for firms filing in Delaware, New York, or other bankruptcy districts. Chapter 5 Financial Distress and Corporate Control 5.1 Abstract We examine the replacement rates of directors and executives in 63 firms filing for bank ruptcy during the 1995-2002 period. We find that over 76% of directors and executives are replaced in the four year period from the year prior to the bankruptcy filing through three years after. These rates are higher than those found in prior research and is consistent with changes in bankruptcy procedures and practice (i.e. the increased secured creditors control over the process due to both DIP financing and changes in the Uniform Commercial Code) having a significant impact on the corporate governance of firms in financial distress. Chapter 6 Financial Statement Restatements: Decision to File for Bankruptcy 6.1 Abstract On a sample of 201 firms that restated their financial statements we analyze the process of regaining investor trust in a two year period after the restatement. We find that 20% of firms that restate their financial statements tile for bankruptcy or restructure out of court. Our results also indicate that the decisions to change auditor or management is correlated with a higher probability of failure. Increased media attention appears to partly explain the decision of firms to restructure their debt or tile for bankruptcy.

La normalisation des services aux Etats-Unis et en Europe : une analyse institutionnelle des formes d'autorité privée

This chapter explores the institutional environments in which standards for the service sector are expected to support the rise of a global knowledgebased economy. The analysis relies on global political economy approaches to extend to the area of services standards the assumption that the process of globalisation is not opposing states and markets, but a joint expression of both of them including new patterns and agents of structural change through formal and informal power and regulatory practices. It analyses how services standards gain authority in the institutional environment in Europe and in the United States and the extent to which this authority is recognised at the transnational level. In contrast to conventional views opposing the European and American standardisation systems, the chapter shows that institutional developments of services standards are likely to face trade-offs and compromises across those systems.

Polymer Additive Ductilad D1002 in a Bituminous Seal Coat, HR-2035, 1994

Seal coat and chip seal treatments are commonly used as an economical treatment to provide a new surface to an old asphalt roadway. To be successful, the aggregate or chips must be held in place on the roadway by the asphalt binder over a long period of time. It is common, over time, that the binder becomes aged and brittle and loses its ability to be flexible and hold the aggregate in place. Modifiers have been introduced to extend the life and adhesion characteristics of asphaltic binders.

Control of Concrete Deterioration Due to Trace Compounds in Deicers, Phase II, HR-299, 1989

This report presents results of research on ways to reduce the detrimental effects of sulfate-tainted rock salt deicers on portland cement concrete used for highway pavements. Repetitious experiments on the influence of fly ash on the mortar phase of concrete showed significant improvement in resistance to deicing brines is possible. Fifteen to twenty percent by weight of fly ash replacement for portland cement was found to provide optimum improvement. Fly ashes from five sources were evaluated and all were found to be equally beneficial. Preliminary results indicate the type of coarse aggregate also plays an important role in terms of concrete resistance to freeze-thaw in deicing brines. This was particularly true for a porous ferroan dolomite thought to be capable of reaction with the brine. In this case fly ash improved the concrete, but not enough for satisfactory performance. An intermediate response was with a porous limestone where undesirable results were observed without fly ash and adequate performance was realized when 15% fly ash was added. The best combination for making deicer-resistant concrete was found to be with a non-porous limestone. Performance in brines was found to be adequate without fly ash, but better when fly ash was included. Consideration was given to treating existing hardened concrete made with poor aggregate and no fly ash to extend pavement life in the presence of deicers, particularly at joints. Sodium silicate was found to improve freeze-thaw resistance of mortar and is a good candidate for field usage because of its low cost and ease of handling.

Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements.

Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients' morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring. Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66 +/- 10% (mean +/- SD), a maximum plasma concentration of 3.1 +/- 0.8 mg/L after a dose of 450 mg and of 6.6 +/- 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0 +/- 1.0 hours, area under the plasma concentration-time curve values of 29.1 +/- 5.3 mg.h/L and 51.9 +/- 18.3 mg.h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 +/- 3.8 L/h, an elimination half-life of 5.3 +/- 1.5 hours and an apparent terminal volume of distribution of 101 +/- 36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption. The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC(50)) among CMV clinical strains of 0.7 mg/L (range 0.2-1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated. The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.

FastEpistasis: a high performance computing solution for quantitative trait epistasis.

Motivation: Genome-wide association studies have become widely used tools to study effects of genetic variants on complex diseases. While it is of great interest to extend existing analysis methods by considering interaction effects between pairs of loci, the large number of possible tests presents a significant computational challenge. The number of computations is further multiplied in the study of gene expression quantitative trait mapping, in which tests are performed for thousands of gene phenotypes simultaneously. Results: We present FastEpistasis, an efficient parallel solution extending the PLINK epistasis module, designed to test for epistasis effects when analyzing continuous phenotypes. Our results show that the algorithm scales with the number of processors and offers a reduction in computation time when several phenotypes are analyzed simultaneously. FastEpistasis is capable of testing the association of a continuous trait with all single nucleotide polymorphism ( SNP) pairs from 500 000 SNPs, totaling 125 billion tests, in a population of 5000 individuals in 29, 4 or 0.5 days using 8, 64 or 512 processors.

An integer-based score to predict functional outcome in acute ischemic stroke: The ASTRAL score.

OBJECTIVE: To develop and validate a simple, integer-based score to predict functional outcome in acute ischemic stroke (AIS) using variables readily available after emergency room admission. METHODS: Logistic regression was performed in the derivation cohort of previously independent patients with AIS (Acute Stroke Registry and Analysis of Lausanne [ASTRAL]) to identify predictors of unfavorable outcome (3-month modified Rankin Scale score >2). An integer-based point-scoring system for each covariate of the fitted multivariate model was generated by their β-coefficients; the overall score was calculated as the sum of the weighted scores. The model was validated internally using a 2-fold cross-validation technique and externally in 2 independent cohorts (Athens and Vienna Stroke Registries). RESULTS: Age (A), severity of stroke (S) measured by admission NIH Stroke Scale score, stroke onset to admission time (T), range of visual fields (R), acute glucose (A), and level of consciousness (L) were identified as independent predictors of unfavorable outcome in 1,645 patients in ASTRAL. Their β-coefficients were multiplied by 4 and rounded to the closest integer to generate the score. The area under the receiver operating characteristic curve (AUC) of the score in the ASTRAL cohort was 0.850. The score was well calibrated in the derivation (p = 0.43) and validation cohorts (0.22 [Athens, n = 1,659] and 0.49 [Vienna, n = 653]). AUCs were 0.937 (Athens), 0.771 (Vienna), and 0.902 (when pooled). An ASTRAL score of 31 indicates a 50% likelihood of unfavorable outcome. CONCLUSIONS: The ASTRAL score is a simple integer-based score to predict functional outcome using 6 readily available items at hospital admission. It performed well in double external validation and may be a useful tool for clinical practice and stroke research.

The lower Triassic anachronistic carbonate facies in space and time

The end-Permian mass extinction greatly affected the sedimentary record, but the sedimentary response was not limited to the Permian-Triassic boundary interval. This transformation extended to sedimentation that spanned the entire Early Triassic. Calcimicrobialites play an important role throughout this time interval, and at least four main events of anomalous carbonate deposition can be shown. A post-extinction calcimicrobial unit occurs above the extensive Permian skeletal carbonate platform exposed in the Taurus Mountains (southern Turkey), in south Armenia, north-west north and Central Iran along the Zagros Mountains. The calcimicrobial unit formed during the flooding of the platform that took place during the earliest Triassic. A similar calcimicrobialite formed during late Griesbachian to Dienerian time atop the shallow Permian skeletal carbonate platform largely exposed in south China. A third event occurred during the Early Olenekian on the first Mesozoic isolated pelagic plateau (Baid seamount, Oman Mountains). Here the change in carbonate sedimentation is reflected in the occurrence of thrombolites and carbonate seafloor fans. Near the end of Early Triassic time, unusual carbonate deposition is recorded both on an isolated pelagic plateau of the Western Tethys (Halstatt limestone of Dobrogea, Romania) and on the eastern Panthalassa margin of the western United States. In the western United States, the event is represented by stromatolites and thrombolites in the Virgin Limestone of the Moenkopi Formation and by seafloor fans in the middle and upper members of the Union Wash Formation. These unusual episodes of anomalous carbonate deposition illustrate a fundamental change in sedimentation that occurred in the aftermath of the end-Permian mass extinction.

High-Resolution Mass Spectrometry applied to the identification of new metabolites and transformation products of quinolones in chicken muscle tissues

The aim of this work was the identification of new metabolites and transformation products (TPs) in chicken muscle from Enrofloxacin (ENR), Ciprofloxacin (CIP), Difloxacin (DIF) and Sarafloxacin (SAR), which are antibiotics that belong to the fluoroquinolones family. The stability of ENR, CIP, DIF and SAR standard solutions versus pH degradation process (from pH 1.5 to 8.0, simulating the pH since the drug is administered until its excretion) and freeze-thawing (F/T) cycles was tested. In addition, chicken muscle samples from medicated animals with ENR were analyzed in order to identify new metabolites and TPs. The identification of the different metabolites and TPs was accomplished by comparison of mass spectral data from samples and blanks, using liquid chromatography coupled to quadrupole time-of-flight (LC-QqToF) and Multiple Mass Defect Filter (MMDF) technique as a pre-filter to remove most of the background noise and endogenous components. Confirmation and structure elucidation was performed by liquid chromatography coupled to linear ion trap quadrupole Orbitrap (LC-LTQ-Orbitrap), due to its mass accuracy and MS/MS capacity for elemental composition determination. As a result, 21 TPs from ENR, 6 TPs from CIP, 14 TPs from DIF and 12 TPs from SAR were identified due to the pH shock and F/T cycles. On the other hand, 14 metabolites were identified from the medicated chicken muscle samples. Formation of CIP and SAR, from ENR and DIF, respectively, and the formation of desethylene-quinolone were the most remarkable identified compounds.

High-Resolution Mass Spectrometry applied to the identification of transformation products of quinolones from stability studies and new metabolites of enrofloxacin in chicken muscle tissues

The aim of this work was the identification of new metabolites and transformation products (TPs) in chicken muscle from Enrofloxacin (ENR), Ciprofloxacin (CIP), Difloxacin (DIF) and Sarafloxacin (SAR), which are antibiotics that belong to the fluoroquinolones family. The stability of ENR, CIP, DIF and SAR standard solutions versus pH degradation process (from pH 1.5 to 8.0, simulating the pH since the drug is administered until its excretion) and freeze-thawing (F/T) cycles was tested. In addition, chicken muscle samples from medicated animals with ENR were analyzed in order to identify new metabolites and TPs. The identification of the different metabolites and TPs was accomplished by comparison of mass spectral data from samples and blanks, using liquid chromatography coupled to quadrupole time-of-flight (LC-QqToF) and Multiple Mass Defect Filter (MMDF) technique as a pre-filter to remove most of the background noise and endogenous components. Confirmation and structure elucidation was performed by liquid chromatography coupled to linear ion trap quadrupole Orbitrap (LC-LTQ-Orbitrap), due to its mass accuracy and MS/MS capacity for elemental composition determination. As a result, 21 TPs from ENR, 6 TPs from CIP, 14 TPs from DIF and 12 TPs from SAR were identified due to the pH shock and F/T cycles. On the other hand, 14 metabolites were identified from the medicated chicken muscle samples. Formation of CIP and SAR, from ENR and DIF, respectively, and the formation of desethylene-quinolone were the most remarkable identified compounds.

High-resolution mass spectrometry applied to theidentification of transformation products of quinolones from stability studies and new metabolites of enrofloxacin in chicken muscle tissues

The aim of this work was the identification of new metabolites and transformation products (TPs) in chicken muscle from Enrofloxacin (ENR), Ciprofloxacin (CIP), Difloxacin (DIF) and Sarafloxacin (SAR), which are antibiotics that belong to the fluoroquinolones family. The stability of ENR, CIP, DIF and SAR standard solutions versus pH degradation process (from pH 1.5 to 8.0, simulating the pH since the drug is administered until its excretion) and freeze-thawing (F/T) cycles was tested. In addition, chicken muscle samples from medicated animals with ENR were analyzed in order to identify new metabolites and TPs. The identification of the different metabolites and TPs was accomplished by comparison of mass spectral data from samples and blanks, using liquid chromatography coupled to quadrupole time-of-flight (LC-QqToF) and Multiple Mass Defect Filter (MMDF) technique as a pre-filter to remove most of the background noise and endogenous components. Confirmation and structure elucidation was performed by liquid chromatography coupled to linear ion trap quadrupole Orbitrap (LC-LTQ-Orbitrap), due to its mass accuracy and MS/MS capacity for elemental composition determination. As a result, 21 TPs from ENR, 6 TPs from CIP, 14 TPs from DIF and 12 TPs from SAR were identified due to the pH shock and F/T cycles. On the other hand, 14 metabolites were identified from the medicated chicken muscle samples. Formation of CIP and SAR, from ENR and DIF, respectively, and the formation of desethylene-quinolone were the most remarkable identified compounds.