Nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus treated with linezolid or vancomycin: A secondary economic analysis of resource use from a Spanish perspective / Neumonía nosocomial causada por Staphylococcus aureusresistente a meticilina tratada con linezolid o vancomicina: análisis económico secundario del uso de recursos sanitarios desde una perspectiva Española

OBJECTIVES: Adopting a unique Spanish perspective, this study aims to assess healthcare resource utilization (HCRU) and the costs of treating nosocomial pneumonia (NP) produced by methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized adults using linezolid or vancomycin. An evaluation is also made of the renal failure rate and related economic outcomes between study groups. DESIGN: An economic post hoc evaluation of a randomized, double-blind, multicenter phase 4 study was carried out. Scope: Nosocomial pneumonia due to MRSA in hospitalized adults. PARTICIPANTS: The modified intent to treat (mITT) population comprised 224 linezolid- and 224 vancomycin-treated patients. INTERVENTIONS: Costs and HCRU were evaluated between patients administered either linezolid or vancomycin, and between patients who developed renal failure and those who did not. Primary endpoints: Analysis of HCRU outcomes and costs. RESULTS: Total costs were similar between the linezolid- (€17,782 ± €9,615) and vancomycin-treated patients (€17,423 ± €9,460) (P = .69). The renal failure rate was significantly lower in the linezolid-treated patients (4% vs. 15%; P<.001). The total costs tended to be higher in patients who developed renal failure (€19,626 ± €10,840 vs. €17,388 ± €9,369; P = .14). Among the patients who developed renal failure, HCRU (days on mechanical ventilation: 13.2 ± 10.7 vs. 7.6 ± 3.6 days; P = .21; ICU stay: 14.4 ± 10.5 vs. 9.9 ± 6.6 days; P = .30; hospital stay: 19.5 ± 9.5 vs. 16.1 ± 11.0 days; P = .26) and cost (€17,219 ± €8,792 vs. €20,263 ± €11,350; P = .51) tended to be lower in the linezolid- vs. vancomycin-treated patients. There were no statistically significant differences in costs per patient-day between cohorts after correcting for mortality (€1000 vs. €1,010; P = .98). CONCLUSIONS: From a Spanish perspective, there were no statistically significant differences in total costs between the linezolid and vancomycin pneumonia cohorts. The drug cost corresponding to linezolid was partially offset by fewer renal failure adverse events

OBJETIVOS: Analizar la utilización de recursos sanitarios (URS) y los costes de la neumonía nosocomial por Staphylococcus aureus resistente a meticilina en adultos hospitalizados tratados con linezolid o vancomicina. También se evaluó el porcentaje de fallo renal entre dichos pacientes. DISEÑO: Análisis post-hoc de un ensayo clínico fase IV multicéntrico, aleatorizado, doble ciego. Ámbito: Pacientes adultos, hospitalizados con neumonía nosocomial por Staphylococcus aureusresistente a meticilina. PARTICIPANTES: Pacientes tratados con linezolid (224) o vancomicina (224). INTERVENCIONES: Desde la perspectiva española se compararon costes y URS entre pacientes tratados con linezolid o vancomicina y entre los que desarrollaron fallo renal y los que no. Principales variables de interés Análisis de costes y URS. RESULTADOS: Los costes totales fueron similares (p = 0,69) en los pacientes tratados con linezolid (17.782 ± 9.615€) o vancomicina (17.423 ± 9.460 €). La tasa de fallo renal fue significativamente menor en los tratados con linezolid (4 vs. 15%, p < 0,001). Los costes totales fueron mayores en aquellos que desarrollaron fallo renal (19.626 ± 10.840€ vs. 17.388 ± 9.369€, p = 0,14). La URS (días de ventilación mecánica: 13,2 ± 10,7 vs. 7,6 ± 3,6, p = 0,21; días en UCI: 14,4 ± 10,5 vs. 9,9 ± 6,6, p = 0,30; días de hospitalización: 19,5 ± 9,5 vs. 16,1 ± 11,0, p = 0,26) y los costes totales (17.219 ± 8.792€ vs. 20.263 ± 11.350€, p = 0,51) tendieron a ser inferiores en los pacientes tratados con linezolid que desarrollan fallo renal. Tras corregir el análisis por mortalidad, los costes diarios por paciente fueron similares (1.000 vs. 1.010€; p = 0,98). CONCLUSIONES: Desde la perspectiva española, no hubo diferencias en la URS y los costes entre los pacientes con neumonía tratados con linezolid o vancomicina. El coste de linezolid fue contrarrestado por la menor incidencia de fallo renal

Small angle neutron scattering contrast variation reveals heterogeneities of interactions in protein gels.

We propose a quantitative approach to probe the spatial heterogeneities of interactions in macromolecular gels, based on a combination of small angle X-ray (SAXS) and neutrons (SANS) scattering. We investigate the structure of model gluten protein gels and show that the gels display radically different SAXS and SANS profiles when the solvent is (at least partially) deuterated. The detailed analysis of the SANS signal as a function of the solvent deuteration demonstrates heterogeneities of sample deuteration at different length scales. The progressive exchange between the protons (H) of the proteins and the deuteriums (D) of the solvent is inhomogeneous and 60 nm large zones that are enriched in H are evidenced. In addition, at low protein concentration, in the sol state, solvent deuteration induces a liquid/liquid phase separation. Complementary biochemical and structure analyses show that the denser protein phase is more protonated and specifically enriched in glutenin, the polymeric fraction of gluten proteins. These findings suggest that the presence of H-rich zones in gluten gels would arise from the preferential interaction of glutenin polymers through a tight network of non-exchangeable intermolecular hydrogen bonds.

Nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus treated with linezolid or vancomycin: A secondary economic analysis of resource use from a Spanish perspective.

OBJECTIVES: Adopting a unique Spanish perspective, this study aims to assess healthcare resource utilization (HCRU) and the costs of treating nosocomial pneumonia (NP) produced by methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized adults using linezolid or vancomycin. An evaluation is also made of the renal failure rate and related economic outcomes between study groups. DESIGN: An economic post hoc evaluation of a randomized, double-blind, multicenter phase 4 study was carried out. SCOPE: Nosocomial pneumonia due to MRSA in hospitalized adults. PARTICIPANTS: The modified intent to treat (mITT) population comprised 224 linezolid- and 224 vancomycin-treated patients. INTERVENTIONS: Costs and HCRU were evaluated between patients administered either linezolid or vancomycin, and between patients who developed renal failure and those who did not. PRIMARY ENDPOINTS: Analysis of HCRU outcomes and costs. RESULTS: Total costs were similar between the linezolid- (€17,782±€9,615) and vancomycin-treated patients (€17,423±€9,460) (P=.69). The renal failure rate was significantly lower in the linezolid-treated patients (4% vs. 15%; P<.001). The total costs tended to be higher in patients who developed renal failure (€19,626±€10,840 vs. €17,388±€9,369; P=.14). Among the patients who developed renal failure, HCRU (days on mechanical ventilation: 13.2±10.7 vs. 7.6±3.6 days; P=.21; ICU stay: 14.4±10.5 vs. 9.9±6.6 days; P=.30; hospital stay: 19.5±9.5 vs. 16.1±11.0 days; P=.26) and cost (€17,219±€8,792 vs. €20,263±€11,350; P=.51) tended to be lower in the linezolid- vs. vancomycin-treated patients. There were no statistically significant differences in costs per patient-day between cohorts after correcting for mortality (€1000 vs. €1,010; P=.98). CONCLUSIONS: From a Spanish perspective, there were no statistically significant differences in total costs between the linezolid and vancomycin pneumonia cohorts. The drug cost corresponding to linezolid was partially offset by fewer renal failure adverse events.

Pathophysiology and burden of infection in patients with diabetes mellitus and peripheral vascular disease: focus on skin and soft-tissue infections.

Diabetes mellitus affects 284 million adults worldwide and is increasing in prevalence. Accelerated atherosclerosis in patients with diabetes mellitus contributes an increased risk of developing cardiovascular diseases including peripheral vascular disease (PVD). Immune dysfunction, diabetic neuropathy and poor circulation in patients with diabetes mellitus, especially those with PVD, place these patients at high risk for many types of typical and atypical infections. Complicated skin and soft-tissue infections (cSSTIs) are of particular concern because skin breakdown in patients with advanced diabetes mellitus and PVD provides a portal of entry for bacteria. Patients with diabetes mellitus are more likely to be hospitalized with cSSTIs and to experience related complications than patients without diabetes mellitus. Patients with PVD requiring lower extremity bypass are also at high risk of surgical site and graft infections. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent causative pathogen in cSSTIs, and may be a significant contributor to surgical site infections, especially in patients who are colonized with MRSA on hospital admission. Patients with cSSTIs and diabetes mellitus or PVD experience lower clinical success rates than patients without these comorbidities, and may also have a longer length of hospital stay and higher risk of adverse drug events. Clinicians should be vigilant in recognizing the potential for infection with multi-drug-resistant organisms, especially MRSA, in these populations and initiating therapy with appropriate antibiotics.

Implementing criteria-based early switch/early discharge programmes: a European perspective.

Early switch (ES) from intravenous (IV) to oral antibiotic therapy programmes is increasingly included as a component of hospital antimicrobial stewardship initiatives that aim to optimize antimicrobial therapy while limiting toxicity and resistance. In terms of prioritizing the most cost-effective stewardship interventions, ES has been seen as a 'low-hanging fruit', which refers to selecting the most obtainable targets rather than confronting more complicated issues. Administration of highly bioavailable oral antibiotics should be considered for nearly all non-critically ill patients and has been recommended as an effective and safe strategy for over two decades. However, to accrue the most benefit from ES, it should be combined with an early discharge (ED) plan, protocol, or care pathway. Benefits of this combined approach include improved patient comfort and mobility, reduced incidence of IV-line-related adverse effects, reduced IV antimicrobial preparation time, decreased hospital stays, reduced antimicrobial purchasing and administration costs, decreased patient deconditioning, and shortened recovery times. Results from published studies document decreases in healthcare resource use and costs following implementation of ES programmes, which in most studies facilitate the opportunity for ED and ED programmes. Barriers to the implementation of these programmes include clinician misconceptions, practical considerations, organizational factors, and a striking lack of awareness of IV to oral switch guidance. These and other barriers will need to be addressed to maximize the effectiveness of ES and ED programmes. As national antimicrobial stewardship programmes dictate the inclusion of ES and ED programmes within healthcare facilities, programmes must be developed and success must be documented.

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus.

Suboptimal antibiotic penetration into soft tissues can occur in patients with poor circulation due to peripheral vascular disease (PVD) or diabetes. We conducted a real-world analysis of antibiotic treatment, hospital resource use and clinical outcomes in patients with PVD and/or diabetes receiving linezolid or vancomycin for the treatment of methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections (MRSA cSSTIs) across Europe. This subgroup analysis evaluated data obtained from a retrospective, observational medical chart review study that captured patient data from 12 European countries. Data were obtained from the medical records of patients ≥ 18 years of age, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Hospital length of stay and length of treatment were compared between the treatment groups using inverse probability of treatment weights to adjust for clinical and demographic differences. A total of 485 patients had PVD or diabetes and received treatment with either vancomycin (n = 258) or linezolid (n = 227). After adjustment, patients treated with linezolid compared with vancomycin respectively had significantly shorter hospital stays (17.9 ± 13.6 vs. 22.6 ± 13.6 days; p < 0.001) and treatment durations (12.9 ± 7.9 vs. 16.4 ± 8.3 days; p < 0.001). The proportions of patients prescribed oral, MRSA-active antibiotics at discharge were 43.2% and 12.4% of patients in the linezolid and vancomycin groups, respectively (p < 0.001). The reduction in resource use may result in lower hospital costs for patients with PVD and/or diabetes and MRSA cSSTIs if treated with linezolid compared with vancomycin.

Weight-based antibiotic dosing in a real-world European study of complicated skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus.

We aimed to characterize real-world dosing of weight-based intravenous (IV) antibiotic therapy in patients hospitalized for methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infections (cSSTIs). This was a subgroup analysis of a retrospective chart review that captured data from 12 European countries. The study included patients ≥18 years old, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Patients treated with IV vancomycin, teicoplanin or daptomycin at any stage during hospitalization were included in this analysis. Analyses were conducted at the regimen level (dosing in mg/kg or in mg, frequency, and total daily dose (TDD)), with potentially multiple regimens per patient, and the patient level, categorizing patients into low, standard (labelled) and high dosing groups according to their initial MRSA-targeted regimen. Among the 1502 patients in the parent study, 998 patients contributed a total of 1050 daptomycin, teicoplanin or vancomycin regimens. Across all regimens, the mean initial TDDs were 6.3 ± 1.9 mg/kg for daptomycin, 10.5 ± 4.9 mg/kg for teicoplanin and 28.5 ± 11.5 mg/kg for vancomycin. A total of 789 patients received first-line therapy with one of the above antibiotics. The majority of patients receiving first-line teicoplanin and daptomycin (96% and 80%, respectively) received higher than labelled cSSTI doses, whereas vancomycin doses were lower than labelled doses in >40% of patients. These real-world data reveal significant deviation from labelled antibiotic dosing in 12 European countries and the potential for suboptimal outcomes in patients with MRSA cSSTIs.

[Two "hybrid" vocational services for people with a severe mental illness in France and Quebec]. / Deux structures d'insertion professionnelle de format hybride pour personnes avec un trouble mental : les ESAT de transition de Messidor (France) et Accès-Cible SMT (Québec).

Many different types of vocational programs (services) exist to help people with severe mental disorders (e.g., schizophrenia) integrate the regular labor market: sheltered workshops, social enterprises, and supported employment programs to name a few. Each type of vocational services has its specificities: on one hand, some of them are following the "train and place" approach. For example, sheltered workshops offer to people with a severe mental illness a training during a long period of, with a small proportion obtaining competitive employment. On the other hand, other programs adopt the "place and train" philosophy, such as supported employment programs, in which employment specialists help people obtain a competitive job as fast as possible with no requested training. This article presents two original vocational services, the Messidor's sheltered workshops in France and the Accès-Cible SMT supported employment program in Quebec, following an "hybrid" approach including both philosophies "place and train" and "train and place". More particularly, they are both aiming at competitive employment on the regular labor market for people with a severe mental illness, with a different length of training. Messidor consists of a sheltered workplace for people with a severe mental illness in France, using this time of transition in the workshops as a tool to obtain a competitive job. Thanks to three key factors, Messidor succeeds in placing many of their workers in the French regular labor market: (1) Workers with severe mental disorders work on tasks and workplaces similar to those in regular labor market; (2) Messidor's managers have small teams (5-7 persons) that offer a nearby and personalized management to workers; (3) Each worker is followed by a Messidor's employment counsellor, to build together a working plan and put in place work strategies to obtain a competitive job. This "double management" seems to be a key ingredient of this support as it promotes some success in getting a job as well as in developing some recovery effects. Accès-Cible SMT located in Montreal (Quebec, Canada) is also an interesting "hybrid" program since people with severe mental disorders can be supported by a counsellor, with a short period of training (a 28-week program with 6 steps) before integrating the regular labor market. The philosophy of Accès-Cible SMT is to consider their clients as normal persons more than as patients, and its objective is mainly to restore confidence and self-esteem of the person by putting emphasis on their professional skills. Meetings in groups, practicums in the workplace, and the utilization of job search strategies are essential ingredients of Accès-Cible SMT, which are also efficient tools to develop a better empowerment of the person. Indeed, the common ingredients/elements of these two vocational services, Messidor and Accès-Cible SMT, seem to be the development of empowerment for people with severe mental disorders. The scientific literature supports that empowerment is one of the key factors of recovery for people with a mental illness, a recovery process that can be illustrated by their work integration in the regular labor market as a final goal.

Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma.

BACKGROUND: To determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study. METHODS: The relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan-Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test. RESULTS: In the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P<0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan-Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P<0.0001). CONCLUSIONS: A positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.

Clinical and economic burden of invasive fungal diseases in Europe: focus on pre-emptive and empirical treatment of Aspergillus and Candida species.

Invasive fungal diseases (IFDs) have been widely studied in recent years, largely because of the increasing population at risk. Aspergillus and Candida species remain the most common causes of IFDs, but other fungi are emerging. The early and accurate diagnosis of IFD is critical to outcome and the optimisation of treatment. Rapid diagnostic methods and new antifungal therapies have advanced disease management in recent years. Strategies for the prevention and treatment of IFDs include prophylaxis, and empirical and pre-emptive therapy. Here, we review the available primary literature on the clinical and economic burden of IFDs in Europe from 2000 to early 2011, with a focus on the value and outcomes of different approaches.

Baseline quality of life as a prognostic survival tool in patients receiving sunitinib for metastatic renal cell carcinoma.

BACKGROUND: In a randomized phase III trial of sunitinib vs interferon-alfa (IFN-α) in metastatic renal cell carcinoma (mRCC), better baseline quality of life (QoL) was predictive of longer survival. Using this dataset, we have developed a novel prognostic tool that establishes a relationship between baseline QoL scores and median survival time. METHODS: Baseline QoL was assessed using the FACT-Kidney Symptom Index-15 item (FKSI-15), its disease-related symptoms (FKSI-DRS) subscale, and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. Weibull models estimated median progression-free survival (mPFS) and overall survival (mOS) as a function of baseline QoL. RESULTS: Longer PFS and OS were associated with higher baseline FKSI-15, FKSI-DRS, and FACT-G scores (P<0.05), and baseline FKSI-15 score was the best predictor of survival. For example, for a baseline FKSI-15 score of 60, the predicted mPFS was 67.9 weeks, and predicted mOS was 240.6 weeks. The magnitude of benefit was greater with sunitinib vs IFN-α for a given baseline QoL score. CONCLUSION: This novel tool indicates that baseline FKSI-15 scores were linked to mPFS and mOS in a clear and interpretable way. The results support evaluation of patient-reported QoL symptoms at baseline as a prognostic indicator of survival in clinical research and practice.

Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis.

BACKGROUND: In a randomised phase III trial, sunitinib significantly improved efficacy over interferon-alpha (IFN-alpha) as first-line therapy for metastatic renal cell carcinoma (mRCC). We report the final health-related quality of life (HRQoL) results. METHODS: Patients (n=750) received oral sunitinib 50 mg per day in 6-week cycles (4 weeks on, 2 weeks off treatment) or subcutaneous IFN-alpha 9 million units three times weekly. Health-related quality of life was assessed with nine end points: the Functional Assessment of Cancer Therapy-General and its four subscales, FACT-Kidney Symptom Index (FKSI-15) and its Disease-Related Symptoms subscale (FKSI-DRS), and EQ-5D questionnaire's EQ-5D Index and visual analogue scale. Data were analysed using mixed-effects model (MM), supplemented with pattern-mixture models (PMM), for the total sample and the US and European Union (EU) subgroups. RESULTS: Patients receiving sunitinib reported better scores in the primary end point, FKSI-DRS, across all patient populations (P<0.05), and in nine, five, and six end points in the total sample, in the US and EU groups respectively (P<0.05). There were no significant differences between the US and EU groups for all end points with the exception of the FKSI item 'I am bothered by side effects of treatment' (P=0.02). In general, MM and PMM results were similar. CONCLUSION: Patients treated with sunitinib in this study had improved HRQoL, compared with patients treated with IFN-alpha. Treatment differences within the US cohort did not differ from those within the EU cohort.

The epidemiologic, health-related quality of life, and economic burden of gastrointestinal stromal tumours.

BACKGROUND AND OBJECTIVES: Gastrointestinal stromal tumours (GIST) are uncommon tumours believed to arise from interstitial cells of Cajal or their precursors in the gastrointestinal (GI) tract, accounting for a small percentage of GI neoplasms and sarcomas. Given the recent recognition of GIST as a distinct cancer, as well as new treatment options available today, a review of the epidemiologic, health-related quality of life (HRQL), and economic burden of GIST is timely from a payer, provider and patient perspective and may provide guidance for treatment decision making and reimbursement. METHODS: A systematic literature review of PubMed and five scientific meeting databases, was conducted to identify published studies and abstracts describing the epidemiologic, HRQL and economic impact of GIST. Publications deemed worthy of further review, based on the information available in the abstract, were retrieved in full text. RESULTS AND DISCUSSION: Thirty-four publications met the review criteria: 29 provided data on GIST epidemiology, one provided cost data, three reported HRQL outcomes, and one reported cost and HRQL outcomes. The annual incidence of GIST (cases per million) ranged from 6.8 in the USA to 14.5 in Sweden, with an estimated 5-year survival rate of 45-64%. On the Functional Illness of Chronic Therapy-fatigue instrument, GIST patients scored 40.0 compared with 37.6 in anaemic cancer patients (0 = worst; 52 = least fatigue). Total costs over 10 years for managing GIST patients with molecularly targeted treatment was estimated at pounds 47 521- pounds 56 146 per patient compared with pounds 4047- pounds 4230 per patient with best supportive care. CONCLUSIONS: The incidence of GIST appears to be similar by country; the lower estimate in one country could be explained by differences in method of case ascertainment. Data suggest that the HRQL burden of GIST is similar to that with other cancers although this requires further exploration. The value of new therapies in GIST needs to consider not only cost but also anticipated benefits and the unmet medical need in this condition.

Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium.

The agouti related protein (AgRP) exerts its anabolic effects on food intake by antagonising the alpha-melanocyte stimulating hormone (alpha-MSH) at its receptors, melanocortin receptors 3 and 4 (MC3R and MC4R). A single nucleotide polymorphism (SNP) in the promoter of the human AgRP (hAgRP), -38C>T, was associated with low body fatness. The -38T allele that was associated with low body fatness also resulted in lower promoter activity. Here we report a novel SNP, -3019G>A, again in the promoter of hAgRP, which is in complete linkage disequilibrium (LD) with the -38C>T SNP (linked alleles: -3019A/-38T and -3019G/-38C). Functional analyses in a human adrenal and two mouse hypothalamus cell lines showed that the -3019A allele had significantly higher promoter activity. Hence, the two linked alleles (-3019A and -38T) had opposite effects on promoter function and yet they were both associated with low body fatness. The region encompassing the -38C>T SNP had approximately 1000-fold higher activity than the region encompassing the -3019G>A SNP, potentially determining the net functional effect between these two SNPs.

Early dialysis in a neonate with intrauterine lisinopril exposure.

In general, angiotensin converting enzyme (ACE) inhibitors should be discontinued in pregnancy, as they can induce an ACE fetopathy. For the treatment of the latter, early peritoneal dialysis is recommended for in utero exposure to captopril and enalapril, although the outcome is poor. Early peritoneal dialysis has not previously been reported for lisinopril induced multiorgan failure. A case is reported in which treatment was given on postnatal day 3. The patient recovered from oligoanuria to almost normal renal function, and heart, brain, and musculoskeletal injury was reversible. This is despite relatively poor clearance of the drug through peritoneal dialysis. Analysis of the pharmacokinetic data suggests that haemodialysis or haemofiltration would be more efficacious for removal of the drug, and these treatments should be performed if available.

The interactions of amphotericin B with various sterols in relation to its possible use in anticancer therapy.

Amphotericin B (AmB) is still the most common anti-fungal agent used to treat systemic fungal infections. It is known that this antibiotic acts by forming pores with the ergosterol contained in the membranes of fungi, but it also interacts with the cholesterol contained in the membranes of eukaryotic cells, hence its toxicity. AmB may also interact with the most common oxidation products of cholesterol found in vivo, together with interacting with biosynthetic precursors of cholesterol, namely, lanosterol and 7-dehydrocholesterol (7-DHC). The purpose of the present work was to study the interactions in solution between AmB and these various sterols, the techniques used being UV-Vis spectroscopy and differential scanning calorimetry. The results are globally interpreted in terms of the structural differences between the sterols. We show that AmB selectively interacts with 7-DHC which, according to a recent hypothesis proposed in the literature, has been identified in connexion with a therapeutic strategy against hepatocellular carcinomas. We find that the affinity of AmB towards 7-DHC is even greater than the affinity of the antibiotic towards ergosterol. We also find that AmB selectively interacts with the principal oxidation product of cholesterol, 7-ketocholesterol, a situation that has to be taken into account when AmB is administered.

Central 5-hydroxytryptamine-2A receptor expression in transgenic mice bearing a glucocorticoid receptor antisense.

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA that partially blocks glucocorticoid receptor expression were used to investigate the long-term effect of hypothalamic-pituitary-adrenal dysfunction on brain 5-hydroxytryptamine-2A (5-HT2A) receptor expression. The brain 5-HT2A receptor mRNA levels in transgenic mice were measured by in situ hybridization and compared to those in control mice. We also studied the effect of a 3-week treatment with fluoxetine on brain 5-HT2A receptor expression in the transgenic mice. No difference in 5-HT2A mRNA levels was observed between transgenic and control mice in cortical or striatal regions, and fluoxetine treatment was without effect. No difference in hypothalamic 5-HT2A mRNA levels was observed between transgenic and control mice, while fluoxetine treatment increased these levels in both transgenic as well as in the hypothalamic ventromedial and paraventricular nuclei of control mice. 5-HT2A receptor mRNA levels were similar in hippocampal CA1 and CA2 subregions of control and transgenic, but were lower in the CA3 and CA4 subregions of transgenic mice. Fluoxetine had no effect on 5-HT2A mRNA levels of transgenic mice but reduced control mouse 5-HT2A receptor mRNA levels in the CA3 subregion. These results suggest that impaired glucocorticoid receptor function can affect hippocampal 5-HT2A receptor expression in transgenic mice and that this is not corrected by fluoxetine treatment.

Effects of in ovo exposure to 2,3,7,8-TCDD on F1 generation adult chickens (Gallus gallus).

White Leghorn chickens (Gallus gallus) were used as surrogate species for the resident wild turkeys found on the Times Beach, Missouri, Superfund site. Parental chickens were injected with concentrations of 2,3,7,8-TCDD which modeled soil concentrations before (200 ppb) and after remediation (1ppb)[1]. Offspring were followed through development to assess alterations in reproductive maturity through the use of a four-way breeding study. F1 adult females exposed to a maternal dose of 8.6 ng/day began egg production approximately two weeks later than did F1 control adult females. By week eight, however, egg production between groups was equivalent. No differences were observed in eggshell gland estrogen or progesterone receptor levels.