Frequency of severe pulmonary hypertension complicating "isolated" atrial septal defect in infancy.

Atrial septal defects (ASDs) are typically asymptomatic in infancy and early childhood, and elective defect closure is usually performed at ages of 4 to 6 years. Severe pulmonary hypertension (PH) complicating an ASD is seen in adulthood and has only occasionally been reported in small children. A retrospective study was undertaken to evaluate the incidence of severe PH complicating an isolated ASD and requiring early surgical correction. During a 10-year period (1996 to 2006), 355 pediatric patients underwent treatment for isolated ASDs either surgically or by catheter intervention at 2 tertiary referral centers. Two hundred ninety-seven patients had secundum ASDs, and 58 had primum ASDs with mild to moderate mitral regurgitation. Eight infants were found with isolated ASDs (6 with secundum ASDs and 2 with primum ASDs) associated with significant PH, accounting for 2.2% of all patients with ASDs at the centers. These 8 infants had invasively measured pulmonary artery pressures of 50% to 100% of systemic pressure. They were operated in the first year of life and had complicated postoperative courses requiring specific treatment for PH for up to 16 weeks postoperatively. The ultimate outcomes in all 8 infants were good, with persistent normalization of pulmonary pressures during midterm follow-up of up to 60 months (median 28). All other patients with ASDs had normal pulmonary pressures, and the mean age at defect closure was significantly older, at 6.2 years for secundum ASDs and 3.2 years for primum ASDs. In conclusion, ASDs were rarely associated with significant PH in infancy but then required early surgery and were associated with excellent midterm outcomes in these patients.

Severe hypertension following accidental clonidine overdose during the refilling of an implanted intrathecal drug delivery system.

BACKGROUND:   Complications associated with intrathecal pumps may be linked to the surgical procedure, the implanted device, or the medication itself.¦CASE REPORTS:   Three patients treated chronically with intrathecal clonidine presented with clonidine overdose due to inadvertent extravasation during the refilling procedure. All patients experienced loss of consciousness and severe systemic hypertension that required aggressive parenteral treatment.¦DISCUSSION:   Clonidine is an alpha-2 agonist with a nearly 100% bioavailability after oral or rectal administration. With high plasma concentration secondary to massive systemic overdose, the specificity for the alpha-2 receptor is lost and an alpha-1 agonist activity predominates and causes marked hypertension. Management of clonidine overdose consists of supportive therapy guided by signs and symptoms.¦CONCLUSION:   Inadvertent injection into the subcutaneous pocket rather than the reservoir is rare but very dangerous as the drug cannot be retrieved and massive doses are involved. Signs and symptoms of systemic overdose with drugs commonly used in implanted drugs delivery system should be well known to ensure early diagnosis and treatment.

Photodynamic therapy for enhanced drug delivery to tumor

Photodynamic therapy (PDT) has been used as an adjunct to cytoreductive surgery in patients with malignant pleura mesothelioma (MPM). However, it was associated with substantial side effects and found to be only of modest clinical benefit. In contrast, Visudyne®-mediated low-dose PDT has been shown to selectively increase the concentration of macromolecular cytostatic compounds in various tumors grown subpleurally on rodent lungs. Consequently, it was thought that PDT-assisted enhanced tumor penetration for cytostatic agents might be better suited to achieve additional tumor control after cytoreductive surgery for mesothelioma. This effect seems to be mainly related to PDT-mediated modulations of tumor vessels which improve the distribution of circulating, systemically administered chemotherapeutic macromolecular agents. However, the mechanisms involved and the optimization of this effect for therapeutic implications remain to be solved. By using the dorsal skin fold chamber method we demonstrated that both angiogenesis and microcirculation of human mesothelioma xenografts can be continuously assessed in vivo by intravital microscopy. We described a new, simple, reproducible and reliable scoring system for the assessment of tumor angiogenesis and microcirculation in this model, thereby allowing the quantitative description of the neo-vascular network development while avoiding a complicated technical setup. This method can serve as a useful tool for the assessment of novel vessel-targeted therapies against MPM. We then applied this newly established model so as to elucidate the underlying mechanisms of PDT-induced extravasation of macromolecular compounds across the endothelial barrier in tumors and surrounding normal tissue. We found that low-dose PDT selectively enhanced the uptake of macromolecular compounds in human mesothelioma xenografts compared to surrounding normal tissue. Interestingly, this increase of effective permeability of tumor vasculature was not related to the inflammatory stimuli generated by PDT such as the mobilization of leucocytes and their adhesion and penetration of the injured vessel wall. We then used the model for optimizing the drug-light conditions of low- dose PDT in order to obtain maximal leakage of the macromolecular compounds in the tumor with minimal uptake in normal surrounding tissue and we were able to identify such a therapeutic window. With these optimized PDT treatment conditions, we assessed the therapeutic effect of this new treatment concept in vivo by measuring tumor growth rates on subcutaneously grown mesothelioma xenografts in nude mice after low-dose PDT of the tumors following systemically administered liposomal (macromolecular) cisplatin, a cytostatic compound commonly used in clinical practice. We were able to demonstrate that low-dose PDT with optimized drug-light conditions combined with systemic chemotherapy indeed resulted in a reduction in tumor growth compared to chemotherapy or PDT alone. In conclusion, our work demonstrates that low-dose PDT may selectively enhance the uptake of macromolecular cytostatic drugs in superficially growing tumors such as mesotheliomas and opens new perspectives for the treatment of these diseases. - Les effets cytotoxiques de la thérapie photodynamique (PDT) sur le mésothéliome pleural malin (MPM) n'ont pas apporté de bénéfice clinique significatif. Toutefois, une application innovante non cytotoxique de la PDT serait la bienvenue en supplément des chimiothérapies pour améliorer le contrôle local de la tumeur. Le prétraitement des néovaisseaux tumoraux par une PDT à bas régime, qui améliorerait la distribution d'une chimiothérapie administrée par voie systémique de façon concomitante, a attiré une attention particulière pour de futures applications cliniques. Toutefois, les mécanismes impliqués dans cet événement et les implications thérapeutiques de ces changements physiopathologiques restent non résolus. Dans cette thèse, nous avons observé en premier que l'angiogenèse et la microcirculation dans les xénogreffes de mésothéliomes humains peuvent être observées et analysées in vivo par microscopie intravitale. Le nouveau système de score appliqué pour l'évaluation de l'angiogenèse et de la microcirculation tumorale dans cette étude est une méthode simple, reproductible et fiable servant à décrire de manière quantitative le réseau néo-vasculaire en développement, tout en évitant d'utiliser une installation technique compliquée. Ce modèle sert de nouvel outil pour l'évaluation des thérapies anti-vasculaires dirigées contre le MPM. Le modèle animal nouvellement établi a alors été utilisé pour élucider les mécanismes sous-jacents de Γ extravasation d'agents macromoléculaires induite par PDT dans les vaisseaux tumoraux et normaux. Nous avons trouvé que la PDT à fable dose améliore la distribution ciblée de drogues macromoléculaires dans des greffes de mésothéliome humain, de manière sélective pour la tumeur. La perméabilité vasculaire tumorale n'est pas influencée par les stimuli inflammatoires générés par la PDT, ce qui joue un rôle important dans la sélectivité de notre photodynamic drug delivery. Ensuite, nous avons recherché la fenêtre thérapeutique optimale de la PDT pour obtenir une accumulation sélective du colorant macromoléculaire dans le tissu tumoral ainsi qu'une efficacité de la PDT combinée avec une chimiothérapie macromoléculaire sur la croissance tumorale. Nous avons démontré que la PDT à faible dose combinée avec une administration systémique de cisplatine liposomale mène à un ralentissement de la croissance tumorale dans notre modèle de mésothéliome malin humain. En conclusion, l'utilisation de la PDT comme prétraitement pour améliorer sélectivement la distribution d'agents thérapeutiques dans des tumeurs poussant superficiellement est prometteuse. Cette observation fourni une preuve du concept remarquable et garanti la suite des investigations, éventuellement ayant pour but de développer de nouveaux concepts de thérapie pour les patients atteints de mésothéliome. Une PDT intra cavitaire à faible dose après pleuro- pneumonectomie pourrait améliorer la pénétration des agents cytostatiques administrés de façon concomitante par voie systémique dans les îlots tumoraux résiduels, et ainsi améliorer le contrôle local.

Vectorisation intra-oculaire [Drug delivery to target the posterior segment of the eye].

Retinal diseases are nowadays the most common causes of vision threatening in developed countries. Therapeutic advances in this field are hindered by the difficulty to deliver drugs to the posterior segment of the eye. Due to anatomical barriers, the ocular biodisponibility of systemically administered drugs remains poor, and topical instillation is not adequate to achieve therapeutic concentrations of drugs in the back of the eye. Ocular drug delivery has thus become one of the main challenges of modern ophthalmology. A multidisciplinary research is being conducted worldwide including pharmacology, biomaterials, ophthalmology, pharmaceutics, and biology. New promising fields have been developed such as implantable or injectable slow release intravitreal devices and degradable polymers, dispersed polymeric systems for intraocular drug delivery, and transscleral delivery devices such as iontophoresis, osmotic pumps or intra-scleraly implantable materials. The first clinical applications emerging from this research are now taking place, opening new avenues for the treatment of retinal diseases.

Systèmes de délivrance des médicaments pour le segment antérieur: bases fondamentales et applications cliniques [Drug delivery systems to target the anterior segment of the eye: fundamental bases and clinical applications].

The development of new drug delivery systems to target the anterior segment of the eye may offer many advantages: to increase the biodisponibility of the drug, to allow the penetration of drug that cannot be formulated as solutions, to obtain constant and sustained drug release, to achieve higher local concentrations without systemic effects, to target more specifically one tissue or cell type, to reduce the frequency of instillation and therefore increase the observance and comfort of the patient while reducing side effects of frequent instillation. Several approaches are developed, aiming to increase the corneal contact time by modified formulation or reservoir systems, or by increasing the tissue permeability using iontophoresis. To date, no ocular drug delivery system is ideal for all purposes. To maximize treatment efficacy, careful evaluation of the specific pathological condition, the targeted Intraocular tissue and the location of the most severe pathology must be made before selecting the method of delivery most suitable for each individual patient.

Free and total plasma levels of lopinavir during pregnancy, at delivery and postpartum: implications for dosage adjustments in pregnant women.

BACKGROUND: Physiological changes associated with pregnancy may alter antiretroviral plasma concentrations and might jeopardize prevention of mother-to-child HIV transmission. Lopinavir is one of the protease inhibitors more frequently prescribed during pregnancy in Europe. We described the free and total pharmacokinetics of lopinavir in HIV-infected pregnant and non-pregnant women, and evaluated whether significant alterations in its disposition and protein binding warrant systematic dosage adjustment. METHODS: Plasma samples were collected at first, second and third trimester of pregnancy, at delivery, in umbilical cord and postpartum. Lopinavir free and total plasma concentrations were measured by HPLC-MS/MS. Bayesian calculations were used to extrapolate total concentrations to trough (Cmin). RESULTS: A total of 42 HIV-positive pregnant women and 37 non-pregnant women on lopinavir/ritonavir were included in the study. Compared to postpartum and control values, total lopinavir Cmin was decreased moderately (31-39%) during pregnancy, and free Cmin minimally, showing significant alteration only at delivery (-35%). However, total and free Cmin remained in all patients above the target concentrations for wild-type virus of 1,000 ng/ml, and above the unbound IC50(WT) of 0.64-0.77 ng/ml of lopinavir, respectively. Lopinavir free fractions remained higher during pregnancy compared to postpartum and controls, and were influenced by α-1-acid-glycoprotein and albumin decrease. Free cord-to-mother ratio (0.43) was 2.7-fold higher than total cord-to-mother ratio (0.16), suggesting higher fetal exposure. CONCLUSIONS: The moderate decrease of total lopinavir concentrations during pregnancy is not associated with proportional decrease in free concentrations. Both reach a nadir at delivery, albeit not to an extent that would put treatment-naive women at risk of insufficient exposure to the free, pharmacologically active concentrations of lopinavir. No dosage adjustment is therefore needed during pregnancy as it is unlikely to further enhance treatment efficacy but could potentially increase the risk of maternal and fetal toxicity. Nonetheless, in case of viral resistance in treatment-experienced pregnant women, loss of virological control or questionable adherence, it is justified to consider lopinavir dosage adjustment based on total plasma concentration measurement.

Surface-functionalized ultrasmall superparamagnetic nanoparticles as magnetic delivery vectors for camptothecin.

Drug-nanoparticle conjugates: The anticancer drug camptothecin (CPT) was covalently linked at the surface of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) via a linker, allowing drug release by cellular esterases. Nanoparticles were hierarchically built to achieve magnetically-enhanced drug delivery to human cancer cells and antiproliferative activity.The linking of therapeutic drugs to ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) allowing intracellular release of the active drug via cell-specific mechanisms would achieve tumor-selective magnetically-enhanced drug delivery. To validate this concept, we covalently attached the anticancer drug camptothecin (CPT) to biocompatible USPIOs (iron oxide core, 9-10 nm; hydrodynamic diameter, 52 nm) coated with polyvinylalcohol/polyvinylamine (PVA/aminoPVA). A bifunctional, end-differentiated dicarboxylic acid linker allowed the attachment of CPT to the aminoPVA as a biologically labile ester substrate for cellular esterases at one end, and as an amide at the other end. These CPT-USPIO conjugates exhibited antiproliferative activity in vitro against human melanoma cells. The intracellular localization of CPT-USPIOs was confirmed by transmission electron microscopy (iron oxide core), suggesting localization in lipid vesicles, and by fluorescence microscopy (CPT). An external static magnetic field applied during exposure increased melanoma cell uptake of the CPT-USPIOs.

Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin.

To determine the separate and interactive effects of fetal inflammation and neonatal hyperoxia on the developing lung, we hypothesized that: 1) antenatal endotoxin (ETX) causes sustained abnormalities of infant lung structure; and 2) postnatal hyperoxia augments the adverse effects of antenatal ETX on infant lung growth. Escherichia coli ETX or saline (SA) was injected into amniotic sacs in pregnant Sprague-Dawley rats at 20 days of gestation. Pups were delivered 2 days later and raised in room air (RA) or moderate hyperoxia (O₂, 80% O₂ at Denver's altitude, ∼65% O₂ at sea level) from birth through 14 days of age. Heart and lung tissues were harvested for measurements. Intra-amniotic ETX caused right ventricular hypertrophy (RVH) and decreased lung vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein contents at birth. In ETX-exposed rats (ETX-RA), alveolarization and vessel density were decreased, pulmonary vascular wall thickness percentage was increased, and RVH was persistent throughout the study period compared with controls (SA-RA). After antenatal ETX, moderate hyperoxia increased lung VEGF and VEGFR-2 protein contents in ETX-O₂ rats and improved their alveolar and vascular structure and RVH compared with ETX-RA rats. In contrast, severe hyperoxia (≥95% O₂ at Denver's altitude) further reduced lung vessel density after intra-amniotic ETX exposure. We conclude that intra-amniotic ETX induces fetal pulmonary hypertension and causes persistent abnormalities of lung structure with sustained pulmonary hypertension in infant rats. Moreover, moderate postnatal hyperoxia after antenatal ETX restores lung growth and prevents pulmonary hypertension during infancy.

Prognostic importance of hyponatremia in patients with acute pulmonary embolism.

Rationale: Although associated with adverse outcomes in other cardiopulmonary conditions, the prognostic value of hyponatremia, a marker of neurohormonal activation, in patients with acute pulmonary embolism (PE) is unknown. Objectives: To examine the associations between hyponatremia and mortality and hospital readmission rates for patients hospitalized with PE. METHODS: We evaluated 13,728 patient discharges with a primary diagnosis of PE from 185 hospitals in Pennsylvania (January 2000 to November 2002). We used random-intercept logistic regression to assess the independent association between serum sodium levels at the time of presentation and mortality and hospital readmission within 30 days, adjusting for patient (race, insurance, severity of illness, use of thrombolytic therapy) and hospital factors (region, size, teaching status). Measurements and Main Results: Hyponatremia (sodium ?135 mmol/L) was present in 2,907 patients (21.1%). Patients with a sodium level greater than 135, 130-135, and less than 130 mmol/L had a cumulative 30-day mortality of 8.0, 13.6, and 28.5% (P < 0.001), and a readmission rate of 11.8, 15.6, and 19.3% (P < 0.001), respectively. Compared with patients with a sodium greater than 135 mmol/L, the adjusted odds of dying were significantly greater for patients with a sodium 130-135 mmol/L (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.33-1.76) and a sodium less than 130 mmol/L (OR, 3.26; 95% CI, 2.48-4.29). The adjusted odds of readmission were also increased for patients with a sodium of 130-135 mmol/L (OR, 1.28; 95% CI, 1.12-1.46) and a sodium less than 130 mmol/L (OR, 1.44; 95% CI, 1.02-2.02). Conclusions: Hyponatremia is common in patients presenting with PE, and is an independent predictor of short-term mortality and hospital readmission.

Derivation and validation of a prognostic model for pulmonary embolism.

RATIONALE: An objective and simple prognostic model for patients with pulmonary embolism could be helpful in guiding initial intensity of treatment. OBJECTIVES: To develop a clinical prediction rule that accurately classifies patients with pulmonary embolism into categories of increasing risk of mortality and other adverse medical outcomes. METHODS: We randomly allocated 15,531 inpatient discharges with pulmonary embolism from 186 Pennsylvania hospitals to derivation (67%) and internal validation (33%) samples. We derived our prediction rule using logistic regression with 30-day mortality as the primary outcome, and patient demographic and clinical data routinely available at presentation as potential predictor variables. We externally validated the rule in 221 inpatients with pulmonary embolism from Switzerland and France. MEASUREMENTS: We compared mortality and nonfatal adverse medical outcomes across the derivation and two validation samples. MAIN RESULTS: The prediction rule is based on 11 simple patient characteristics that were independently associated with mortality and stratifies patients with pulmonary embolism into five severity classes, with 30-day mortality rates of 0-1.6% in class I, 1.7-3.5% in class II, 3.2-7.1% in class III, 4.0-11.4% in class IV, and 10.0-24.5% in class V across the derivation and validation samples. Inpatient death and nonfatal complications were <or= 1.1% among patients in class I and <or= 1.9% among patients in class II. CONCLUSIONS: Our rule accurately classifies patients with pulmonary embolism into classes of increasing risk of mortality and other adverse medical outcomes. Further validation of the rule is important before its implementation as a decision aid to guide the initial management of patients with pulmonary embolism.

Human fetal bone cells in delivery systems for bone engineering.

The aim of this study was to culture human fetal bone cells (dedicated cell banks of fetal bone derived from 14 week gestation femurs) within both hyaluronic acid gel and collagen foam, to compare the biocompatibility of both matrices as potential delivery systems for bone engineering and particularly for oral application. Fetal bone cell banks were prepared from one organ donation and cells were cultured for up to 4 weeks within hyaluronic acid (Mesolis(®)) and collagen foams (TissueFleece(®)). Cell survival and differentiation were assessed by cell proliferation assays and histology of frozen sections stained with Giemsa, von Kossa and ALP at 1, 2 and 4 weeks of culture. Within both materials, fetal bone cells could proliferate in three-dimensional structure at ∼70% capacity compared to monolayer culture. In addition, these cells were positive for ALP and von Kossa staining, indicating cellular differentiation and matrix production. Collagen foam provides a better structure for fetal bone cell delivery if cavity filling is necessary and hydrogels would permit an injectable technique for difficult to treat areas. In all, there was high biocompatibility, cellular differentiation and matrix deposition seen in both matrices by fetal bone cells, allowing for easy cell delivery for bone stimulation in vivo. Copyright © 2011 John Wiley & Sons, Ltd.

Pretransplant pulmonary hypertension and long-term allograft right ventricular function.

Background: Graft right ventricular (RV) function is compromised directly posttransplant, especially in heart transplantation (HTx) recipients with pretransplant pulmonary hypertension (PH). Graft RV size and systolic function, and the effect of the recipient's pulmonary haemodynamics on the graft extracellular matrix are not well characterised in the patients long-term after HTx. Aim: Comparison of RV size and systolic function in HTx recipients' long-term posttransplant stratified by the presence of pretransplant PH. Methods: HTx survivors >/=2 years posttransplant were divided into group I without pretransplant PH (pulmonary vascular resistance, PVR <2.5Wood units, n=37) and group II with PH (PVR >/=2.5Wood units, n=16). RV size and systolic function were measured using cardiac magnetic resonance imaging (CMR). The collagen content was assessed in septal endomyocardial biopsies obtained at HTx and at study inclusion. Results: Mean posttransplant follow-up was 5.2+/-2.9 years (group I) and 4.9+/-2.2 years (group II) (p=0.70). PVR was 1.5+/-0.6 vs 4.1+/-1.7Wood units pretransplant (p<0.001), and 1.2+/-0.5 vs 1.3+/-0.5Wood units at study inclusion (p=0.43). Allograft RV size and systolic function were similar in both groups (p always >/=0.07). Collagen content at transplantation and at follow-up were not different (p always >/=0.60). Conclusion: Posttransplant normalisation of pretransplant PH is associated with normal graft RV function long-term after HTx.

Infections pulmonaires : le point de vue du radiologue [Pulmonary infections: the radiologist's point of view]

La place de l'imagerie est essentielle au cours des infections pulmonaires. La TDM doit être effectuée en cas de forte suspicion clinique de pneumonie avec aspect radiographique normal, équivoque ou non spécifique, ce qui concerne particulièrement les sujets immunodéprimés. Elle permet de détecter les anomalies associées ou une affection sous-jacente, d'orienter un lavage broncho-alvéolaire ou de guider une biopsie pulmonaire percutanée ou transbronchique. Les expressions d'un germe peuvent varier selon le degré d'immunodépression. Il en est ainsi pour la tuberculose au cours du sida. Les germes impliqués varient selon le type d'immunodépression, certaines infections pouvant engager rapidement le pronostic vital. Le spectre radiologique de l'aspergillose pulmonaire, complexe, doit être connu, ce diagnostic devant être proposé dans des conditions particulières.