Five years of sleep apnea treatment with a mandibular advancement device. Side effects and technical complications

Objective: To determine the variation in prevalence of temporomandibular disorders (TMD), other side effects, and technical complications during 5 years of sleep apnea treatment with a mandibular advancement device. Materials and Methods: Forty patients diagnosed with obstructive sleep apnea received an adjustable appliance at 70% of the maximum protrusion. The protrusion was then progressively increased. TMD (diagnosed according to the Research Diagnostic Criteria for TMD), overjet, overbite, occlusal contacts, subjective side effects, and technical complications were recorded before and a mean of 14, 21, and 58 months after treatment and analyzed by the Wilcoxon test (P Less-than .05). Results: Fifteen patients still used the oral appliance at the 5-year follow-up, and no significant variation in TMD prevalence was observed. Subjective side effects were common, and a significant reduction was found in overjet, overbite, and in the number of occlusal contacts. Furthermore, the patients made a mean of 2.5 unscheduled dental visits per year and a mean of 0.8 appliance repairs/relines per year by a dental technician. The most frequent unscheduled visits were needed during the first year and were a result of acrylic breakage on the lateral telescopic attachment, poor retention, and other adjustments to improve comfort. Conclusions: Five-year oral appliance treatment does not affect TMD prevalence but is associated with permanent occlusal changes in most sleep apnea patients during the first 2 years. Patients seek several unscheduled visits, mainly because of technical complications.

Gene transfer of programmed death ligand-1.Ig prolongs cardiac allograft survival.

BACKGROUND: The CD28 homologue programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2 (which are homologous to B7), constitute an inhibitory pathway of T cell costimulation. The PD-1 pathway is of interest for immune-mediated diseases given that PD-1-deficient mice develop autoimmune diseases. We have evaluated the effect of local overexpression of a PD-L1.Ig fusion protein on cardiac allograft survival. METHODS: Adenovirus-mediated PD-L1.Ig gene transfer was performed in F344 rat donor hearts placed in the abdominal position in Lewis recipients. Inflammatory cell infiltrates in the grafts were assessed by immunohistochemistry. RESULTS: Allografts transduced with the PD-L1.Ig gene survived for longer periods of time compared with those receiving noncoding adenovirus or virus dilution buffer alone: median survival time (MST), 17 (range: 16-20) days vs. 11 (8-14) and 9 (8-13) days, respectively (P < 0.001). PD-L1.Ig gene transfer combined with a subtherapeutic regimen of cyclosporin A (CsA) was superior to CsA alone: MST, 25 (15-42) vs. 15 (13-19) days (P < 0.05). PD-L1.Ig gene transfer was associated with decreased numbers of CD4 cells and monocytes/macrophages infiltrating the graft (P < 0.05). CONCLUSIONS: Localized PD-L1.Ig expression in donor hearts attenuates acute allograft rejection in a rat model. The effect is additive to that of a subtherapeutic regimen of CsA. These results suggest that targeting of PD-1 by gene therapy may inhibit acute cardiac allograft rejection in vivo.

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.

Overfishing of small pelagic fishes increases trophic overlap between immature and mature striped dolphins in the Mediterranean Sea

The interactions among diet, ecology, physiology, and biochemistry affect N and C stable isotope signatures in animal tissues. Here, we examined if ecological segregation among animals in relation to sex and age existed by analyzing the signatures of delta15N and delta13C in the muscle of Western Mediterranean striped dolphins. Moreover, we used a Bayesian mixing model to study diet composition and investigated potential dietary changes over the last two decades in this population. For this, we compared isotope signatures in samples of stranded dolphins obtained during two epizootic events occurring in 1990 and 2007-2008. Mean delta13C values for females and males were not significantly different, but age-related variation indicated delta13C enrichment in both sexes, suggesting that females and males most likely fed in the same general areas, increasing their consumption of benthic prey with age. Enrichment of delta15N was only observed in females, suggesting a preference for larger or higher trophic level prey than males, which could reflect different nutritional requirements. delta13C values showed no temporal variation, although the mean delta15N signature decreased from 1990 to 2007-2008, which could indicate a dietary shift in the striped dolphin over the last two decades. The results of SIAR indicated that in 1990, hake and sardine together contributed to 60% on the diet of immature striped dolphins, and close to 90% for mature striped dolphins. Conversely, the diet of both groups in 2007-2008 was more diverse, as hake and sardine contributed to less than 40% of the entire diet. These results suggest a dietary change that was possibly related to changes in food availability, which is consistent with the depletion of sardine stocks by fishing.

Stable C and N isotope concentration in several tissues of the loggerhead sea turtle Caretta caretta from the western Mediterranean and dietary implications

The isotopic concentrations of carapace scutes, skin, muscle and blood of loggerhead sea turtles (Caretta caretta) from the Balearic Archipelago were analysed to investigate the pattern of variation between tissues and to assess the position of this species in the trophic webs of the Algerian Basin. Skin showed higher δ13C values than muscle or carapace scutes and these showed higher values than blood. Conversely, muscle showed higher δ15N values than skin, skin showed higher values than blood and blood showed higher values than carapace scutes. Dead and live sea turtles from the same habitat did not differ in the concentration of stable isotopes. However, some of the tissues of the turtles caught in drifting longlines in the oceanic realm showed higher δ13C values than those from the turtles caught by hand or in trammel nets over the continental shelf, although they did not differ in the δ15N. Comparison of the concentration of stable isotopes in the turtles with that of other species from several areas of the Algerian Basin revealed that they consumed planktonic prey and that the trophic level of the sea turtles was higher than that of carnivorous cnidarians but lower than that of zooplanktophagous fish and crustaceans.

Tagging reveals limited exchange of immature loggerhead sea turtles (Caretta caretta) between regions in the western Mediterranean.

Exchange of immature loggerhead sea turtles (Caretta caretta) between the northern and southern regions of the western Mediterranean was investigated using data obtained from several Spanish tagging programmes. Tagged turtles ranged in straight carapace length from 23.0 to 74.0 cm. Thirty-six turtles were recaptured after an average interval of 390.5±462.6 days (SD). As the mean dispersal distance (MDD) of a turtle population that spreads over the western Mediterranean would stabilize after 117 days (CI 95%: 98 to 149), two analyses were conducted that included data from turtles recaptured after 98 and 149 days respectively. In both analyses, turtles were recaptured more often than expected in the same region where they had been tagged. No difference was found in either of the two regions between the average distance between the capture and recapture locations and the expected MDD if the turtles were to remain in the region where they were first captured. Turtles recaptured after 15 and 25 days respectively were excluded from the analysis to ensure data independence. The overall evidence indicates that immature turtles exhibit strong site fidelity to certain areas and that there is a strong barrier to dispersal between the northern and southern parts of the western Mediterranean. Therefore, loggerhead turtles in the western Mediterranean should be split into at least two management units.

Changes in the foraging strategy of female South American sea lions (Carnivora: Pinnipedia) after parturition.

This study tests the hypothesis that female South American sea lions shift from off-shore, pelagic prey to coastal, benthic prey after parturition in order to reduce the foraging trip duration and hence the time pups remain unattended on the beach during early lactation. The δ13C and δ15N values of the serum and blood cells of 26 South American sea lion suckling pups from northern Patagonia were used to track the dietary changes of their mothers from late pregnancy to early lactation, after correction for differential isotopic fractionation between tissues. Primary producers and potential prey species were also analysed to establish a baseline for interpreting the stable isotope concentration of serum and blood cells. Isotopic ratios revealed a generalized increase in the consumption of coastal-benthic prey after parturition. Such a generalized post-partum shift will allow females to spend more time on land and look after their pups. The effects of this foraging strategy on the nutritional quality of the female"s diet are discussed.

Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients.

We assessed the impact of antiviral prophylaxis and preemptive therapy on the incidence and outcomes of cytomegalovirus (CMV) disease in a nationwide prospective cohort of solid organ transplant recipients. Risk factors associated with CMV disease and graft failure-free survival were analyzed using Cox regression models. One thousand two hundred thirty-nine patients transplanted from May 2008 until March 2011 were included; 466 (38%) patients received CMV prophylaxis and 522 (42%) patients were managed preemptively. Overall incidence of CMV disease was 6.05% and was linked to CMV serostatus (D+/R- vs. R+, hazard ratio [HR] 5.36 [95% CI 3.14-9.14], pâeuro0/00<âeuro0/000.001). No difference in the incidence of CMV disease was observed in patients receiving antiviral prophylaxis as compared to the preemptive approach (HR 1.16 [95% CI 0.63-2.17], pâeuro0/00=âeuro0/000.63). CMV disease was not associated with a lower graft failure-free survival (HR 1.27 [95% CI 0.64-2.53], pâeuro0/00=âeuro0/000.50). Nevertheless, patients followed by the preemptive approach had an inferior graft failure-free survival after a median of 1.05 years of follow-up (HR 1.63 [95% CI 1.01-2.64], pâeuro0/00=âeuro0/000.044). The incidence of CMV disease in this cohort was low and not influenced by the preventive strategy used. However, patients on CMV prophylaxis were more likely to be free from graft failure.

Limited sampling strategies for monitoring tacrolimus in paediatric liver transplant recipients

Ce travail de recherche a été réalisé dans le laboratoire de pharmacologie clinique, au Centre Hospitalier Universitaire Sainte-Justine, à Montréal. C'est une étude rétrospective basée sur le suivi thérapeutique du Tacrolimus prescrit chez les enfants après transplantation hépatique. Ce suivi est nécessaire car le Tacrolimus possède une importante variabilité pharmacocinétique inter et intra-individuelle ainsi qu'un index thérapeutique très étroit. Actuellement, l'individualisation des doses prescrites est basée sur la mesure de la concentration de base - du médicament dans le sang (C0), mais des études récentes montrent que cette mesure ne reflète pas précisément l'exposition du Tacrolimus dans l'organisme chez les enfants. Le meilleur reflet de cette exposition est la mesure de l'aire sous la courbe (AUC). Cependant, cette dernière implique la mesure de multiples concentrations tout au long de l'intervalle entre 2 doses de médicament (Tacrolimus: 12 heures) ce qui est long, cher et impraticable en ambulatoire. De nouvelles méthodes utilisant un nombre limité de prélèvements ont donc été développées pour prédire au mieux cette AUC. Ce sont les "Limited sampling strategies" ou LSS. La plupart de ces LSS pour le Tacrolimus ont été développées et validées chez des patients transplantés adultes et leur application directe chez les transplantés pédiatriques n'est pas possible en raison de différences importantes au niveau des paramètres pharmacocinétiques du médicament entre ces deux populations. Aussi, le but de ce travail était de développer et valider, pour la première fois, des LSS chez les enfants transplantés hépatiques. Pour cela, une analyse de 36 profils pharmacocinétiques de 28 patients transplantés hépatiques âgés de 0.4- 18.5 ans a été effectuée. Tous les profils ont été réalisés au Centre Hospitalier Universitaire Sainte-Justine entre janvier 2007 et janvier 2009. Les LSS comportant au maximum 4 mesures de concentration ont été développées en utilisant une analyse de régression multiple. Parmi tous les modèles obtenus, cinq ont été sélectionnés sur la base de critères précis puis validés selon la méthode décrite par Sheiner et Beal.¦Les résultats montrent que ces cinq modèles peuvent prédire l'AUC du Tacrolimus avec une précision cliniquement acceptable de ± 15% alors que la C0 présente la plus faible corrélation avec l'AUC.¦En conclusion, cette étude confirme que la C0 ne permet pas de prédire de manière efficace l'exposition du Tacrolimus dans l'organisme dans notre population de patients pédiatriques contrairement aux LSS analysées qui offrent une méthode pratique et fiable. Par ailleurs, en permettant d'obtenir une estimation précise et simplifiée de l'AUC complète du Tacrolimus chez les patients, ces LSS ouvrent la porte à de futures études prospectives visant à mieux définir l'AUC cible du médicament et à déterminer si le suivi basé sur la mesure de l'AUC est plus efficace et plus sûr que celui basé sur la mesure de la C0.

Mortality rates in by-caught loggerhead turtle Caretta caretta in the Mediterranean Sea and implications for the Atlantic populations

Reliable estimates of the post-release mortality probability of marine turtles after incidental by-catch are essential for assessing the impact of longline fishing on these species.Large numbers of loggerhead turtles Caretta caretta from rookeries in the northwestern Atlantic Ocean have been by-caught annually in the southwestern Mediterranean Sea since the 1980s, but nothing is known about their post-release mortality probability under natural conditions. Pop-up archival transmitting tags were attached to 26 loggerhead turtles following incidental capture by Spanish longliners. Hooks were not removed, and 40 cm of line was left in place. The post-release mortality probability during the 90 d following release ranged from 0.308 to 0.365, and was independent of hook location. When the post-release mortality probability was combined with previously reported estimates of the mortality probability before hauling, the aggregated by-catch mortality probability ranged from 0.321 to 0.378. Assuming a total annual by-catch of 10656 loggerhead turtles by the Spanish longline fleet operating in the southwestern Mediterranean, by-catch results in 3421 to 4028 turtle deaths annually. This range is equivalent to 8.5−10.1% of the approximately 40000 turtles inhabiting the fishing grounds used by Spanish longliners, most of them from rookeries in the northwestern Atlantic. As a consequence, the accumulated mortality during the oceanic stage is expected to be larger for those loggerhead turtles of Atlantic origin that spend several years in the Mediterranean Sea than for turtles of the same cohort that remain in the Atlantic. For this reason, the Mediterranean can be considered a dead end for loggerhead turtle populations nesting in the Atlantic, although the actual demographic relevance of by-catch mortality of loggerhead turtles in the Mediterranean remains unknown.

Photonic characteristics of Langmuir-Blodgett self-assembled monolayers of colloidal silica particles

Monodispersed colloidal crystals based on silica sub-micrometric particles were synthesized using the Stöber-Fink-Bohn process. The control of nucleation and coalescence result in improved characteristics such as high sphericity and very low size dispersion. The resulting silica particles show characteristics suitable for self-assembling across large areas of closely-packed 2D crystal monolayers by an accurate Langmuir-Blodgett deposition process on glass, fused silica and silicon substrates. Due to their special optical properties, colloidal films have potential applications in fields including photonics, electronics, electro-optics, medicine (detectors and sensors), membrane filters and surface devices. The deposited monolayers of silica particles were characterized by means of FESEM, AFM and optical transmittance measurements in order to analyze their specific properties and characteristics. We propose a theoretical calculation for the photonic band gaps in 2D systems using an extrapolation of the photonic behavior of the crystal from 3D to 2D. In this work we show that the methodology used and the conditions in self-assembly processes are decisive for producing high-quality two-dimensional colloidal crystals by the Langmuir-Blodgett technique.

Adverse side effects of statins in the oral cavity

Increased plasma levels of cholesterol are high risk factors of cardiovascular disease. Statins are drugs that inhibit cholesterol synthesis at both pancreatic and extrahepathic levels, being the treatment of choice for hypercholesterolemia. Objective: To analyze the side effects of statins in the mouth cavity, and to analyze the symptoms after interruption of the treatment. Design: Observational study, preliminary. Material and methods: Patients aged 50-70, diagnosed with hypercholesterolemia and undergoing treatment with statins, referred from their primary care physician to the dentist"s office. Anamnesis over oral symptoms was performed in the first visit. Statin treatment was discontinued, followed by lab tests and control visits seven and fifteen days later. We monitored the improvement and/or remission of oral symptoms. Statin treatment was resumed, sending out a report of the patient evolution to the PCP. Symptoms were registered in sheet specially designed for the study. Exclusion criteria: patient refusal, use of drugs for dry mouth treatment, Sjögren"s syndrome. Results: n=26 patients. Dry mouth patients: improvement in 17 out of 23 patients (88.5%). Itchiness: 6 out of 15 cases improved (57.7%). Bitterness: improvement in 13 out of 14 patients (53.8%). Cough: improvement in 11 out of 12 patients (46.1%). Discussion: A high percentage of oral symptoms are associated to treatment with statins. There is a marked improvement after temporary interruption of the treatment. Little is known regarding the side effects of oral treatment with statins. This preliminary study includes a relatively small number of patients. The design of experimental treatments will be required to establish a true correlation between statin treatment and oral symptoms

Role of the naive and memory CD4+T-cell repertoire in transplantation

Purpose: The exact role of individual T cell-subsets in the development of rejection is not clearly defined. Given their distinct phenotypes, effector functions and trafficking patterns, naïve (CD45RBhiCD44lo) and memory (CD45RBloCD44hi) T cells may play distinct roles in anti-donor immunity after transplantation. Furthermore, only the CD4+CD45RBlo population contains CD4+CD25+ T cells, a subset with suppressive functions playing a major role in the maintenance of peripheral tolerance. The aim of this work was to study the contribution of these individual subsets in alloresponses via the direct and indirect pathways using a murine experimental model. Methods and materials: Purified naïve or memory CD4+ T cells were adoptively transferred into lymphopenic mice undergoing a skin allograft. Donor to recipient MHC combinations were chosen in order to study the direct and the indirect pathways of allorecognition separately. Graft survival and in vivo expansion, effector function and trafficking of the transferred T cells was assessed at different time points after transplantation. Results: We found that the cross-reactive CD4+CD45RBlo memory T-cell pool was heterogeneous and contained cells with regulatory potentials, both in the CD4+CD25+ and CD4+CD25-populations. CD4+ T cells capable of inducing strong primary alloreactive responses in vitro and rejection of a first allograft in vivo were mainly contained within the CD45RBhi naïve CD4+ T-cell compartment. CD4+CD45RBlo T cells proliferated less abundantly to allogeneic stimulation than their naïve counterparts both in vitro and in vivo, and allowed prolonged allograft survival even after the depletion of the CD4+CD25+ subset. Interestingly, CD4+CD25-CD45RBlo T cells were capable of prolonging allograft survival, mainly when the indirect pathway was the only mechanism of allorecognition. The indirect pathway response, which was shown to drive true chronic rejection and contribute to chronic allograft dysfunction, was predominantly mediated by naïve CD4+ T cells. Conclusion: This work provides new insights into the mechanisms that drive allograft rejection and should help develop new clinical immunosuppressive protocols. In particular, our results highlight the importance of selectively targeting individual T-cell subsets to prevent graft rejection but at the same time maintain immune protective responses to common pathogens.