Search

Peroxisome Proliferator-Activated Receptor Beta (PPARβ) is a transcription factor playing an important role in both muscle myogenesis and remodeling, and in inflammation. However, its role in the coordination of the transient muscle inflammation and reparation process following muscle injury has not yet been fully determined. We postulated that activation of the PPARβ pathway alters the early phase of the muscle regeneration process, i.e. when immune cells infiltrate in injured muscle. Tibialis anteriors of C57BL6/J mice treated or not with the PPARβ agonist GW0742 were injected with cardiotoxin (or with physiological serum for the contralateral muscle). Muscle regeneration was monitored on days 4, 7, and 14 post-injury. We found that treatment of mice with GW0742 increased, at day 4 post-damage, the recruitment of immune cells (M1 and M2 macrophages) and upregulated the expression of the anti-inflammatory cytokine IL-10 and TGF-β mRNA. Those effects were accompanied by a significant increase at day 4 of myogenic regulatory factors (Pax7, MyoD, Myf5, Myogenin) mRNA in GW0742-treated mice. However, we showed an earlier return (7 days vs 14 days) of Myf5 and Myogenin to basal levels in GW0742- compared to DMSO-treated mice. Differential effects of GW0742 observed during the regeneration were associated with variations of PPARβ pathway activity. Collectively, our findings indicate that PPARβ pathway activity shortens the early phases of skeletal muscle regeneration by increasing the immune response.

Metabolism plays an important role in T cell biology and changes in metabolism drive T cell differentiation and fate. Most research on the role of metabolism in T lymphocytes focuses on mature T cells while only few studies have investigated the role of metabolism in T cell development. In this study, we report that activation or overexpression of the transcription factor Peroxisome Proliferator-Activated Receptor β (PPARβ) increases fatty acid oxidation in T cells. Furthermore, using both in vivo and in vitro models, we demonstrate that PPARβ activation/overexpression inhibits thymic T cell development by decreasing proliferation of CD4−CD8− double-negative stage 4 (DN4) thymocytes. These results support a model where PPARβ activation/overexpression favours fatty acid- instead of glucose-oxidation in developing T cells, thereby hampering the proliferative burst normally occurring at the DN4 stage of T cell development. As a consequence, the αβ T cells that are derived from DN4 thymocytes are dramatically decreased in peripheral lymphoid tissues, while the γδ T cell population remains untouched. This is the first report of a direct role for a member of the PPAR family of nuclear receptors in the development of T cells.

Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma plays beneficial roles in cardiovascular disorders such as atherosclerosis and heart reperfusion. Although PPARalpha and gamma have been documented to reduce oxidative stress in the vasculature and the heart, the role of PPARdelta remains poorly studied.We focused on PPARdelta function in the regulation of oxidative stress-induced apoptosis in the rat cardiomyoblast cell line H9c2. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we showed that PPARdelta is the predominantly expressed isotype whereas PPARalpha was weakly detected. By performing cell viability assays, we also showed that the selective PPARdelta agonist GW501516 protected cells from H(2)O(2)-induced cell death. The protective effect of GW501516 was due to an inhibition of H(2)O(2)-triggered apoptosis as shown by annexin-V labeling, DNA fragmentation analysis, and caspase-3 activity measurement. We demonstrated by transient transfection of a dominant negative mutant of PPARdelta that the protection induced by GW501516 was totally dependent on PPARdelta. Semi-quantitative RT-PCR and Western blotting analysis demonstrated that GW501516 treatment upregulated catalase. Moreover, forced overexpression of catalase inhibited H(2)O(2)-triggered apoptosis, as evidenced by annexin-V labeling.Taken together, our results account for an important role of PPARdelta in inhibiting the onset of oxidative stress-induced apoptosis in H9c2 cells. PPARdelta appears to be a new therapeutic target for the regulation of heart reperfusion-associated oxidative stress and stimulation of enzymatic antioxidative defences.

Introduction et but de l’etude L’obesite conduit a une augmentation de cellules pro-inflammatoires qui provoque une inflammation chronique du tissu adipeux et systemique conduisant au developpement d’une insulinoresistance et d’un diabete de type 2. Les cellules pro-inflammatoires utilisent principalement le glucose comme source d’energie, alors que les cellules anti-inflammatoires ont un metabolisme oxydolipidique. Il a ete montre qu’il est possible de modifier le devenir de certaines cellules immunitaires en modifiant leur metabolisme. PPARβ est un facteur de transcription qui agit sur le metabolisme des cellules en favorisant l’oxydation des lipides. Le but de cette etude est de verifier si en favorisant un metabolisme oxydolipidique dans les lymphocytes T grâce a la surexpression de PPARβ, il est possible de diminuer l’inflammation du tissu adipeux dans un contexte d’obesite. Materiel et methodes Nous avons genere un modele de souris surexprimant PPARβ specifiquement dans les lymphocytes T (Tg T-PPARβ) grâce au systeme Cre-Lox. Des souris mâles âgees de 12 semaines (16 Tg T-PPARβ et 17 temoins Lck-CRE), ont ete nourries avec un regime riche en graisse (60 % des calories provenant des lipides) pendant 16 semaines. Des tests de tolerance a l’insuline et au glucose ont ete realises respectivement aux semaines 11 et 13 de regime. Le jour du sacrifice des souris, les cellules stromales des tissu adipeux sous-cutane et epididymal ont ete extraites et les cellules immunitaires marquees et analysees par cytometrie en flux. Une Anova a mesure repetee ou des tests non parametriques ont ete utilises pour l’analyse statistique des resultats. Resultats Le poids des souris Tg T-PPARβ etait diminue de 8 % par rapport aux souris temoins a la fin du regime (p Conclusion La surexpression de PPARβ specifiquement dans les lymphocytes T semble provoquer : – une augmentation de la proportion de lymphocytes T γδ ; – une reduction de l’inflammation des tissus adipeux (sous-cutanee et epididymale) ; – un ralentissement de l’apparition de l’obesite et de l’insulinoresistance lors d’un regime riche en graisse. Notre hypothese est que les effets benefiques observes seraient la consequence d’une diminution du nombre de lymphocytes T αβ (provoquant une augmentation de la proportion des lymphocytes T γδ) consecutive a un changement de metabolisme induit par la surexpression de PPARβ.

Fatty acid translocase (FAT/CD36) is a cell-surface glycoprotein that functions as a receptor/transporter for long-chain fatty acids (LCFAs), and interacts with other protein and lipid ligands. FAT/CD36 is expressed by various cell types, including platelets, monocytes/macrophages and endothelial cells, and tissues with an active LCFA metabolism, such as adipose, small intestine and heart. FAT/CD36 expression is induced during adipose cell differentiation and is transcriptionally up-regulated by LCFAs and thiazolidinediones in pre-adipocytes via a peroxisome-proliferator-activated receptor (PPAR)-mediated process. We isolated and analysed the murine FAT/CD36 promoter employing C2C12N cells directed to differentiate to either adipose or muscle. Transient transfection studies revealed that the 309bp upstream from the start of exon 1 confer adipose specific activity. Sequence analysis of this DNA fragment revealed the presence of two imperfect direct repeat-1 elements. Electrophoretic mobility-shift assay demonstrated that these elements were peroxisome-proliferator-responsive elements (PPREs). Mutagenesis and transfection experiments indicated that both PPREs co-operate to drive strong promoter activity in adipose cells. We conclude that murine FAT/CD36 expression in adipose tissue is dependent upon transcriptional activation via PPARs through binding to two PPREs located at −245 to −233bp and −120 to −108bp from the transcription start site.

Over the past 10 years it has become evident that fatty acids regulate cellular functions by modulating gene expression. Fatty acids and fatty acid metabolites exert some of their effects on gene expression by affecting the activity of nuclear transcription factors, peroxisome proliferator-activated receptors and sterol regulatory element binding protein type 1. The present review describes the latest developments in the field, with particular emphasis on the physiological roles of the various peroxisome proliferator-activated receptor isotypes, including their implication in the control of proliferation and differentiation of normal and malignant cells, and on the mechanisms implicated in the regulation of sterol regulatory element binding protein type 1 activity by polyunsaturated fatty acids.

Nutritional long-chain fatty acids control adipose tissue mass by regulating the number and the size of adipocytes. It is now established that peroxisome-proliferator-activated receptors (PPARs) play crucial functions in the control of gene expression and the level of cell differentiation. PPARgamma, which is activated by specific prostanoids, is a key factor in activating terminal differentiation and adipogenesis. We have recently demonstrated that PPARdelta, once activated by fatty acids, drives the expression of a limited set of genes, including that encoding PPARgamma, thereby inducing adipose differentiation. Thus far, the mechanism of action of fatty acids in the control of preadipocyte proliferation has remained unknown. We show here that PPARdelta is directly implicated in fatty acid-induced cell proliferation. Ectopic expression of PPARdelta renders 3T3C2 cells capable of responding to treatment with long-chain fatty acids by a resumption of mitosis, and this effect is limited to a few days after confluence. This response is restricted to PPARdelta activators and, for fatty acids, takes place within the range of concentrations found to trigger differentiation of preadipocytes both in vitro and in vivo. Furthermore, the use of a mutated inactive PPARdelta demonstrated that transcriptional activity of the nuclear receptor is required to mediate fatty acid-induced proliferation. These data demonstrate that PPARdelta, as a transcription factor, is directly implicated in fatty acid-induced proliferation, and this could explain the hyperplastic development of adipose tissue that occurs in high-fat-fed animals.

AMP-activated protein kinases (AMPK) are heterotrimeric, αβγ, serine/threonine kinases. The γ3-AMPK subunit is particularly interesting in muscle physiology because 1) it is specifically expressed in skeletal muscle, 2) α2β2γ3 is the AMPK heterotrimer activated during exercise in humans, and 3) it is down-regulated in humans after a training period. However, mechanisms underlying this decrease of γ3-AMPK expression remained unknown. We investigated whether the expression of AMPK subunits and particularly that of γ3-AMPK are regulated by the PPARβ pathway. We report that PPARβ activation with GW0742 induces a rapid (2 h) and sustained down-regulation of γ3-AMPK expression both in mouse skeletal muscles and in culture myotubes. Concomitantly, phosphorylation levels of both AMPK and acetyl-coenzyme A carboxylase are rapidly modified. The γ3-AMPK down-regulation is also observed in muscles from young and adult transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor β (PPARβ). We showed that γ3-AMPK down-regulation is a rapid physiological muscle response observed in mouse after running exercise or fasting, two situations leading to PPARβ activation. Finally, using C2C12, we demonstrated that dose and time-dependent down-regulation of γ3-AMPK expression upon GW0742 treatment, is due to decrease γ3-AMPK promoter activity.

This review focuses on the emerging knowledge about peroxisome proliferator-activated receptor beta regulatory functions on metabolism, inflammation, and cellular stress.Recent publications have confirmed the important roles of peroxisome proliferator-activated receptor beta in adaptive metabolic responses of skeletal muscle and have also implicated the nuclear receptor in the regulation of inflammation and oxidative stress in various tissues. The mechanisms implicated in these effects have been partially elucidated.Peroxisome proliferator-activated receptors mediate the transcriptional effects of fatty acids and fatty acid derivatives and regulate many physiological functions, including metabolism and development. Use of potent and specific agonists revealed that activation of peroxisome proliferator-activated receptor beta efficiently reverses some metabolic syndrome-associated abnormalities by affecting metabolic, inflammatory, and oxidative stress responses in several tissues through both genomic and nongenomic modes of action.

Long-chain fatty acids (FA) have been shown to regulate expression of the gene for the adipocyte FA-binding protein aP2. We examined whether this effect was exerted by FA themselves or by a FA metabolite. The alpha-bromo derivative of palmitate, an inhibitor of FA oxidation, was synthesized in the radioactive form, and its metabolism was investigated and correlated with its ability to induce aP2 in Ob1771 preadipocytes. alpha-Bromopalmitate was not utilized by preadipocytes. It was not cleared from the medium over a 24-hr period and was not incorporated into cellular lipids. Short incubations indicated that alpha-bromopalmitate exchanged across the preadipocyte membrane but remained in the free form inside the cell. In line with this, preadipocyte homogenates did not activate alpha-bromopalmitate to the acyl form. However, although it was not metabolized, bromopalmitate was much more potent than native FA in inducing aP2 gene expression. Induction exhibited the characteristics previously described for native FA, indicating that a similar if not identical mechanism was involved. The data indicated that induction of aP2 was exerted by unprocessed FA. Finally, in contrast to preadipocytes, adipocytes metabolized bromopalmitate. This reflected increased activity with cell differentiation of a palmitoyl-CoA synthase that could activate palmitate and bromopalmitate at about one-fifth the rate for palmitate. In preadipocytes, the predominant fatty-acyl-CoA synthase, arachidonyl-CoA synthase, had very low affinity for both FA. Increased activity of the palmitoyl-CoA synthase, which has a wider substrate range, is likely to be important for initiation of lipid deposition.

C2C12 cells exposed to hyperthermia (41 degrees C) experienced an increase in both protein synthesis and degradation. The addition of IL15 under hyperthermic conditions resulted in an important increase in protein synthesis with no changes in protein degradation, except when cells overexpressed PPARdelta. The PPARdelta agonist GW501516 exerted similar effects on protein synthesis to IL15. Expression of a mutant dominant negative form of PPARdelta prevented the effect of the cytokine on protein synthesis, suggesting that this transcription factor is involved in the anabolic action of IL15. The present study also suggests that the effects of IL15 on lipid oxidation could be mediated by PPARdelta.

C2C12 cells exposed to hyperthermia (41 degrees C) experienced an increase in both protein synthesis and degradation. The addition of IL15 under hyperthermic conditions resulted in an important increase in protein synthesis with no changes in protein degradation, except when cells overexpressed PPARdelta. The PPARdelta agonist GW501516 exerted similar effects on protein synthesis to IL15. Expression of a mutant dominant negative form of PPARdelta prevented the effect of the cytokine on protein synthesis, suggesting that this transcription factor is involved in the anabolic action of IL15. The present study also suggests that the effects of IL15 on lipid oxidation could be mediated by PPARdelta.

Providers should be aware of the following recent developments in the Medicare Part D program: The standard plan will cost more in 2007. The coverage gap will remain a source of discontent. The recently streamlined Drug Plan Finder eases decision making. The weighting method used to calculate the national average bid has been modified. The Part D audit guide has been finalized. Rebates and other price concessions face greater scrutiny. There is renewed debate over negotiated drug prices.

Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a comprehensive and integrated approach to the delivery of early intervention and treatment services through universal screening for persons with substance use disorders and those at risk. This paper describes research on the components of SBIRT conducted during the past 25 years, including the development of screening tests, clinical trials of brief interventions and implementation research. Beginning in the 1980s, concerted efforts were made in the US and at the World Health Organization to provide an evidence base for alcohol screening and brief intervention in primary health care settings. With the development of reliable and accurate screening tests for alcohol, more than a hundred clinical trials were conducted to evaluate the efficacy and cost effectiveness of alcohol screening and brief intervention in primary care, emergency departments and trauma centers. With the accumulation of positive evidence, implementation research on alcohol SBI was begun in the 1990s, followed by trials of similar methods for other substances (e.g., illicit drugs, tobacco, prescription drugs) and by national demonstration programs in the US and other countries. The results of these efforts demonstrate the cumulative benefit of translational research on health care delivery systems and substance abuse policy. That SBIRT yields short-term improvements in individuals’ health is irrefutable; long-term effects on population health have not yet been demonstrated, but simulation models suggest that the benefits could be substantial.

Metabolic disturbances associated with alterations in lipid metabolism, such as obesity, type 2 diabetes, and syndrome X, are becoming more and more prominent in Western societies. Despite extensive research in such pathologies and their molecular basis, we are still far from completely understanding how these metabolic perturbations are produced and interrelate and, consequently, how to treat them efficiently. The discovery that adipose tissue is, in fact, an endocrine tissue able to secrete active molecules related to lipid homeostasis--the adipokines--has dramatically changed our understanding of the molecular events that take place in such diseases. This knowledge has been further improved by the discovery of peroxisome proliferator-activated receptors and their ligands, at present commonly used for the clinical treatment of lipid disturbances. However, a key point remains to be solved, and that is the role of muscle lipid metabolism, notably because of the main role played by this tissue in the development of such pathologies. In addition, a reciprocal regulation between adipose tissue and skeletal muscle has been proposed. New discoveries on the role of peroxisome proliferator-activated receptor-delta in skeletal muscle functions as well as the secretory capabilities of muscle, now considered as an endocrine tissue, have changed the general point of view on lipid homeostasis, opening new and promising doors for the treatment of lipid disorders.

It has been suggested that the teratogenic effects of the antiepileptic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferator-activated receptor delta (PPARdelta), and inhibition of histone deacetylases (HDACs). The aim of this study was to identify genes involved in the differentiation of F9 cells induced by VPA, teratogenic VPA derivatives, or the HDAC inhibitor trichostatin A (TSA) and to characterize the role of PPARdelta. Treatment of the cells with teratogenic VPA derivatives or TSA induced differentiation of F9 cells, mRNA, and protein expression of the neural cell adhesion molecule (NCAM) as well as activated the 5'-flanking region of the NCAM promoter, whereas nonteratogenic VPA derivatives had no effect at all. The polysialyltransferases [ST8SiaIV (PST1) and ST8SiaII] are responsible for the addition of polysialic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA derivatives and TSA. As shown by fluorescence-activated cell sorting analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA derivatives. It is interesting that overexpression of the PPARdelta but not PPARalpha or PPARgamma in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than in mock-transfected F9 cells. Furthermore, repression of PPARdelta activity in F9 cells inhibited these effects. We conclude that NCAM and PST1 are molecular markers in F9 cell differentiation caused by treatment with teratogenic VPA compounds or TSA and suggest that in addition to HDAC inhibition PPARdelta is involved in the signaling pathway.

All compensation arrangements contain incentives. Fee-for-service encourages physicians to render excessive services: capitation does the opposite. The federal government has published regulations that govern managed care organizations' physician incentive plans. Most health plans already comply with the new requirements.

Developed primarily for consumers, Medicare's Compare web sites permit immediate access to information about most nursing homes and home health agencies, including indicators of the quality of care they provide. But hospital staff, too--most notably strategic and discharge planners--can benefit by consulting Compare.

We have recently established that the blood concentrations of gallic acid (GA), a polyphenolic component naturally found in food, and its O-methyl derivatives are very low (practically ⩽1 μM) in physiological (postprandial) condition. Using acellular oxidant systems and macrophage-differentiated promonocytes (MDPs) THP-1, we show here that the direct and indirect (through depressing effect on the superoxide cell production) antioxidant properties of these components were not effective at these concentrations. In contrast, 4-O-methyl GA was the most efficient component to depress AT1R and CD36 mRNA expression in Ang II-treated MDPs, suggesting a strong inhibition of Ang II-triggered pro-atherogenic mechanisms of foam cell formation.

Medicare's drug discount card program is expected to help participants save an average of 10 to 15 percent on the cost of outpatient prescription drugs. Many of the beneficiaries signing up for the program will also qualify for financial assistance. In 2006, the program will be replaced by Medicare's outpatient drug benefit. Data from the card program should help federal actuaries estimate the cost of the drug benefit.

Introduction Une activite physique aerobie, moderee et reguliere, permet de reduire l’incidence du diabete de type II chez des sujets « metaboliquement » exposes, en augmentant le catabolisme lipidique et les capacites antioxydantes musculaire. Ce remodelage oxydatif peut etre induit chez la souris par l’activation de la voie PPARbeta. Nous avons montre que l’expression de PPARbeta etait diminuee dans deux situations physiologiques d’exposition au stress oxydant (l’exercice intense « aigu » et le vieillissement). Objectif Montrer que le statut redox des cellules musculaires determine les effets geniques de PPARbeta (potentiel contractile et metabolique) par une modulation de l’activation des voies de signalisation « redox-sensibles ». Materiels et methodes Nous avons maintenu des myotubes C2C12 et C2C12 surexprimant PPARbeta (C2C12 – PPARbeta) dans des conditions normales ou stressantes (TNF–, LPS). Nous avons co-traite les cellules par un antioxydant puissant : l’acide –-lipoique (ALA) et par du GW0742 (agoniste specifique de PPARbeta). Par l’ajout d’inhibiteurs et d’activateurs, nous avons determine les voies de signalisation affectees par ces conditions. L’expression genique et proteique de PPARbeta et de ses genes cibles a ete mesuree. Resultats Nos resultats montrent que l’activite de NFKB et les concentrations de glutathion total (GSHtot) sont PPARbeta dependantes. L’ALA augmente l’expression genique et proteique de PPARbeta d’un facteur 2 dans les C2C12 et permet l’acquisition d’un statut en GSHtot similaire a celui des C2C12-PPARbeta. Le traitement a l’ALA des C2C12 a des effets geniques communs et additifs a ceux d’un traitement au GW0742 sans qu’il ne soit demontre que l’ALA soit un activateur de PPARbeta. Ces effets semblent passer par une modulation de l’activite de kinases du stress. Conclusion De mimer les effets « benefiques » d’une activation de PPARbeta permet d’envisager des nouvelles strategies therapeutiques et preventives du diabete de type II en maitrisant les conditions de stress cellulaire.

Ambulance fees vary with the level of service and length of the beneficiary's trip. New fee schedule is expected to trim Medicare spending. Higher fees have been implemented for rural transports and air ambulance services. Lower fees have been implemented for urban transports. Providers and suppliers must revise chargemasters, policies, and procedures.

Medicare's hospital outpatient prospective payment system (OPPS) went live on August 1, 2000, after a decade of developmental work. The new system introduced a fee schedule that replaced the cost-related methods that Medicare previously used to reimburse various hospital outpatient services. Hospitals are now paid predetermined rates or fees based on the Ambulatory Patient Classification (APC) groups assigned to the services that Medicare patients receive during outpatient encounters. The new system aims to simplify Medicare's intricate cost-based reimbursement policies, improve hospital efficiency, ensure that payments are sufficient to compensate hospitals for reasonable Medicare costs, and reduce Medicare coinsurance amounts for beneficiaries. Implementation of OPPS-related administrative and operational changes has been a major challenge for hospitals.

On July 1, 1998, Medicare's cost-related reimbursement method for skilled nursing facility care was replaced with a prospective payment system that includes a case-mix adjustment based on the Resource Utilization Groups to which Medicare residents are assigned. Shortly thereafter, Congress modified the new system in response to the industry's complaints about low payment rates. The new system aims to align Medicare payments more closely with the costs facility's incur in serving Medicare residents and slow Medicare spending growth. Recent rate increases have reduced the new system's ability to trim Medicare outlays.

Since 1997, the method to establish capitation rates for Medicare beneficiaries who are members of risk-bearing managed care plans has undergone several important developments. This includes the factoring of beneficiary health status into the rate-setting calculations. These changes were expected to increase the number of participating health plans, accelerate Medicare enrollment growth, and slice Medicare spending.

On January 1, 2002, Medicare began to replace its cost-related inpatient reimbursement method for rehabilitation hospitals and rehabilitation units in hospitals with a prospective payment system. Under the new system, Medicare pays a predetermined, fixed amount per discharge, depending on the patient's impairment level, functional status, comorbid conditions, and age. Reduced or additional amounts are paid for early transfers, short-stay outliers, patients who expire before transfer, and cost outliers. The overall objective of the new case-based system is to provide incentives for rehabilitation facilities to furnish intensive inpatient services efficiently without tarnishing the quality of care or constraining access to care. Federal actuaries estimate that the new system will cost Medicare an additional $70 million between January 1, 2002, and September 30, 2003. The actual increase may be larger.

Starting October 1, 2000, Medicare began paying providers of home health care at fixed, predetermined rates for services and items bundled into 60-day episodes of home health care. The episode payment rates vary with the patient's clinical, functional, and services utilization characteristics. This new approach was expected to redistribute Medicare payments among home health agencies, extend the cost savings introduced by the Interim Payment System, improve the coordination of services, and reduce the number of unnecessary home health visits.

Beginning January 1, 1992, Medicare has relied on a resource-based relative value scale (RBRVS) to establish physician fees. Medicare pays 80 percent of the lower of the amount a physician bills for the service or the fee schedule amount. The patient is responsible for the remaining 20 percent, as well as the annual Part B deductible of $100, plus any additional amount the physician may be allowed to bill. Rarely is the billed amount below Medicare's fee schedule amount. Adoption of the RBRVS fee schedule severed the link between the amount a physician charged for a service and the amount Medicare paid for it. RBRVS implementation required significant changes in the coding system used to document and bill physician services, particularly medical visits and consultations.

Introduction Une activite physique reguliere permet de reduire l’incidence de l’obesite et des maladies metaboliques associees comme le diabete de type 2, en provoquant un remodelage oxydatif du muscle squelettique. Nous avons montre que ce type de remodelage pouvait etre induit chez la souris par l’activation ou la surexpression « muscle specifique » de PPARβ (Peroxisome Proliferator-Activated Receptor beta). L’exercice modifie aussi la composition d’une proteine kinase trimerique αβγ, principal senseur des niveaux d’energie dans la cellule : l’AMP-activated protein kinase (AMPK). En effet, l’expression de sa sous-unite « muscle specifique » γ3 (γ3AMPK) est fortement diminuee chez des individus entraines. Notre objectif a ete d’etudier les consequences de l’activation de PPARβ sur la composition de l’AMPK. Materiels et methodes Les niveaux d’expression des sous-unites de l’AMPK ont ete analyses par PCR quantitative et western blot. Des souris (C57Bl6) et des cellules (C2C12) ont ete traitees ou non avec le GW0742 (activateur specifique de PPARβ). Les effets de la surexpression musculaire de PPARβ, de l’entrainement et du jeune, ont egalement ete analyses. Resultats Nos resultats montrent une diminution de l’expression de γ3AMPK dans les situations physiologiques necessitant une augmentation de l’oxydation des acides gras dans le muscle squelettique. Cette diminution est proportionnelle aux niveaux d’activation de PPARβ. L’activation pharmacologique de PPARβ induit, in vivo et in cellulo, une diminution (−50%) rapide (2 h) et soutenue (48 h) de l’expression de γ3AMPK. Cette diminution est retrouvee dans les muscles de souris transgeniques surexprimant PPARβ. Enfin, le GW0742 reprime de facon dose dependante l’activite du promoteur de γ3AMPK. Conclusion Notre etude met en evidence une nouvelle interaction entre PPARβ et l’AMPK. Les modifications rapides de la composition de l’AMPK induites par PPARβ sont un evenement precoce qui permettraient une flexibilite metabolique du muscle et l’amelioration des parametres biologiques des diabetiques de type 2.

Introduction La prevalence mondiale croissante du diabete de type 2 (DT2) rend prioritaire la recherche de nouvelles voies therapeutiques. Notre laboratoire a identifie PPARβ/δ (peroxisome proliferator-activated receptors β/δ) comme une cible prometteuse dans le muscle squelettique (l’activation pharmacologique de PPARβ/δ induit un remodelage musculaire comparable a celui provoque par l’adaptation a l’entrainement d’endurance et implique des modifications de l’AMP-activated protein kinase, une kinase reconnue comme senseur des niveaux d’energie de la cellule. L’objectif de ce travail a ete d’evaluer la disponibilite des triglycerides intramusculaires : IMTGs) pouvant concourir au remodelage oxydatif du muscle squelettique consecutif a l’activation pharmacologique de PPARβ/δ. Materiels et methodes Deux modeles cellulaires (myotubes differencies de C2C12 et C2C12-PPARβ/δ) et deux modeles animaux (souris C57Bl6 et souris transgeniques B6D2 surexprimant PPARβ/δ dans leurs muscles squelettiques) ont ete soumis a differentes conditions : traitement au GW0742 (activateur specifique de PPARβ/δ), regime hypercalorique hyperlipidique, ou entrainement physique pour les animaux. Nous avons quantifie les contenus en IMTGs, mesure la quantite (ARNm et proteine) de ATGL et HSLa (acteurs majeurs de la lipolyse musculaire) et evalue les modifications de Plin2 et DGAT1 (proteines cles de la mise en reserve des IMTGs). Resultats Nos resultats montrent que la surexpression de PPARβ/δ augmente la mise en reserve des IMTGs alors que son activation pharmacologique s’accompagne 1) d’une augmentation de la lipolyse (expression de ATGL et HSLa) lorsque le traitement au GW0742 est de courte duree (24 h de traitement) mais aussi 2) d’une augmentation du potentiel de stockage des IMTGs (Plin2 et DGAT1) dans les cellules musculaires. Conclusion Nous avons decouvert une implication centrale de PPARβ/δ dans les phenomenes de stockage et de degradation des triglycerides musculaires. Ce mecanisme pourrait etre necessaire au changement de preference de substrats energetiques du muscle squelettique des glucides au profit des acides gras « plus disponibles », conduisant ainsi a une « Transition metabolique » glucido-lipidique. Ces resultats confirment le fort potentiel des activateurs de PPARβ/δ dans la lutte contre le DT2.

Introduction L'exercice induit un remodelage oxydatif du muscle squelettique caracterise par une augmentation du nombre de fibres oxydatives et de capillaires sanguins. Chez la souris, l'activation ou la surexpression « muscle specifique » de PPARβ (Peroxisome Proliferator-Activated Receptor beta) donne lieu aux memes modifications. Chez les animaux traites avec un agoniste de PPARβ ce remodelage est extremement rapide puisque termine en 48 heures. Nos travaux recents montrent que dans ce laps de temps, le remodelage musculaire s'accompagne, comme chez les individus entraines, d'une augmentation de la densite myonucleaire et d'un changement de la composition trimerique de l'AMPK (AMP-activated protein kinase). Materiels et methodes La densite myonucleaire a ete mesuree chez des souris transgeniques qui sur-expriment ou non PPARβ specifiquement au niveau musculaire, ainsi que chez des souris traitees ou non avec du GW0742, activateur specifique de PPARβ. Les niveaux d'expression des sous-unites de l'AMPK ont ete analyses par PCR quantitative et par western blot. Les effets de l'entrainement et du jeune, ont egalement ete analyses. Resultats Nous montrons d'une part que l'activation pharmacologique de PPARβ provoque une accretion myonucleaire rapide et massive (+20 % apres 48h), qui semble resulter de la fusion de precurseurs musculaires pre-existant avec les fibres musculaires. D'autre part, l'activation de PPARβ induit, in vivo et in cellulo, une diminution (- 50 %) rapide (2h) et soutenue (48h) de l'expression de l'AMPKγ3, sous-unite de l'AMPK exprimee uniquement au niveau musculaire. L'augmentation de la densite myonucleaire et la diminution de l'expression de l'AMPK γ 3 sont aussi retrouvees dans les muscles de souris surexprimant PPARβ. Conclusion : La rapidite remarquable de tous ces evenements chez des souris traitees avec un agoniste specifique de PPARβ temoigne de l'extreme flexibilite du muscle squelettique tant au niveau structural que metabolique. L'importante accretion myonucleaire et les modifications de la composition de l'AMPK peuvent expliquer en partie la reprogrammation des fibres.

This article updates nurse managers on the social and political aspects of how Medicare beneficiaries pay for outpatient drug bills.

A medicare proposal to adjust capitation rates according to health factors would boost the predictability of care costs and capitation accuracy, but lower payments to managed care organizations.

Medicare, Medicaid, and urban-based commercial health plans are attempting to increase managed care's presence in the nation's rural areas, prompting rural-based providers to sponsor their own managed-care plans.

In Part 1, the author explained Medicare's Quality Improvement System for Managed Care, Medicare's first consistent set of standards to monitor and evaluate the quality of managed care for its members. This month, read about the plans' need to meet certain patient-focused standards and the strain this places on plans' administrations.

Can teaching hospitals continue operating graduate medical education programs in a world of cost-conscious purchasers, competitive marketplaces, and cutbacks in Medicare's financial support? The absence of widely evident financial problems may slow efforts to establish national trust funds for graduate medical education.

Prospective payment systems are replacing the methods Medicare uses to reimburse home health agencies, skilled nursing facilities, and rehabilitation hospitals, as well as imposing new limits on payments for outpatient rehabilitation services. Medicare stands to save substantial sums of money and possibly to hasten the formation of integrated delivery systems for postacute care.

The federal government has issued the solvency standards that provider-sponsored organizations (PSOs) must meet to serve Medicare beneficiaries on a capitated basis. These standards are intended to make certain that PSOs are financially able to serve Medicare beneficiaries and protect them from financial harm should an organization go broke. More than a few of these organizations may lose a lot of money.

National concern about the quality of managed care organizations (MCOs) is evident in two recent developments: (1) the new application form that MCOs must complete to become Medicare risk contractors; and (2) the National Committee for Quality Assurance (NCQA) plans to launch performance-based accreditation for MCOs, beginning mid-1999.