C. elegans PlexinA PLX-1 mediates a cell contact-dependent stop signal in vulval precursor cells

AbstractPLX-1 is a PlexinA transmembrane protein in Caenorhabditis elegans, and the transmembrane-type semaphorin, SMP-1, is a ligand for PLX-1. The SMP-1/PLX-1 system has been shown to be necessary for proper epidermal morphogenesis in the male tail and seam cells. Here, we show that the SMP-1/PLX-1 system also regulates vulval morphogenesis. In plx-1 and smp-1 mutants, hermaphrodites sometimes exhibit a protruding vulva or multiple vulva-like protrusions. Throughout the vulval development of plx-1 and smp-1 mutants, the arrangement of vulval cells is often disrupted. In the initial step of vulval morphogenesis, vulval precursor cells (VPCs) are generated normally but are subsequently arranged abnormally in mutants. Continuous observation revealed that plx-1 VPC fails to terminate longitudinal extension after making contact with neighbor VPCs. The arrangement defects of VPCs in plx-1 and smp-1 mutants are rescued by expressing the respective cDNA in VPCs. plx-1::egfp and smp-1::egfp transgenes are both expressed in all vulval cells, including VPCs, throughout vulval development. We propose that the SMP-1/PLX-1 system is responsible for a cell contact-mediated stop signal for VPC extension. Analyses using cell fate-specific markers showed that the arrangement defects of VPCs also affect cell fate specification and cell lineages, but in a relatively small fraction of plx-1 mutants

Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice

Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome

Cellular analysis of SOD1 protein-aggregation propensity and toxicity: a case of ALS with slow progression harboring homozygous SOD1-D92G mutation

Mutations within Superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS), accounting for approximately 20% of familial cases. The pathological feature is a loss of motor neurons with enhanced formation of intracellular misfolded SOD1. Homozygous SOD1-D90A in familial ALS has been reported to show slow disease progression. Here, we reported a rare case of a slowly progressive ALS patient harboring a novel SOD1 homozygous mutation D92G (homD92G). The neuronal cell line overexpressing SOD1-D92G showed a lower ratio of the insoluble/soluble fraction of SOD1 with fine aggregates of the misfolded SOD1 and lower cellular toxicity than those overexpressing SOD1-G93A, a mutation that generally causes rapid disease progression. Next, we analyzed spinal motor neurons derived from induced pluripotent stem cells (iPSC) of a healthy control subject and ALS patients carrying SOD1-homD92G or heterozygous SOD1-L144FVX mutation. Lower levels of misfolded SOD1 and cell loss were observed in the motor neurons differentiated from patient-derived iPSCs carrying SOD1-homD92G than in those carrying SOD1-L144FVX. Taken together, SOD1-homD92G has a lower propensity to aggregate and induce cellular toxicity than SOD1-G93A or SOD1-L144FVX, and these cellular phenotypes could be associated with the clinical course of slowly progressive ALS

Expression of 11beta-hydroxysteroid dehydrogenase 2 contributes to glucocorticoid resistance in lymphoblastic leukemia cells

Synthetic glucocorticoids (GC) form a crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However prolonged GC therapy frequently leads to GC-resistance with an unclear molecular mechanism. 11β-hydroxysteroid dehydrogenase (11β-HSD) 2 inactivates GCs within cells. Here, we show the association between GC sensitivity and 11β-HSD2 expression in human T-cell leukemic cell lines. 11β-HSD2 mRNA and protein levels were considerably higher in GC-resistant MOLT4F cells than in GC-sensitive CCRF-CEM cells. The 11β-HSD inhibitor, carbenoxolone pre-treatment resulted in greater cell death with prednisolone assesed by methyl-thiazol-tetrazolium assay and Caspase-3/7 assay, suggesting that 11β-HSD2 is a cause of GC-resistance in ALL

Accelerometer-based physical activity in a large observational cohort - study protocol and design of the activity and function of the elderly in Ulm (ActiFE Ulm) study

<p>Abstract</p> <p>Background</p> <p>A large number of studies have demonstrated a positive effect of increased physical activity (PA) on various health outcomes. In all large geriatric studies, however, PA has only been assessed by interview-based instruments which are all subject to substantial bias. This may represent one reason why associations of PA with geriatric syndromes such as falls show controversial results. The general aim of the Active-Ulm study was to determine the association of accelerometer-based physical activity with different health-related parameters, and to study the influence of this standardized objective measure of physical activity on health- and disability-related parameters in a longitudinal setting.</p> <p>Methods</p> <p>We have set up an observational cohort study in 1500 community dwelling older persons (65 to 90 years) stratified by age and sex. Addresses have been obtained from the local residents registration offices. The study is carried out jointly with the IMCA - Respiratory Health Survey in the Elderly implemented in the context of the European project IMCA II. The study has a cross-sectional part (1) which focuses on PA and disability and two longitudinal parts (2) and (3). The primary information for part (2) is a prospective 1 year falls calendar including assessment of medication change. Part (3) will be performed about 36 months following baseline. Primary variables of interest include disability, PA, falls and cognitive function. Baseline recruitment has started in March 2009 and will be finished in April 2010.</p> <p>All participants are visited three times within one week, either at home or in the study center. Assessments included interviews on quality of life, diagnosed diseases, common risk factors as well as novel cognitive tests and established tests of physical functioning. PA is measured using an accelerometer-based sensor device, carried continuously over a one week period and accompanied by a prospective activity diary.</p> <p>Discussion</p> <p>The assessment of PA using a high standard accelerometer-based device is feasible in a large population-based study. The results obtained from cross-sectional and longitudinal analyses will shed light on important associations between PA and various outcomes and may provide information for specific interventions in older people.</p

60歳以上の造血器悪性腫瘍に対して施行した臍帯血移植の3例

(症例1)68歳男性.2002年12月に発症したmantle cell lymphoma,clinical stage III A.CHOP療法,rituximab-CHOP療法により完全寛解となった.治療中に直腸癌が認められたため手術を施行した.その後頚部再発をきたし,化学療法,放射線局所照射を行ったが寛解には到らず,2004年4月に,膀帯血移植を施行した.Day19に生着,day28に完全キメラを確認した.Day44に頚部再発を認め,FK506中止し,腫瘍は縮小となったが再び増大し,化学療法を施行中である.(症例2)62歳男性.2002年7月に発症した.myelodysplastic syndrome (MDS) refractory anemia with excess of blasts(RAEB).Acute myeloblastic leukemia(AML)への進展を認めたため2004年5月に膀帯血移植を施行した.Day31に生着,day28に完全キメラを確認した.現在完全寛解を維持している.(症例3)60歳女性.2004年6月に発症したMDS(RAEB in transformation).早々にAMLへ移行したため,PS1で2004年8月に臍帯血移植を施行した.Day78に生着,day28に完全キメラを確認した.Day61に皮膚stage3・grade IIのacute graft versus host diseaseが出現したが,predonisolone 0.5mg/kg開始し速やかに消退した.現在完全寛解を維持している.最近施行されるようになってきた高齢者に対する造血幹細胞移植は,患者の高齢化に伴い健常な同胞ドナー候補を探すことが困難であり,また病勢によっては骨髄バンクからドナー候補を探す時間的な余裕がないことなどが問題となっている.一方,膀帯血移植は当初は小児領域で施行されていたが,最近では主に成人に対して施行されるようになっている.今回60歳以上の高齢者の造血器悪性腫瘍3例に対して臍帯血移植を施行し,その経過,合併症について検討した.高齢者の造血器悪性腫瘍に対して移植を考慮する場合に同胞に適するドナーがいない場合,非血縁骨髄移植のみならず,今後は臍帯血移植も選択肢の一つとして考慮し得るということが示された.Allogenic stem cell transplantation is now done not only for younger but also for elderly patients. It is very difficult for elderly patients to find healthy, suitable related donors, and in many cases there is not enough time to find unrelated bone marrow donors due to disease status. Cord blood transplantation was originally done for pediatric patients, but is now done for more adult patients than pediatric patients. We performed cord blood transplantation for 3 patients over 60 years old with hematological malignancies. We report their clinical courses and complications. If there are no suitable related donors for elderly patients, it is possible to choose not only unrelated bone marrow transplantation, but also cord blood transplantation

The Long-Term Care Workforce: Overview and Strategies to Adapt Supply to a Growing Demand

This working paper offers an overview of the LTC workforce and reviews country responses to a growing demand for LTC workers. In the context of ageing societies, the importance of long-term care is growing in all OECD countries. In 2005, long-term care expenditure accounted for slightly over 1% of GDP across OECD countries (OECD Health Data 2008), but this is projected to reach between 2% and 4% of GDP by 2050 (Oliveira Martins et al., 2006). Spending on long-term care as a share of GDP rises with the share of the population that is over 80 years old, which is expected to triple from 4 per cent to 11-12 per cent between 2005 and 2050. In addition to ageing, there are other factors likely to affect future spending. Trends in severe disability among elderly populations across 12 OECD countries for which data are available do not show a consistent sign of decline (Lafortune and Balestat, 2007), while the number of elderly that need assistance in carrying out activities of daily living is also growing. Meanwhile, societal changes – notably possible reductions in the importance of informal care due to rising labour market participation by women and declining family size, as well as growing expectations for more responsive, quality health and social-care systems – are creating pressures to improve value for money in long-term care systems. These factors add pressures on the workforce of this highly labour-intensive sector. Adding to this are the difficulties in attracting and retaining caregivers to a physically and mentally gruelling profession. Soins de longue durée: l'accroissement de la demande de travailleurs du secteur Ce document de travail présente une vue d’ensemble sur les travailleurs du secteur des soins de longue durée (SLD) et passe en revue les réponses des pays à l'accroissement de la demande de travailleurs des SLD. Dans le contexte du vieillissement des sociétés, l’importance des soins de longue durée va se développer dans tous les pays de l’OCDE. En 2005, les dépenses de SLD ne représentaient guère plus de 1 % du PIB dans ces différents pays (Éco-Santé OCDE 2008), mais d’après les projections, cette proportion pourrait atteindre entre 2 et 4 % du PIB à l’horizon 2050 (Oliveira Martins et al., 2006). La part des dépenses de SLD exprimées en pourcentage du PIB augmente en même temps que s’accroît la part de la population âgée de plus de 80 ans. Or, cette part devrait tripler entre 2005 et 2050 et passer de 4 % à 11 ou 12 % sur cette période. Outre le vieillissement, d’autres facteurs pouvant affecter les dépenses futures sont impliqués. Dans 12 pays de l’OCDE pour lesquels on dispose de données, la tendance à l’incapacité sévère chez les personnes âgées ne diminue pas de manière régulière (Lafortune et Balestat, 2007), tandis que le nombre de personnes âgées ayant besoin d’aide pour accomplir les activités élémentaires de la vie quotidienne est en augmentation. En même temps, l’évolution de la société (notamment, la possible diminution d’importance qui devrait être accordée aux soins informels du fait de l’accroissement du taux d’activité des femmes et de la diminution de la taille des familles, mais aussi les attentes croissantes face à des systèmes de soins de santé et de protection sociale que l’on voudrait plus réactifs et de meilleure qualité) accroît la nécessité d’une utilisation plus efficiente des ressources des systèmes de SLD. Ces facteurs renforcent la pression qui s’exerce sur les travailleurs de ce secteur à très forte intensité de main-d’oeuvre. S’y ajoutent les difficultés rencontrées pour attirer des soignants vers un métier pénible à la fois physiquement et psychologiquement et pour les retenir.

Reversible inhibition of Ca2+- or Mg2+-dependent ATPase activity in the rat brain by local anesthetics

Background: Local anesthetics can easily pass through the blood-brain barrier and may cause adverse effects in the brain; however, the direct influence of these effects on the central nervous system remains to be clarified. ATPases activated by Ca2+ (Ca-ATPase) or Mg 2+ (Mg-ATPase), which are different from the plasma membrane (PMCA) or the sarco-endoplasmic reticulum (SERCA) Ca, Mg-ATPases, exist in the brain. There are some reports on the effect of local anesthetics on PMCA and SERCA, but few have described the effects on Ca- or Mg-ATPase. The aim of our study was to describe the effect of local anesthetics on these ATPases. Methods: We isolated plasma membrane (PII) and microsomal (PIII) fractions from rat brain homogenates and examined the effects of local anesthetics, procaine, tetracaine, lidocaine, prilocaine, bupivacaine, and dibucaine on Ca- or Mg-ATPase activities at pH 7.4 or 9.5. Results: The Ca- and Mg-ATPase activities of the PII fraction were inhibited in a dose-dependent manner by all local anesthetics at pH 9.5, which is the range of clinical use. Tetracaine and dibucaine, which are clinically strong anesthetics, showed strong inhibitory effects on ATPase activity. The inhibition of activity by lidocaine, tetracaine, and dibucaine was recovered after their concentrations were diluted, suggesting that their inhibitory actions were reversible. Conclusion: These results suggest that local anesthetics at concentrations available for dental use, reversibly inhibit PII Ca- or Mg-ATPase activities in the rat brain

OECD Health Care Quality Indicators Project

Projekt OECD o kazalcih kakovosti zdravstvenega varstva (HCQI) nadaljuje z delom, s katerim sta začela Sklad britanske zveze države (Commonwealth Fund) in Nordijski svet ministrov (Nordic Council of Ministers). Dolgoročni cilj je razvoj in vzpostavitev zbirke kazalcev kakovosti na mednarodni ravni, ki bi lahko v končni fazi služila primerjavam med državami. Zbirka podatkov HCQI sestoji iz dveh glavnih področij: prva so redno zbirani kazalniki, druga pa kazalniki, ki se zbirajo v določenih podskupinah, kot so duševno zdravje, varnost bolnikov, promocija zdravja, preventiva in primarno zdravstvo ter odzivnost/izkušnje bolnikov. Prvi rezultati so bili objavljeni v Delovnih zvezkih OECD št. 22 in 29 in v poglavju o kakovosti oskrbe v publikaciji Health at a Glance 2007 in 2009. Trenutno obstaja okrog 40 kazalcev kakovosti,ki so jih nacionalni strokovnjaki potrdili kot ustrezne za zbiranje podatkov na mednarodni ravni ob upoštevanju vseh omejitev. Merjenje kakovosti v zdravstvenem varstvu na mednarodni ravni omogoča državam identificirati razlike v kakovosti zdravstvenega varstva in analizirati, zakaj do razlik prihaja. Informacije o učinkih storitev prispevajo k boljšemu razumevanju učinkovitosti ukrepov, ki so povezani z modelom zdravstvenega sistema in politik, ki lahko izboljšajo kakovost. Mednarodne primerjave prav tako podpirajo razvoj nacionalnih sistemov poročanja o učinkih, kot rezultat pa se poveča preglednost in zanesljivost.The OECD Health Care Quality Indicators Project (HCQI) builds on initial work by the Commonwealth Fund and Nordic Council of Ministers. The long-term goal is to develop and implement a set of quality indicators at the international level that could ultimately be used to produce benchmarks for countries. HCQI data collection is comprised of two main work areas: regularly collected indicators and those collected through subgroups such as mental health, patient safety, health promotion, prevention and primary care, and responsiveness/patient experiences. Initial results have been published in OECD Health Working Papers No. 22 and No. 29, and in a chapter on quality of care in Health at a Glance 2007 and 2009. At present there are approximately 40 health care quality indicators that have been considered suitable by national experts for cross-national data collection taking into consideration the appropriate caveats about limitations. Measuring health care quality at the international level allows countries to identify differences in health care quality and to analyse why such disparities exist. Performance information contributes to better understanding of effective interventions related to health system design and policies that can improve quality. International comparisons also support the development of national performance reporting systems and as a result increase transparency and accountability