RESUMO
BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.
Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Hormônios/uso terapêutico , Humanos , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2/genética , Receptores de Progesterona/genéticaRESUMO
BACKGROUND: For primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC. PATIENTS AND METHODS: We combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs. RESULTS: A total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10-40). There was a positive correlation between RD TIL levels and CD8+ T-cell density (ρ = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79-0.92; P < 0.001), and improved OS (HR: 0.87; 95% CI 0.80-0.94; P < 0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P < 0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (PInt=0.003) and OS (PInt=0.008) with a greater magnitude of positive effect observed for RCB class II than class III. CONCLUSIONS: TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante/mortalidade , Neoplasia Residual/patologia , Neoplasias de Mama Triplo Negativas/patologia , Idoso , Linfócitos T CD8-Positivos/imunologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/imunologia , Prognóstico , Receptor ErbB-2/metabolismo , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologiaRESUMO
BACKGROUND AND OBJECTIVE: Current treatments for Alzheimer's Disease (AD) do not affect the course of the illness and brain stimulation techniques are increasingly promoted as potential therapeutic interventions for AD. This study reviews the effects of electromagnetic field (EMF) exposure versus sham exposure on working memory (WM) performance of healthy human participants. METHOD: Online literature databases and previous systematic reviews were searched for studies of EMF and WM in participants without reported memory problems. Two thousand eight hundred and fifty seven studies were identified, and 10 studies met the inclusion criteria. An assessment of study quality was completed, and separate, random effects meta-analyses were conducted for each of the three WM tasks included: n-back, substitution and digit span forward. RESULTS: No differences were found between participants exposed to active EMF versus sham conditions in any of the three working memory tasks examined. CONCLUSION: Results indicate that EMF does not affect WM during the n-back, substitution and digit-span tasks. Future studies should focus on the possible effects of chronic exposure to EMF in older adults with AD using a battery of comparable WM and attention tasks, before EMF can be seriously considered as a potential modulator of WM in AD. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Campos Eletromagnéticos , Memória de Curto Prazo/fisiologia , Doença de Alzheimer/terapia , Atenção/fisiologia , HumanosRESUMO
AIMS: Socioeconomic inequalities in both disability retirement and mortality are large. The aim of this study was to examine socioeconomic differences in cause-specific mortality after disability retirement due to different diseases. METHODS: We used administrative register data from various sources linked together by Statistics Finland and included an 11% sample of the Finnish population between the years 1987 and 2007. The data also include an 80% oversample of the deceased during the follow-up. The study included men and women aged 30-64 years at baseline and those who turned 30 during the follow-up. We used Cox regression analysis to examine socioeconomic differences in mortality after disability retirement. RESULTS: Socioeconomic differences in mortality after disability retirement were smaller than in the population in general. However, manual workers had a higher risk of mortality than upper non-manual employees after disability retirement due to mental disorders and cardiovascular diseases, and among men also diseases of the nervous system. After all-cause disability retirement, manual workers ran a higher risk of cardiovascular and alcohol-related death. However, among men who retired due to mental disorders or cardiovascular diseases, differences in social class were found for all causes of death examined. For women, an opposite socioeconomic gradient in mortality after disability retirement from neoplasms was found. Conclusions: The disability retirement process leads to smaller socioeconomic differences in mortality compared with those generally found in the population. This suggests that the disability retirement system is likely to accurately identify chronic health problems with regard to socioeconomic status.
Assuntos
Causas de Morte/tendências , Pessoas com Deficiência/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Aposentadoria , Adulto , Doença Crônica , Comorbidade , Feminino , Finlândia/epidemiologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores SocioeconômicosRESUMO
Blastocystis has been reported in pig feces but the sites of development in the gastrointestinal tract are unknown. The present study was undertaken to determine predilection sites of Blastocystis in 11 naturally infected pigs examined at 20 weeks of age. At necropsy, feces and contents of the duodenum, jejunum, ileum, and cecum were examined by immunofluorescence (IFA) microscopy and PCR and tissues from these sites as well as the proximal and distal colon were processed for histology from pigs 1 to 5. Feces were examined by IFA microscopy, and segments from the jejunum and ileum were processed for histology from pigs 6 to 11. Multiple sections were cut from each tissue segment, and each was stained with the following: hematoxylin and eosin, polyclonal rabbit antibody to Blastocystis, and ParaFlor B monoclonal antibody to Blastocystis. Blastocystis was detected in feces of all 11 pigs by IFA microscopy and determined by PCR and gene sequencing to be subtype 5 for pigs 1-5. Blastocystis was also detected in the lumen contents removed from the cecum of pigs 1-5 examined by IFA microscopy and in the cecum of pigs 4 and 5 by PCR. Blastocystis was also observed in tissue sections from the jejunum of 7 of the 11 pigs, in the proximal and distal colon of pigs 1-5, and in the cecum of 4 of these 5 pigs but was not detected in the duodenum or ileum of any pigs. In tissue sections, Blastocystis was found primarily in the lumen usually associated with digested food debris, sometimes in close proximity or appearing to adhere to the epithelium, but no stages were found to penetrate the epithelium or the lamina propria.
Assuntos
Blastocystis/crescimento & desenvolvimento , Intestinos/parasitologia , Sus scrofa/parasitologia , Animais , Ceco/parasitologia , Ceco/patologia , Colo/parasitologia , Colo/patologia , Duodeno/parasitologia , Duodeno/patologia , Fezes/parasitologia , Conteúdo Gastrointestinal/parasitologia , Íleo/parasitologia , Íleo/patologia , Intestinos/patologia , Jejuno/parasitologia , Jejuno/patologia , TropismoRESUMO
BACKGROUND: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design: Randomized, parallel, multi-center, feasibility trial. SETTING: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23. PARTICIPANTS: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control. INTERVENTION: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables. MAIN OUTCOMES: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period. CONCLUSION: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.
Assuntos
Cuidadores , Estudos de Viabilidade , Doença dos Neurônios Motores , Humanos , Doença dos Neurônios Motores/psicologia , Doença dos Neurônios Motores/terapia , Masculino , Feminino , Cuidadores/psicologia , Pessoa de Meia-Idade , Idoso , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/terapia , AdultoRESUMO
Stargardt-like macular dystrophy (STGD3, MIM 600110) and autosomal dominant macular dystrophy (adMD) are inherited forms of macular degeneration characterized by decreased visual acuity, macular atrophy and extensive fundus flecks. Genetic mapping data suggest that mutations in a single gene may be responsible for both conditions, already known to bear clinical resemblance. Here we limit the minimum genetic region for STGD3 and adMD to a 0.6-cM interval by recombination breakpoint mapping and identify a single 5-bp deletion within the protein-coding region of a new retinal photoreceptor-specific gene, ELOVL4, in all affected members of STGD3 and adMD families. Bioinformatic analysis of ELOVL4 revealed that it has homology to a group of yeast proteins that function in the biosynthesis of very long chain fatty acids. Our results are therefore the first to implicate the biosynthesis of fatty acids in the pathogenesis of inherited macular degeneration.
Assuntos
Proteínas do Olho/genética , Genes Dominantes/genética , Degeneração Macular/genética , Proteínas de Membrana/genética , Deleção de Sequência/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 6/genética , Clonagem Molecular , Análise Mutacional de DNA , Éxons/genética , Proteínas do Olho/química , Proteínas do Olho/metabolismo , Feminino , Humanos , Hibridização In Situ , Íntrons/genética , Escore Lod , Macaca mulatta/genética , Degeneração Macular/patologia , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Camundongos , Dados de Sequência Molecular , Linhagem , RNA Mensageiro/análise , RNA Mensageiro/genética , Retina/metabolismo , Retina/patologia , Alinhamento de SequênciaRESUMO
Peripheral nerve myelin contains a dominant low molecular weight glycoprotein called Po. To study the metabolism of this glycoprotein, tritiated fucose was injected into the peripheral nerves of adult mice and developing rats, and the temporal distribution of label was examined by autoradiography and gel electrophoresis. Mice and rat pups, injected with fucose, were sacrificed from 1 h to 98 days later. Series of autoradiographs were prepared. At the shortest labeling periods, newly formed product was confined to juxtanuclear Schwann cell cytoplasm, in association with regions rich in Golgi apparatus. After longer labeling periods, silver grain levels in Schwann cell cytoplasm decreased; concomitantly, there was an increase of silver grains associated with myelin. In adult animals, label associated with myelin was concentrated over outer layers of thickly myelinated fibers. Even at the longest time intervals examined (72 and 98 days), this distribution of label was largely retained. In contrast, in developing animals, label became associated with inner layers of the thicker sheaths. At no time was label observed over axons. Gel electrophoresis revealed that tritiated fucose was a suitable precursor for the faster migrating peripheral nerve glycoprotein(s). At all times examined, there was a single major peak of radioactivity that co-migrated on sodium dodecyl sulfate (SDS) acrylamide gels with the Po protein. Sometimes, a faster migrating shoulder of radioactivity was noted. With increased labeling periods, there was an enrichment of radioactivity associated with Po, indicative of a relatively slow turnover rate.
Assuntos
Glicoproteínas/metabolismo , Bainha de Mielina/metabolismo , Nervos Periféricos/metabolismo , Animais , Fucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Microscopia Eletrônica , Bainha de Mielina/ultraestrutura , Nervos Periféricos/citologia , Nervos Periféricos/ultraestrutura , RatosRESUMO
The assembly and composition of basal bodies was investigated in the single-celled, biflagellate green alga, Chlamydomonas reinhardtii, using the cell wall-less strain, cw15. In the presence of EDTA, both flagellar axonemes remained attached to their basal bodies while the entire basal body-axoneme complex was separated from the cell body, without cell lysis, by treatment with polyethylene glycol-400. The axonemes were then removed from the basal bodies in the absence of EDTA, leaving intact basal body pairs, free from particulate contamination from other regions of the cell. The isolated organelles produced several bands on sodium dodecyl sulfate-urea polyacrylamide gels, including two tubilin bands which co-electrophoresed with flagellar tubulin. The formation of probasal bodies was observed by electron microscopy of whole mount preparations. Synchronous cells were lysed, centrifuged onto carbon-coated grids, and either negatively stained or shadowed with platinum. The two probasal bodies of each cell appeared shortly after mitosis as thin "annuli," not visible in thin sections, each consisting of nine rudimentary triplet microtubules. Each annulus remained attached to one of the mature basal bodies by several filaments about 60 in diameter, and persisted throughout interphase until just before the next cell division. It then elongated into a mature organelle. The results revive the possibility of the nucleated assembly of basal bodies.
Assuntos
Chlamydomonas/ultraestrutura , Chlamydomonas/análise , Grânulos Citoplasmáticos/análise , Grânulos Citoplasmáticos/ultraestrutura , Ácido Edético , Eletroforese em Gel de Poliacrilamida , Flagelos/análise , Microscopia Eletrônica , Microscopia de Contraste de Fase , Proteínas/análiseRESUMO
Radioactive choline was used to study the metabolism and movement of choline-containing phospholipids in peripheral nerve myelin of adult mice. Incorporation at various times after intraperitoneal injection was measured in serial segments of sciatic nerve as well as in myelin isolated from those segments. At no time (1 h to 35 days) could a proximal-distal difference in the extent of labeling be demonstrated. This finding suggests that incorporation of precursor choline phospholipids into nerve membranes is a local event, with little contribution from the neuronal perikaryon via axoplasmic transport. Autoradiographic investigations were undertaken to elucidate the pattern of movement of radioactive choline-labeled phospholipids, predominantly lecithin, into the myelin sheaths of the sciatic nerve. A sequence of autoradiographs was prepared from animals sacrificed between 20 min and 35 days after a microinjection of precursor directly into the nerve. Analysis of these autoradiograms revealed that labeling is initially concentrated in the Schwann cell cytoplasm. Later, the label moves first into the outer regions of the myelin sheaths and is eventually distributed evenly throughout the inner and outer layers of the sheath. At no time is there a build-up of label in the axon. The rate of uptake of precursor and subsequent redistribution of lecithin into the myelin were also examined in frog sciatic nerve (18 degrees C). Both uptake and redistribution processes were considerably slower in the cold-blooded animal.
Assuntos
Bainha de Mielina/metabolismo , Fosfatidilcolinas/metabolismo , Animais , Anuros , Axônios/metabolismo , Cinética , Camundongos , Rana temporaria , Células de Schwann/metabolismo , Nervo IsquiáticoRESUMO
The structure and function of the centrosomes from Chinese hamster ovary (CHO) cells were investigated by electron microscopy of negatively stained wholemount preparations of cell lysates. Cells were trypsinized from culture dishes, lysed with Triton X-100, sedimented onto ionized, carbon-coated grids, and negatively stained with phosphotungstate. The centrosomes from both interphase and dividing cells consisted of pairs of centrioles, a fibrous pericentriolar material, and a group of virus-like particles which were characteristic of the CHO cells and which served as markers for the pericentriolar material. Interphase centrosomes anchored up to two dozen microtubules when cells were lysed under conditions which preserved native microtubules. When Colcemid-blocked mitotic cells, initially devoid of microtubules, were allowed to recover for 10 min, microtubules formed at the pericentriolar material, but not at the centrioles. When lysates of Colcemid-blocked cells were incubated in vitro with micotubule protein purified from porcine brain tissue, up to 250 microtubules assembled at the centrosomes, similar to the number of microtubules that would normally form at the centrosome during cell division. A few microtubules could also be assembled in vitro onto the ends of isolated centrioles from which the pericentriolar material had been removed, forming characteristic axoneme- like bundles. In addition, microtubules; were assembled onto fragments of densely staining, fibrous material which was tentatively identified as periocentriolar material by its association of CHO can initiate and anchor microtubules both in vivo and in vitro.
Assuntos
Divisão Celular , Microtúbulos , Organoides , Ovário/citologia , Animais , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Colchicina/farmacologia , Cricetinae , Feminino , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Organoides/fisiologia , Organoides/ultraestrutura , Tubulina (Proteína)/biossínteseRESUMO
The venom protein, s-echistatin, originally derived from the saw-scaled viper Echis carinatus, was found to be a potent inhibitor of bone resorption by isolated osteoclasts. This Arg24-Gly25-Asp26-(RGD)-containing protein inhibited the excavation of bone slices by rat osteoclasts (IC50 = 0.1 nM). It also inhibited the release of [3H]proline from labeled bone particles by chicken osteoclasts (IC50 = 100 nM). By comparison, the tetrapeptide Arg-Gly-Asp-Ser (RGDS) inhibited resorption by rat or chicken osteoclasts with an IC50 of 0.1 mM while ala24-echistatin was inactive. Video microscopy showed that rat osteoclast attachment to substrate was more sensitive to s-echistatin than was the attachment of mononuclear cells or chicken osteoclasts. The difference in sensitivity of rat and chicken osteoclasts to s-echistatin may be due to differences between receptors on rat and chicken osteoclasts for s-echistatin. Antibody localization of echistatin on these cells showed much greater echistatin binding to rat osteoclasts than to chicken osteoclasts. Laser scanning confocal microscopy after immunohistochemical staining showed that s-echistatin binds to osteoclasts, that s-echistatin receptors are most abundant at the osteoclast/glass interface, and that s-echistatin colocalizes with vinculin. Confocal interference reflection microscopy of osteoclasts incubated with s-echistatin, demonstrated colocalization of s-echistatin with the outer edges of clusters of grey contacts at the tips of some lamellipodia. Identification of the echistatin receptor as an integrin was confirmed by colocalization of echistatin fluorescence with staining for an alpha-like subunit. Attachment of bone particles labeled with [3H]proline to chicken osteoclasts confirmed that the mechanism of action of echistatin was to inhibit osteoclast binding to bone presumably by disrupting adhesion structures. These data demonstrate that osteoclasts bind to bone via an RGD-sequence as an obligatory step in bone resorption, that this RGD-binding integrin is at adhesion structures, and that it colocalizes with vinculin and has an alpha-like subunit.
Assuntos
Reabsorção Óssea , Osteoclastos/efeitos dos fármacos , Venenos de Víboras/farmacologia , Sequência de Aminoácidos , Animais , Adesão Celular/fisiologia , Galinhas , Técnicas In Vitro , Integrinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Dados de Sequência Molecular , Oligopeptídeos/farmacologia , Osteoclastos/metabolismo , Peptídeos/farmacologia , RatosRESUMO
Autoradiography with 3H-labeled phorbol dibutyrate was used for the light microscopic detection of phorbol ester receptors in rat fetuses. In 15- and 18-day fetuses, as well as in adult rats, receptors were found to be concentrated in the central nervous system. The localization of receptors in the ventral marginal zone of the fetal neural tube, the lens of the eye, and other sites suggests a role for phorbol ester receptors in cellular process extension and cell-cell interaction.
Assuntos
Proteínas de Caenorhabditis elegans , Sistema Nervoso Central/embriologia , Feto/análise , Ésteres de Forbol/metabolismo , Forbóis/metabolismo , Proteína Quinase C , Receptores de Superfície Celular/análise , Receptores de Droga , Animais , Autorradiografia , Encéfalo/embriologia , Química Encefálica , Proteínas de Transporte , Comunicação Celular , Divisão Celular , Sistema Nervoso Central/análise , Olho/embriologia , Intestinos/embriologia , Cristalino/embriologia , Dibutirato de 12,13-Forbol , Ratos , Ratos EndogâmicosRESUMO
OBJECTIVES: The aim of this study was to investigate whether burnout predicts new disability pension at population level during a follow-up of approximately 4 years. The diagnosis for which the disability pension was granted was also examined in relation to the level of burnout. METHODS: We used a population-based cohort sample (n = 3125) of 30-60-year-old employees from an epidemiological health study, the Health 2000 Study, gathered during 2000-2001 in Finland. The data collection comprised an interview, a clinical health examination including a standardised mental health interview, and a questionnaire including the Maslach Burnout Inventory-General Survey. Disability pensions and their causes until December 2004 were extracted from national pension records. The association between burnout and new disability pension was analysed with logistic regression models adjusted for sociodemographic factors and health at baseline. RESULTS: Altogether 113 persons were granted a new disability pension during the follow-up: 22% of those with severe burnout, 6% of those with mild burnout, and 2% of those with no burnout at baseline. After sociodemographic factors and health were adjusted for, each one-point increase in the overall burnout sum score was related to 49% increase in the odds for a future disability pension. A disability pension was most often granted on the basis of mental and behavioural disorders and diseases of the musculoskeletal system among those with burnout. After adjustments, exhaustion dimension among men and cynicism dimension among a combined group of men and women predicted new disability pensions. CONCLUSION: Burnout predicts permanent work disability and could therefore be used as a risk marker of chronic health-related work stress. To prevent early exit from work life, working conditions and employee burnout should be regularly assessed with the help of occupational health services.
Assuntos
Esgotamento Profissional/psicologia , Avaliação da Deficiência , Doenças Profissionais/psicologia , Pensões/estatística & dados numéricos , Adulto , Esgotamento Profissional/epidemiologia , Feminino , Finlândia/epidemiologia , Seguimentos , Nível de Saúde , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/epidemiologia , Saúde Ocupacional , Medição de Risco , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
The myelin proteolipid proteins (PLP and DM20) are believed to act as "adhesive struts" in the extracellular apposition of the CNS myelin sheath. These proteins have been considered late evolutionary developments, which arose de novo in the antecedents of early tetrapods. However, PCR primed with degenerate oligonucleotides corresponding to common segments of rat PLP/DM20 revealed three novel mRNAs in the brains of two elasmobranchs. These mRNAs are closely related to each other and to mammalian DM20, but lack the sequence that distinguishes PLP from DM20. We term the novel proteolipid proteins DM alpha, DM beta, and DM gamma. At least DM alpha and DM gamma are highly expressed in white matter in myelinating shark brain. The DMs not only are highly homologous to each other, but also contain regions bearing similarities with segments of channel-forming regions of the nicotinic acetylcholine receptor and the glutamate receptor macromolecular complexes. Significantly, we find that across these segments, DM alpha and DM gamma are more similar to the channel proteins than the two channel proteins are to each other.
Assuntos
Apoproteínas/genética , Expressão Gênica , Genes , Proteínas da Mielina/genética , Proteína Proteolipídica de Mielina/genética , Proteínas do Tecido Nervoso , Tubarões/genética , Rajidae/genética , Sequência de Aminoácidos , Animais , Apoproteínas/metabolismo , Sequência de Bases , Evolução Biológica , Encéfalo/metabolismo , Clonagem Molecular , Dados de Sequência Molecular , Proteínas da Mielina/metabolismo , Proteína Proteolipídica de Mielina/metabolismo , Sondas de Oligonucleotídeos/genética , RNA Mensageiro/metabolismo , Ratos/genética , TorpedoRESUMO
Myelin, the insulating sheath made by extensive plasma membrane wrapping, is dependent on the presence of highly adhesive molecules that keep the two sides of the membrane in tight contact. The Po glycoprotein (Po) is the major component of the peripheral nervous system (PNS) myelin of mammals. The exact role that Po protein has played in the evolution of myelin is still unclear, but several phylogenetic observations suggest that it is a crucial component in the development of myelin as a multi-lamellar membrane structure. Sharks, which appeared in the fossil record about 400 million years ago, are the first fully myelinated organisms. In this study we investigated the expression pattern of shark myelin Po to suggest a way it might have played a role in the evolution of myelin in the central nervous system. We found that sharks have more than two isoforms (32, 28 and 25 kD), and that some of these might not be fully functional because they lack the domains known for Po homophilic adhesion.
Assuntos
Proteína P0 da Mielina/química , Tubarões/metabolismo , Squalus acanthias/metabolismo , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos , Western Blotting , Sistema Nervoso Central/química , Sistema Nervoso Central/embriologia , Epitopos/imunologia , Evolução Molecular , Glicosilação , Humanos , Dados de Sequência Molecular , Peso Molecular , Proteína P0 da Mielina/análise , Proteína P0 da Mielina/imunologia , Proteína P0 da Mielina/isolamento & purificação , Sistema Nervoso Periférico/química , Sistema Nervoso Periférico/embriologia , Isoformas de Proteínas/análise , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/isolamento & purificação , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Coelhos , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Tubarões/embriologia , Tubarões/imunologia , Especificidade da Espécie , Squalus acanthias/imunologia , Vertebrados/metabolismoRESUMO
Within the past 2 decades, the number of CT examinations performed has increased almost 10-fold. This is in large part due to advances in multidetector-row CT technology, which now allows faster image acquisition and improved isotropic imaging. The increased use, along with multidetector technique, has led to a significantly increased radiation dose to the patient from CT studies. This places increased responsibility on the radiologist to ensure that CT examinations are indicated and that the "as low as reasonably achievable" concept is adhered to. Neuroradiologists are familiar with factors that affect patient dose such as pitch, milliamperes, kilovolt peak (kVp), collimation, but with increasing attention being given to dose reduction, they are looking for additional ways to further reduce the radiation associated with their CT protocols. In response to increasing concern, CT manufacturers have developed dose-reduction tools, such as dose modulation, in which the tube current is adjusted along with the CT acquisition, according to patient's attenuation. This review will describe the available techniques for reducing dose associated with neuroradiologic CT imaging protocols.
Assuntos
Neurorradiografia/métodos , Guias de Prática Clínica como Assunto , Lesões por Radiação/prevenção & controle , Proteção Radiológica/métodos , Tomografia Computadorizada por Raios X/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Humanos , Neurorradiografia/tendências , Padrões de Prática Médica/tendências , Doses de Radiação , Lesões por Radiação/etiologiaRESUMO
OBJECTIVES: It is believed that children are more sensitive to ionising radiation than adults. This work reviewed the reported radiation dose estimates for paediatric cardiac catheterisation. A systematic literature review was performed by searching healthcare databases for studies reporting radiation dose using predetermined key words relating to children having cardiac catheterisation. The quality of publications was assessed using relevant Critical Appraisal Skills Programme questions and their reported radiation exposures were evaluated. KEY FINDINGS: It is only in recent years that larger cohort observations have been undertaken. Although radiation dose from paediatric cardiac catheterisation has decreased in recent years, the literature indicated that it remains varied and potentially substantial. CONCLUSION: Standardisation of weight categories and procedure types such as those recommended by the PiDRL project could help compare current and future radiation dose estimates.
Assuntos
Cateterismo Cardíaco , Doses de Radiação , Radiografia Intervencionista , Criança , HumanosRESUMO
RATIONALE: Studies have demonstrated that brain dopamine D2/D3 receptors (D2/D3R) and the reinforcing effects of cocaine can be influenced by a monkey's position in the social dominance hierarchy. OBJECTIVE: In this study, we manipulated the social ranks of monkeys by reorganizing social groups and assessed effects on D2/D3R availability and cocaine self-administration. METHODS: Male cynomolgus monkeys (N = 12) had been trained to self-administer cocaine under a concurrent cocaine-food reinforcement schedule. Previously, PET measures of D2/D3R availability in the caudate nucleus and putamen had been obtained with [18F]fluoroclebopride during cocaine abstinence, while monkeys lived in stable social groups of four monkeys/pen. For this study, monkeys were reorganized into groups that consisted of (1) four previously dominant, (2) four previously subordinate, and (3) a mix of previously dominant and subordinate monkeys. After 3 months, D2/D3R availability was redetermined and cocaine self-administration was reexamined. RESULTS: D2/D3R availability significantly increased after reorganization in monkeys who were formerly subordinate, with the greatest increases observed in those that became dominant. No consistent changes in D2/D3R availability were observed in formerly dominant monkeys. Cocaine self-administration did not vary according to rank after reorganization of social groups. However, when compared to their previous cocaine self-administration data, the potency of cocaine as a reinforcer decreased in 9 of 11 monkeys. CONCLUSIONS: These results indicate that changing the social conditions can alter D2/D3R availability in subordinate monkeys in a manner suggestive of environmental enrichment. In most monkeys, social reorganization shifted the cocaine dose-response curve to the right, also consistent with environmental enrichment.