RESUMO
The ability to assess various cellular events consequent to perturbations, such as genetic mutations, disease states and therapies, has been recently revolutionized by technological advances in multiple "omics" fields. The resulting deluge of information has enabled and necessitated the development of tools required to both process and interpret the data. While of tremendous value to basic researchers, the amount and complexity of the data has made it extremely difficult to manually draw inference and identify factors key to the study objectives. The challenges of data reduction and interpretation are being met by the development of increasingly complex tools that integrate disparate knowledge bases and synthesize coherent models based on current biological understanding. This chapter presents an example of how genomics data can be integrated with biological network analyses to gain further insight into the developmental consequences of genetic perturbations. State of the art methods for conducting similar studies are discussed along with modern methods used to analyze and interpret the data.
Assuntos
Biologia Computacional , Biologia de Sistemas , Genômica , Músculo Esquelético , Bases de ConhecimentoRESUMO
Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed. The expert working group agreed that the diversity of lysosomal accumulations requires a case-by-case weight-of-evidence approach and outlined several factors to consider in the adversity assessment, including location and type of cell affected, lysosomal contents, severity of the accumulation, and related pathological effects as evidence of cellular or organ dysfunction. Lysosomal accumulations associated with cytotoxicity, inflammation, or fibrosis were generally considered to be adverse, while those found in isolation (without morphologic or functional consequences) were not. Workshop examples highlighted the importance of thoroughly characterizing the biological context of lysosomal effects, including mechanistic data and functional in vitro readouts if available. The information provided here should facilitate greater consistency and transparency in the interpretation of lysosomal effects.
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Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Fenômenos Toxicológicos , AnimaisRESUMO
BACKGROUND: It is unclear whether cemented or uncemented hemiarthroplasty is the best treatment option in elderly patients with displaced femoral neck fractures. Previous randomized trials comparing cemented and uncemented hemiarthroplasty have conflicting results. We conducted a randomized controlled trial to compare cemented and uncemented hemiarthroplasty. METHODS: This multicenter parallel-randomized controlled trial included patients of 70 years and older with a displaced femoral neck fracture (Garden type III or IV). Inclusion was between August 2008 and June 2012. Patients were randomized between a cemented hemiarthroplasty, type Müller Straight Stem or an uncemented hemiarthroplasty, type DB-10. Primary outcomes were complications, operation time, functional outcome (measured by Timed-Up-and-Go (TUG) and Groningen Activity Restriction Scale (GARS)) and mid-thigh pain. Health Related Quality of Life (HRQoL, expressed with the SF-12) was measured as an secondary outcome. Follow up was 1 year. RESULTS: In total 201 patients were included in the study (91 uncemented, 110 cemented hemiarthroplasties) The uncemented group showed more major local complications (intra- and postoperative fractures and dislocations) odds ratio (95% confidence interval) 3.36 (1.40 to 8.11). There was no difference in mean operation time (57.3 vs 55.4 min). There were no differences in functional outcomes (TUG 12.8 (9.4) vs. 13.9 (9.0), GARS 43.2 (19.7) vs. 39.2 (16.5)) and mid-thigh pain (18.6 vs 21.6%). Physical component SF-12 HRQoLwas lower in the uncemented group (30.3 vs. 35.3 p < 0.05 after six weeks, 33.8 vs 38.5 p < 0.05 after 12 weeks). CONCLUSION: A cemented hemiarthroplasty in elderly patients with a displaced femoral neck fracture results in less complications compared to an uncemented hemiarthroplasty. TRIAL REGISTRATION: Netherlands Trial Registry; NTR 1508 , accepted date 27 okt 2008.
Assuntos
Artroplastia de Quadril/estatística & dados numéricos , Fraturas do Colo Femoral/cirurgia , Complicações Pós-Operatórias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/métodos , Cimentos Ósseos , Feminino , Seguimentos , Humanos , Masculino , Países Baixos/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do TratamentoRESUMO
S-nitrosoglutathione (GSNO) is an endogenously produced S-nitrosylating compound that controls the function of various proteins. While a number of rodent cell lines have been used to study GSNO-induced apoptosis, the mechanisms of action remain to be evaluated in human cells and in parallel with other common apoptosis-inducing agents. In this study, we compared the pro-apoptotic effects of GSNO and staurosporine (STS) on human neural progenitors (NT2, hNP1) and neuroblasts (SH-SY5Y). We show that these cells exhibit comparable levels of susceptibility to GSNO- and STS-induced apoptotic cell death, as demonstrated by condensed nuclei and CASP3 activation. Mechanistic differences in apoptotic responses were observed as differential patterns of DNA fragmentation and levels of BAX, BCL-XL, CASP8, and p-ERK in response to GSNO and STS treatment. Mitochondrial membrane potential analysis revealed that NT2 and hNP1 cells, but not SH-SY5Y cells, undergo mitochondrial hyperpolarization in response to short-term exposure to STS prior to undergoing subsequent depolarization. This is the first study to report differences in apoptotic responses to GSNO and STS in 3 complementary human neural cell lines. Furthermore, these cells represent useful tools in cell pharmacological paradigms in which susceptibility to apoptosis-inducing agents needs to be assessed at different stages of neural cell fate commitment and differentiation.
Assuntos
Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , S-Nitrosoglutationa/farmacologia , Estaurosporina/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Diferenciação Celular , Linhagem Celular , Núcleo Celular/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , S-Nitrosoglutationa/metabolismoRESUMO
Automated high-throughput immunoassays are emerging as reliable analytic techniques for the quantitative detection of proteins from a variety of sample types. Herein, we describe a method using the Protein Simple Wes capillary-based automated immunoassays platform for the quantification of His- and HA-tagged antibody transcytosis across an in vitro transwell blood-brain barrier (BBB) model. Compared to conventional ELISA, fluorescence, and Mass Spec-based detection approaches, Wes provides comparable datasets with additional information regarding size, aggregation, and potential degradation of samples before and after BBB transcytosis. In this chapter, we have benchmarked our Wes technique against ELISA and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), using known BBB crossing (FC5) and non-crossing (A20.1) single domain antibodies.
Assuntos
Barreira Hematoencefálica , Células Endoteliais , Anticorpos/química , Barreira Hematoencefálica/metabolismo , Cromatografia Líquida , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Imunoensaio , Espectrometria de Massas em Tandem , TranscitoseRESUMO
Human induced pluripotent stem cell (iPSC)-derived neurons are of interest for studying neurological disease mechanisms, developing potential therapies and deepening our understanding of the human nervous system. However, compared to an extensive history of practice with primary rodent neuron cultures, human iPSC-neurons still require more robust characterization of expression of neuronal receptors and ion channels and functional and predictive pharmacological responses. In this study, we differentiated human amniotic fluid-derived iPSCs into a mixed population of neurons (AF-iNs). Functional assessments were performed by evaluating electrophysiological (patch-clamp) properties and the effect of a panel of neuropharmacological agents on spontaneous activity (multi-electrode arrays; MEAs). These electrophysiological data were benchmarked relative to commercially sourced human iPSC-derived neurons (CNS.4U from Ncardia), primary human neurons (ScienCell™) and primary rodent cortical/hippocampal neurons. Patch-clamp whole-cell recordings showed that mature AF-iNs generated repetitive firing of action potentials in response to depolarizations, similar to that of primary rodent cortical/hippocampal neurons, with nearly half of the neurons displaying spontaneous post-synaptic currents. Immunochemical and MEA-based analyses indicated that AF-iNs were composed of functional glutamatergic excitatory and inhibitory GABAergic neurons. Principal component analysis of MEA data indicated that human AF-iN and rat neurons exhibited distinct pharmacological and electrophysiological properties. Collectively, this study establishes a necessary prerequisite for AF-iNs as a human neuron culture model suitable for pharmacological studies.
Assuntos
Células-Tronco Pluripotentes Induzidas , Animais , Benchmarking , Fenômenos Eletrofisiológicos , Humanos , Neurônios , Ratos , RoedoresRESUMO
BACKGROUND: Modern metal-on-metal hip resurfacing was introduced as a bone-preserving method of joint reconstruction for young and active patients; however, the large diameter of the bearing surfaces is of concern for potentially increased metal ion release. PATIENTS AND METHODS: 71 patients (< 65 years old) were randomly assigned to receive either a resurfacing (R) hip arthroplasty (n = 38) or a conventional metal-on-metal (C) hip arthroplasty (n = 33). Functional outcomes were assessed preoperatively and at 6, 12, and 24 months. Cobalt and chromium blood levels were analyzed preoperatively and at 3, 6, 12, and 24 months. RESULTS: All functional outcome scores improved for both groups. At 12 and 24 months, the median UCLA activity score was 8 in the R patients and 7 in the C patients (p < 0.05). At 24 months, OHS was median 16 in C patients and 13 in R patients (p < 0.05). However, in spite of randomization, UCLA scores also appeared to be higher in R patients at baseline. Satisfaction was similar in both groups at 24 months. Cobalt concentrations were statistically significantly higher for R patients only at 3 and 6 months. Chromium levels remained significantly higher for R patients until 24 months. No pseudotumors were encountered in either group. One R patient was revised for early aseptic loosening and in 2 C patients a cup insert was exchanged for recurrent dislocation. INTERPRETATION: R patients scored higher on UCLA, OHS, and satisfaction at some time points; however, as for the UCLA, preoperative levels were already in favor of R. The differences, although statistically significant, were of minor clinical importance. Chromium blood levels were statistically significantly higher for R patients at all follow-up measurements, whereas for cobalt this was only observed up to 6 months. The true value of resurfacing hip arthroplasty over conventional metal-on-metal hip arthroplasty will be determined by longer follow-up and a possible shift of balance between their respective (dis)advantages.
Assuntos
Artroplastia de Quadril , Prótese de Quadril , Metais , Adulto , Fatores Etários , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/métodos , Cromo/sangue , Cobalto/sangue , Feminino , Seguimentos , Prótese de Quadril/efeitos adversos , Humanos , Íons/sangue , Masculino , Metais/sangue , Pessoa de Meia-Idade , Osteoartrite do Quadril/cirurgia , Satisfação do Paciente , Desenho de Prótese , Falha de Prótese , Reoperação , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
Cerebral ischemia (CI) induces dramatic changes in synaptic structure and function that precedes delayed post-ischemic neuronal death. Here, a proteomic analysis was used to identify the effects of focal CI on synaptosomal protein levels. Contralateral and ipsilateral synaptosomes, prepared from adult mice subjected to 60 min middle cerebral artery occlusion, were isolated following 3, 6 and 20 h of reperfusion. Synaptosomal protein samples (n=3) were labeled using the cleavable ICAT system prior to analysis with nanoLC-MS/MS. Each sample was analyzed by LC-MS to identify differential expressions using InDEPT software and differentially expressed peptides were identified by targeted LC-MS/MS. A total of 62 differentially expressed proteins were identified and Gene Ontology classification (cellular component) indicated that the majority of the proteins were located in the mitochondria and other components consistent with synaptic localization. The observed alterations in synaptic protein levels poorly correlated with gene expression, indicating the involvement of post-transcriptional regulatory mechanisms in determining post-ischemic synaptic protein content. Additionally, immunohistochemistry analysis of prosaposin (Psap) and saposin C (SapC) indicates that CI disrupts Psap processing and glycosphingolipid metabolism. These results demonstrate that the synapse is adversely affected by CI and may play a role in mediating post-ischemic neuronal viability.
Assuntos
Isquemia Encefálica/metabolismo , Lisossomos/química , Proteínas Inativadoras de Ribossomos Tipo 1/metabolismo , Sinaptossomos/química , Animais , Isquemia Encefálica/genética , Regulação da Expressão Gênica , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Saporinas , Sinaptossomos/metabolismoRESUMO
As cytokines are involved in wound healing and other inflammatory processes, it could be valuable to measure their levels at the operative site. This study was conducted to investigate whether different cytokines are measurable in drainage fluid and, when measurable, whether we can find a difference in cytokine levels between one and six hours postoperatively. Samples from the drainage system in 30 consecutive patients undergoing primary total hip replacement were collected at one and six hours after closure of the wound. Levels of several cytokines were measured in the drainage fluids. A significant elevation of almost all cytokines was observed between the sample after one hour and six hours postoperatively. We found a strong correlation between the different pro-inflammatory cytokines. The IL-6 to IL-10 ratio were also raised, showing a pro-inflammatory predominance. Levels were much higher than those previously shown in serum.
Assuntos
Artroplastia de Quadril , Líquidos Corporais/química , Citocinas/análise , Cicatrização/fisiologia , Drenagem , HumanosRESUMO
In a randomised clinical trial in 50 patients with symptomatic osteoarthritis of the medial compartment of the knee, the clinical results of high tibial osteotomy (HTO) according to the open wedge osteotomy (OWO) and closed wedge osteotomy (CWO) were compared. In both groups locked plate fixation was used. Clinical and radiological assessments were performed preoperatively and after one year. Postoperative hip-knee-ankle (HKA) correction angles were monitored on standing leg X-rays. The effect of HTO on collateral laxity of the knee was measured with a specially designed varus-valgus device. The WOMAC osteoarthritis index, the modified knee society score (KS) and visual analogue scales (VAS) were used to assess symptoms of osteoarthritis, function, pain and patient satisfaction. At one-year follow-up we found accurate corrections in both groups and the planned correction angles were achieved. No loss of correction was observed. Furthermore, the medial collateral laxity and the patellar height significantly decreased after OWO. Significant improvements of WOMAC and KS scores were found in both groups. All patients had significantly less pain and were very satisfied with the results. Surgery time was significantly longer in the CWO group, and complications were more frequent in this group. Both techniques led to good and comparable clinical results. The choice of whether to perform an open or a closed wedge osteotomy may be based on preoperative patellar height or concomitant collateral laxity.
Assuntos
Artroplastia/métodos , Deformidades Articulares Adquiridas/cirurgia , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia , Osteotomia/métodos , Tíbia/cirurgia , Artroplastia/efeitos adversos , Artroplastia/instrumentação , Feminino , Humanos , Deformidades Articulares Adquiridas/etiologia , Deformidades Articulares Adquiridas/fisiopatologia , Instabilidade Articular/etiologia , Instabilidade Articular/fisiopatologia , Articulação do Joelho/patologia , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/fisiopatologia , Osteotomia/efeitos adversos , Osteotomia/instrumentação , Dor/etiologia , Dor/fisiopatologia , Dor/cirurgia , Patela/diagnóstico por imagem , Patela/patologia , Complicações Pós-Operatórias , Radiografia , Recuperação de Função Fisiológica , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
Free radicals, hydrogen atoms, and electrons produced in rigid organic glasses at sufficiently low temperatures have lifetimes of minutes to years. They can be studied by their electron spin resonance spectra and, in the case of electrons, by their optical spectra, recombination luminescence, and electrical conductivity. The decay kinetics of these reaction intermediates serve to distinguish those trapped as geminate pairs or in spurs of high concentration from those formed with random distributions. Electron spin resonance studies of relaxation times and of the spectra of radical pairs provide further evidence on geometrical distributions. The decay rates of radicals combining with reactive geminate partners are dependent on the size and shape of the radical, the temperature, and the nature of the matrix. Decay is much slower in deuterated matrices than in protiated matrices. The factors that control the physical trapping of electrons in organic glasses are under intensive investigation. There is evidence that many electrons trapped relatively weakly during irradiations at 4 degrees K deepen their traps by orientation of dipoles when the matrix is warmed; that most electrons are trapped in the field of the geminate positive ion; that in some matrices the traps have a bound excited state to which the electron can be promoted without detrapping; and that trapped electrons can tunnel to solute molecules with a higher electron affinity than the trap depth.
RESUMO
BACKGROUND: A discussion is ongoing whether displaced femoral neck fractures in elderly patients should be treated with a non-cemented or a cemented hemiarthroplasty. A recent Cochrane analysis stresses the importance of further research into the relative merits of these techniques. We hypothesise that non-cemented hemiarthroplasty will result in at least the same technical-functional outcome and complication rate, with a shorter operation time. METHODS AND DESIGN: A randomised controlled multicentre trial will be performed.The study population consists of 200 patients of 70 years and older. Patients with a displaced femoral neck fracture will be allocated randomly to have a cemented or a non-cemented hemiarthroplasty. Data will be collected preoperatively, immediately postoperatively, and 6 weeks, 3 months and 1 year postoperatively.The main outcome measures of this study are technical-functional results of the hemiarthroplasty, duration of surgery, complications, and mid-thigh pain. Secondary outcome measures are living conditions at final follow up, self-reported health-related quality of life, and radiological evaluation of the hemiarthroplasty. CONCLUSION: A recent Cochrane analysis did not find arguments in favour of either non-cemented or cemented hemiarthroplasty. The forthcoming trial will compare treatment for a displaced femoral neck fracture by cemented versus non-cemented hemiarthroplasty. Our results will be published as soon as they become available. TRIAL REGISTRATION: Trial Registration Number NTR1508.
Assuntos
Artroplastia de Quadril/métodos , Cimentos Ósseos/uso terapêutico , Fraturas do Colo Femoral/cirurgia , Colo do Fêmur/cirurgia , Próteses e Implantes/normas , Atividades Cotidianas/psicologia , Fatores Etários , Idoso , Cimentos Ósseos/normas , Ensaios Clínicos como Assunto/métodos , Determinação de Ponto Final , Feminino , Fraturas do Colo Femoral/diagnóstico por imagem , Fraturas do Colo Femoral/patologia , Colo do Fêmur/lesões , Colo do Fêmur/patologia , Migração de Corpo Estranho/prevenção & controle , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde/métodos , Dor Pós-Operatória/prevenção & controle , Qualidade de Vida/psicologia , Radiografia , Projetos de Pesquisa , Fatores de Tempo , Resultado do TratamentoRESUMO
The esophagus is a muscular tube which transports swallowed content from the oral cavity and the pharynx to the stomach. Early in mouse development, an entire layer of the esophagus, the muscularis externa, consists of differentiated smooth muscle cells. Starting shortly after mid-gestation till about two weeks after birth, the muscularis externa almost entirely consists of striated muscle. This proximal-to-distal replacement of smooth muscle by the striated muscle depends on a number of factors. To identify the nature of the hypothetical "proximal" (mainly striated muscle originating) and "distal" (mainly smooth muscle originating) signals that govern the striated-for-smooth muscle replacement, we compared the esophagus of Myf5:MyoD null fetuses completely lacking striated muscle to the normal control using cDNA microarray analysis, followed by a comprehensive database search. Here we provide an insight into the nature of "proximal" and "distal" signals that govern the striated-for-smooth muscle replacement in the esophagus.
Assuntos
Esôfago/embriologia , Desenvolvimento Muscular , Músculo Liso/embriologia , Músculo Estriado/embriologia , Animais , CamundongosRESUMO
Synaptic pathology is observed during hypoxic events in the central nervous system in the form of altered dendrite structure and conductance changes. These alterations are rapidly reversible, on the return of normoxia, but are thought to initiate subsequent neuronal cell death. To characterize the effects of hypoxia on regulators of synaptic stability, we examined the temporal expression of cell adhesion molecules (CAMs) in synaptosomes after transient middle cerebral artery occlusion (MCAO) in mice. We focused on events preceding the onset of ischemic neuronal cell death (<48 h). Synaptosome preparations were enriched in synaptically localized proteins and were free of endoplasmic reticulum and nuclear contamination. Electron microscopy showed that the synaptosome preparation was enriched in spheres (approximately 650 nm in diameter) containing secretory vesicles and postsynaptic densities. Forebrain mRNA levels of synaptically located CAMs was unaffected at 3 h after MCAO. This is contrasted by the observation of consistent downregulation of synaptic CAMs at 20 h after MCAO. Examination of synaptosomal CAM protein content indicated that certain adhesion molecules were decreased as early as 3 h after MCAO. For comparison, synaptosomal Agrn protein levels were unaffected by cerebral ischemia. Furthermore, a marked increase in the levels of p-Ctnnb1 in ischemic synaptosomes was observed. p-Ctnnb1 was detected in hippocampal fiber tracts and in cornu ammonis 1 neuronal nuclei. These results indicate that ischemia induces a dysregulation of a subset of synaptic proteins that are important regulators of synaptic plasticity before the onset of ischemic neuronal cell death.
Assuntos
Moléculas de Adesão Celular/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Vesículas Secretórias/metabolismo , Sinapses/metabolismo , Sinaptossomos/metabolismo , Agrina/metabolismo , Animais , Morte Celular , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Infarto da Artéria Cerebral Média/patologia , Camundongos , Plasticidade Neuronal , Neurônios/metabolismo , Neurônios/ultraestrutura , Prosencéfalo/metabolismo , Prosencéfalo/ultraestrutura , RNA Mensageiro/metabolismo , Vesículas Secretórias/ultraestrutura , Sinapses/ultraestrutura , Sinaptossomos/ultraestrutura , Fatores de Tempo , beta Catenina/metabolismoRESUMO
Short-term (4-8 weeks) placebo-controlled trials are used to evaluate new antihypertensive drug treatment. To evaluate the consequences of such practice, a descriptive meta-analysis was conducted, consisting of blinded review of original case report forms for all patients who died or left a study before its completion for all short-term, placebo-controlled hypertension trials submitted to the Food and Drug Administration from 1973 through 2001. There were 93 marketing applications or supplements involving 590 individual trials that involved 86137 randomized patients (64438 randomized to experimental drug and 21 699 randomized to placebo) with 12658 patient years of observation. There were 9636 dropouts (mean time to dropout was 28 days) and relative risk (RR (placebo/drug))= 1.33 (95% confidence limits, 1.28, 1.39; P < 10(-16)). As expected, lack of blood pressure (BP) control was far more common in patients randomized to placebo; therapeutic failure, RR = 2.53 (2.35, 2.73; P < 10(s15)) and hypertensive emergency, RR = 2.75 (2.19, 3.57; P < 10(-15)). When administrative dropouts and dropouts resulting from inadequate BP control were excluded, the remaining 38% of dropouts were disproportionately more from drug (2810 drug, 816 placebo), RR = 0.80 (0.74, 0.86; P < 10(-8)). There were 43 deaths, RR=0.72 (0.33, 1.45; P=0.37); 40 strokes, RR = 1.43 (0.68, 2.81; P=0.33) and 77 myocardial infarctions, RR=1.06 (0.62, 1.75; P= 0.82). Irreversible harm (a combination of death, stroke and myocardial infarction, 160 total events) was equally distributed between the drug and placebo groups, RR=1.03 (0.71, 1.47; P=0.86).
Assuntos
Anti-Hipertensivos/uso terapêutico , Grupos Controle , Ensaios Clínicos Controlados como Assunto , Hipertensão/tratamento farmacológico , Placebos , Esquema de Medicação , Humanos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Medição de RiscoRESUMO
The reverse shoulder prosthesis is designed for the treatment of glenohumeral arthritis with irreparable cuff arthropathy. Although it has given good short term results the prosthesis is not free of complications. In this case report we describe an implant-related complication.
Assuntos
Artrite/cirurgia , Prótese Articular , Articulação do Ombro/cirurgia , Idoso , Feminino , Humanos , Falha de Prótese , Manguito RotadorRESUMO
Synthetic cannabinoids are marketed as legal alternatives to Δ9-THC, and are a growing worldwide concern as these drugs are associated with severe adverse effects. Unfortunately, insufficient information regarding the physiological and pharmacological effects of emerging synthetic cannabinoids (ESCs) makes their regulation by government authorities difficult. One strategy used to evade regulation is to distribute isomers of regulated synthetic cannabinoids. This study characterized the pharmacological properties of a panel of ESCs in comparison to Δ9-THC, as well as six JWH-122 isomers relative to its parent compound (JWH-122-4). Two cell-based assays were used to determine the potency and efficacy of ESCs and a panel of reference cannabinoids. HEK293T cells were transfected with human cannabinoid receptor 1 (CB1) and pGloSensor-22F, and the inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live cells. All ESCs examined were classified as agonists, with the following rank order of potency: Win 55,212-2 > CP 55,940 > JWH-122-4 > Δ9-THC ≈ RCS-4 ≈ THJ-2201 > JWH-122-5 > JWH-122-7 > JWH-122-2 ≈ AB-CHMINACA > JWH-122-8 > JWH-122-6 > JWH-122-3. Evaluation of ESC-stimulated Ca2+ transients in cultured rat primary hippocampal neurons confirmed the efficacy of four of the most potent ESCs (JWH-122-4, JWH-122-5, JWH-122-7 and AB-CHMINACA). This work helps regulatory agencies make informed decisions concerning these poorly characterized recreational drugs.
Assuntos
Canabinoides/farmacologia , Hipocampo/citologia , Indazóis/farmacologia , Indóis/química , Naftalenos/química , Neurônios/efeitos dos fármacos , Valina/análogos & derivados , Canabinoides/química , Células HEK293 , Humanos , Indazóis/química , Isomerismo , Naftalenos/farmacologia , Valina/química , Valina/farmacologiaRESUMO
In an attempt to reduce health care expenses, regulated competition between health care providers has been introduced in The Netherlands. As for total hip and knee arthroplasties, health care providers have to publish their prices to make them available for the insurance companies and the public. Eventually, competition between health care providers should result in optimal care for lower prices. The purpose of this study was to define the patients' consciousness of the overall costs and specialist's fee for a total knee arthroplasty. Thirty-nine patients with a recent total knee arthroplasty were asked to estimate the total costs and the surgeon's fee of this procedure. The average overall cost of a total knee arthroplasty in our hospital was Euro 11.500. The orthopaedic surgeon's fee represents a non-negotiable 5% of these total costs. The mean estimate of the overall costs of a total knee arthroplasty by the patients was Euro 10.000 (range: Euro 600 to Euro 55.000). Only 26% of the patients (n = 10) gave an estimate within the accepted "correct" range of Euro 8.500 to Euro 14.500. The surgeon's fee was estimated at 32% (range: 5% to 75%) of the total costs and a majority reckoned the actual fraction of 5% was low. Patients have a poor notion of the overall costs of a total knee arthroplasty and strongly overestimate the specialist's fee. Whether the introduction of budget competition in health care may actually result in a decrease in health care costs remains to be seen.
Assuntos
Artroplastia do Joelho/economia , Honorários Médicos , Ortopedia/economia , Pacientes/psicologia , Idoso , Feminino , Humanos , Países BaixosRESUMO
The current paper is a continuation of our work described in Rot and Kablar, 2010. Here, we show lists of 10 up- and 87 down-regulated genes obtained by a cDNA microarray analysis that compared developing Myf5-/-:Myod-/- (and Mrf4-/-) petrous part of the temporal bone, containing middle and inner ear, to the control, at embryonic day 18.5. Myf5-/-:Myod-/- fetuses entirely lack skeletal myoblasts and muscles. They are unable to move their head, which interferes with the perception of angular acceleration. Previously, we showed that the inner ear areas most affected in Myf5-/-:Myod-/- fetuses were the vestibular cristae ampullaris, sensitive to angular acceleration. Our finding that the type I hair cells were absent in the mutants' cristae was further used here to identify a profile of genes specific to the lacking cell type. Microarrays followed by a detailed consultation of web-accessible mouse databases allowed us to identify 6 candidate genes with a possible role in the development of the inner ear sensory organs: Actc1, Pgam2, Ldb3, Eno3, Hspb7 and Smpx. Additionally, we searched for human homologues of the candidate genes since a number of syndromes in humans have associated inner ear abnormalities. Mutations in one of our candidate genes, Smpx, have been reported as the cause of X-linked deafness in humans. Our current study suggests an epigenetic role that mechanical, and potentially other, stimuli originating from muscle, play in organogenesis, and offers an approach to finding novel genes responsible for altered inner ear phenotypes.