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1.
J Spinal Cord Med ; : 1-10, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31977291

RESUMO

Objective: To investigate the burden of sleep problems within the Spinal Cord injured (SCI) community with respect to the general population (GP) in Switzerland. The study further explored potential predictors for receiving treatment for sleep problems after SCI.Design: Cross-sectional study.Setting: SCI community in Switzerland.Participants: Individuals diagnosed with an SCI, aged 16 years or older that permanently reside in Switzerland (N = 1549).Interventions: Not applicable.Outcome measures: Perceived sleep problems within the SCI community and GP. For those with sleep problems and SCI, an indicator for having received treatment was measured.Results: 58.8% of survey participants indicated having a sleep problem; 69.4% of those with a sleep problem did not indicate receiving treatment. Amongst people living with an SCI, individuals between the ages of 46-60 years (adjusted Odds Ratio, OR = 3.07; 95% CI 1.54-6.16), participants reporting severe financial hardship (OR = 2.90; 95% CI) 1.69-4.96, and those that indicated having pain (OR = 5.62; 95% CI 3.52-8.98) were more likely to have a chronic sleep problem. In comparison to the Swiss GP, the prevalence of having a sleep problem was 18% higher among persons with SCI, with the largest discrepancy for males with paraplegia between the ages of 46-60 years (Prevalence ratio, PR = 1.28; 95% CI, 1.21-1.36).Conclusion: Individuals with SCI experience more sleep problems compared to the Swiss GP. Findings from this study suggest that clinical screening for sleep issues targeting high risk groups is needed to reduce the large prevalence of non-treatment in individuals with SCI.

2.
Mol Pharmacol ; 97(3): 212-225, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31871304

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor family, playing pivotal roles in regulating glucose and lipid metabolism as well as inflammation. While characterizing potential PPARγ ligand activity of natural compounds in macrophages, we investigated their influence on the expression of adipophilin [perilipin 2 (PLIN2)], a well-known PPARγ target. To confirm that a compound regulates PLIN2 expression via PPARγ, we performed experiments using the widely used PPARγ antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662). Surprisingly, instead of blocking upregulation of PLIN2 expression in THP-1 macrophages, expression was concentration-dependently induced by GW9662 at concentrations and under conditions commonly used. We found that this unexpected upregulation occurs in many human and murine macrophage cell models and also primary cells. Profiling expression of PPAR target genes showed upregulation of several genes involved in lipid uptake, transport, and storage as well as fatty acid synthesis by GW9662. In line with this and with upregulation of PLIN2 protein, GW9662 elevated lipogenesis and increased triglyceride levels. Finally, we identified PPARδ as a mediator of the substantial unexpected effects of GW9662. Our findings show that: 1) the PPARγ antagonist GW9662 unexpectedly activates PPARδ-mediated signaling in macrophages, 2) GW9662 significantly affects lipid metabolism in macrophages, 3) careful validation of experimental conditions and results is required for experiments involving GW9662, and 4) published studies in a context comparable to this work may have reported erroneous results if PPARγ independence was demonstrated using GW9662 only. In light of our findings, certain existing studies might require reinterpretation regarding the role of PPARγ SIGNIFICANCE STATEMENT: Peroxisome proliferator-activated receptors (PPARs) are targets for the treatment of various diseases, as they are key regulators of inflammation as well as lipid and glucose metabolism. Hence, reliable tools to characterize the molecular effects of PPARs are indispensable. We describe profound and unexpected off-target effects of the PPARγ antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662) involving PPARδ and in turn affecting macrophage lipid metabolism. Our results question certain existing studies using GW9662 and make better experimental design of future studies necessary.

3.
Sci Rep ; 9(1): 19478, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863016

RESUMO

Overactive bladder and voiding dysfunction are highly prevalent and often associated with malfunction of the bladder afferent pathways. Appropriate diagnostic tools for an objective assessment of afferent nerve function of the human bladder are currently missing. One promising possibility is the assessment of sensory evoked potentials (SEP) during repetitive electrical bladder stimulation, which proved feasible in healthy subjects. For an implementation into clinical practice, however, further refinements for efficient and reliable data acquisition are crucial. The aim of this randomized study was to find the optimal measurement settings regarding stimulation frequency, repetition number, and data acquisition. Forty healthy subjects underwent two visits of SEP (Cz-Fz) assessments using repetitive (500 stimuli) electrical stimulation of 0.5 Hz, 1.1 Hz, and 1.6 Hz and pulse width of 1 ms at the bladder dome or trigone. SEP analyses revealed higher amplitudes and better signal-to-noise ratio (SNR) with lower stimulation frequencies, while latencies remained unchanged. Decreasing amplitudes and SNR were observed with continuing stimulation accompanied by decreasing responder rate (RR). When applying stimuli at a frequency of 0.5 Hz, averaging across 200 stimuli revealed optimal reliability with best SNR, RR and sufficiently high amplitudes. This constitutes an optimal compromise between the duration of the assessment and SEP peak-to-peak amplitudes.

4.
Sci Rep ; 9(1): 19728, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31871322

RESUMO

Designing modern photonic devices often involves traversing a large parameter space via an optimization procedure, gradient based or otherwise, and typically results in the designer performing electromagnetic simulations of a large number of correlated devices. In this paper, we investigate the possibility of accelerating electromagnetic simulations using the data collected from such correlated simulations. In particular, we present an approach to accelerate the Generalized Minimal Residual (GMRES) algorithm for the solution of frequency-domain Maxwell's equations using two machine learning models (principal component analysis and a convolutional neural network). These data-driven models are trained to predict a subspace within which the solution of the frequency-domain Maxwell's equations approximately lies. This subspace is then used for augmenting the Krylov subspace generated during the GMRES iterations, thus effectively reducing the size of the Krylov subspace and hence the number of iterations needed for solving Maxwell's equations. By training the proposed models on a dataset of wavelength-splitting gratings, we show an order of magnitude reduction (~10-50) in the number of GMRES iterations required for solving frequency-domain Maxwell's equations.

5.
Eur Urol Focus ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771934

RESUMO

Pelvic neurophysiology testing uniquely evaluates the sacral S2-S4 segmental innervation, but most of these tests assess only somatic innervation and not the splanchnic nerves innervating the lower urinary tract, genitalia, and lower bowel. Nevertheless, there are specific situations in which these tests play an important role in evaluating patients with urogenital complaints.

6.
Sci Rep ; 9(1): 14268, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582760

RESUMO

In this paper we present a contactless transient carrier spectroscopy and imaging technique for traps in silicon. At each pixel, we fit the transient decay of the trap emission which allows us to obtain both the trap time constant and trap concentration. Here we show that this technique allows for high-resolution images. Furthermore, this technique also allows to discriminate between the presence of thermal donors or oxygen precipitates in as-grown wafers, without requiring a thermal donor killing step.

7.
Eur Urol Focus ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31601539

RESUMO

Transcutaneous tibial nerve stimulation has the potential to revolutionize the management of lower urinary tract dysfunction in patients with acute spinal cord injury. TASCI is a nationwide randomized, sham-controlled, double-blind clinical trial for which the preparatory phase has been successfully completed.

8.
Chiropr Man Therap ; 27: 60, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632640

RESUMO

Background: A recent hypothesis purports that spinal manipulation may cause changes at a brain level. Functional Neurology, a mainly chiropractic approach, promotes the use of spinal manipulation to improve 'brain function' as if it were a proven construct. No systematic review has been performed to investigate how well founded this hypothesis is. Objective: To investigate whether spinal manipulation has an effect on 'brain function' that is associated with any clinical benefits. Method: In this systematic review, the literature was searched in PubMed, Embase, and PEDro (final search February 2018). We included randomized or non-randomized controlled studies, in which spinal manipulation was performed to any region of the spine, applied on either symptomatic or asymptomatic humans, and compared to a sham or to another type of control. The outcome measures had to be stated as direct or proxy markers of 'brain function'. Articles were reviewed blindly by at least two reviewers, using a quality checklist designed for the specific needs of the review. Studies were classified as of 'acceptable', 'medium', or 'low' methodological quality. Results were reported in relation to (i) control intervention (sham, 'inactive control', or 'another physical stimulus') and (ii) study subjects (healthy, symptomatic, or with spinal pain" subjects/spinal pain"), taking into account the quality. Only results obtained from between-group or between-intervention comparisons were considered in the final analysis. Results: Eighteen of 1514 articles were included. Studies were generally of 'low' or 'medium' methodological quality, most comparing spinal manipulation to a control other than a sham. Thirteen out of the 18 studies could be included in the final analysis. Transitory effects of different types of 'brain function' were reported in the three studies comparing spinal manipulation to sham (but of uncertain credibility), in "subclinical neck/spinal pain" subjects or in symptomatic subjects. None of these three studies, of 'medium' or 'acceptable' quality, investigated whether the neurophysiological effects reported were associated with clinical benefits. The remaining 10 studies, generally of 'low' or 'medium' quality, compared spinal manipulation to 'inactive control' or 'another physical stimulus' and similarly reported significant between-group differences but inconsistently. Conclusion: The available evidence suggests that changes occur in 'brain function' in response to spinal manipulation but are inconsistent across and - sometimes - within studies. The clinical relevance of these changes is unknown. It is therefore premature to promote the use of spinal manipulation as a treatment to improve 'brain function'.


Assuntos
Dor nas Costas/terapia , Encéfalo/fisiopatologia , Manipulação da Coluna , Cervicalgia/terapia , Adolescente , Adulto , Dor nas Costas/fisiopatologia , Encéfalo/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cervicalgia/fisiopatologia , Neurologia , Adulto Jovem
9.
Materials (Basel) ; 12(17)2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450575

RESUMO

Medical treatment is increasingly benefiting from biomedical microsystems, especially the trending telemedical application. A promising modality for tumor therapy showed the application of nanosecond pulsed electric fields (nsPEF) on cells to achieve nanoporation, cell death, and other cell reactions. A key technology for this method is the generation of pulsed fields in the nanosecond range with high-field strengths in the range of several kilovolts per centimeter. For further biomedical applications, state-of-the-art setups need to decrease in size and improve their capability of integration into microsystems. Due to demanding electronic requirements, i.e., using high voltages and fast pulses, miniaturization and low-cost fabrication of the electrode is first considered. This paper proposes a proof-of-concept for a miniaturized printed flexible electrode that can apply nsPEF on adherent fibroblast cells. The interdigital gold electrode was printed on polyimide with line-width of about 10 µm using an electrohydrodynamic inkjet printer. Furthermore, an electrical circuit was developed to generate both electrical pulses in the nano-second range and voltages up to 180 V. The electrode was integrated into an experimental setup for in-vitro application to human fibroblasts. Field strengths up to 100 kV/cm with 45 ns pulse duration were applied, depending on the degree of cell confluence. The cells show contraction, detachment from the electrode, and lethal reactions after the nsPEF treatment. Furthermore, this printed miniaturized electrode was found to be suitable for subsequent microsystem integration and further cell experiments to optimize pulse parameters for control of cell reaction and behavior.

10.
Neurorehabil Neural Repair ; 33(11): 902-910, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31455175

RESUMO

Background. Predicting functional outcomes after traumatic spinal cord injury (SCI) is essential for counseling, rehabilitation planning, and discharge. Moreover, the outcome prognosis is crucial for patient stratification when designing clinical trials. However, no valid prediction rule is currently available for bowel outcomes after a SCI. Objective. To generate a model for predicting the achievement of independent, reliable bowel management at 1 year after traumatic SCI. Methods. We performed multivariable logistic regression analyses of data for 1250 patients with traumatic SCIs that were included in the European Multicenter Study about Spinal Cord Injury. The resulting model was prospectively validated on data for 186 patients. As potential predictors, we evaluated age, sex, and variables from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the Spinal Cord Independence Measure (SCIM), measured within 40 days of the injury. A positive outcome at 1 year post-SCI was assessed with item 7 of the SCIM. Results. The model relied on a single predictor, the ISNCSCI total motor score-that is, the sum of muscle strengths in 5 key muscle groups in each limb. The area under the receiver operating characteristics curve (aROC) was 0.837 (95% CI: 0.815-0.859). The prospective validation confirmed high predictive power: aROC = 0.817 (95% CI: 0.754-0.881). Conclusions. We generated a valid model for predicting independent, reliable bowel management at 1 year after traumatic SCI. Its application could improve counseling, optimize patient-tailored rehabilitation planning, and become crucial for appropriate patient stratification in future clinical trials.

11.
Spinal Cord ; 57(11): 909-923, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31337870

RESUMO

STUDY DESIGN: Narrative review. OBJECTIVES: To discuss how electrophysiology may contribute to future clinical trials in spinal cord injury (SCI) in terms of: (1) improvement of SCI diagnosis, patient stratification and determination of exclusion criteria; (2) the assessment of adverse events; and (3) detection of therapeutic effects following an intervention. METHODS: An international expert panel for electrophysiological measures in SCI searched and discussed the literature focused on the topic. RESULTS: Electrophysiology represents a valid method to detect, track, and quantify readouts of nerve functions including signal conduction, e.g., evoked potentials testing long spinal tracts, and neural processing, e.g., reflex testing. Furthermore, electrophysiological measures can predict functional outcomes and thereby guide rehabilitation programs and therapeutic interventions for clinical studies. CONCLUSION: Objective and quantitative measures of sensory, motor, and autonomic function based on electrophysiological techniques are promising tools to inform and improve future SCI trials. Complementing clinical outcome measures, electrophysiological recordings can improve the SCI diagnosis and patient stratification, as well as the detection of both beneficial and adverse events. Specifically composed electrophysiological measures can be used to characterize the topography and completeness of SCI and reveal neuronal integrity below the lesion, a prerequisite for the success of any interventional trial. Further validation of electrophysiological tools with regard to their validity, reliability, and sensitivity are needed in order to become routinely applied in clinical SCI trials.

12.
Int J Public Health ; 64(7): 1097-1105, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147730

RESUMO

OBJECTIVES: To estimate excess mortality and life years lost in a Swiss cohort of individuals with traumatic spinal cord injury (TSCI). METHODS: This study uses population-based data collected in the Swiss Spinal Cord Injury Cohort (SwiSCI) study, which covers all specialized rehabilitation centres. Flexible parametric survival models were used to model life years remaining (LYR), potential years life lost (PYLL), relative survival and excess hazard ratios. RESULTS: Men and women with TSCI and an attained age of 30 were estimated to have 42 LYR (95% CI = 37.9-45.5) and 43 LYR (95% CI = 40.1-45.5), respectively; this equates to a life expectancy (LE) of 80.6 and 76.9% of that of the Swiss general population. With respect to lesion level and completeness, persons with incomplete paraplegia had 45.1 LYR at an attained age of 30, whereas individuals with complete tetraplegia only had 28.7 LYR. This pattern was similar for PYLL. CONCLUSIONS: The extended LE following TSCI, even for the most severe lesions, underscores the need for sustained follow-up to support functioning and health for individuals ageing with SCI.


Assuntos
Expectativa de Vida , Traumatismos da Medula Espinal/mortalidade , Adulto , Idoso , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraplegia/mortalidade , Modelos de Riscos Proporcionais , Análise de Sobrevida , Índices de Gravidade do Trauma
13.
Proc Natl Acad Sci U S A ; 116(17): 8597-8602, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30944225

RESUMO

In plants, postembryonic formation of new organs helps shape the adult organism. This requires the tight regulation of when and where a new organ is formed and a coordination of the underlying cell divisions. To build a root system, new lateral roots are continuously developing, and this process requires the tight coordination of asymmetric cell division in adjacent pericycle cells. We identified EXPANSIN A1 (EXPA1) as a cell wall modifying enzyme controlling the divisions marking lateral root initiation. Loss of EXPA1 leads to defects in the first asymmetric pericycle cell divisions and the radial swelling of the pericycle during auxin-driven lateral root formation. We conclude that a localized radial expansion of adjacent pericycle cells is required to position the asymmetric cell divisions and generate a core of small daughter cells, which is a prerequisite for lateral root organogenesis.

14.
Nutrients ; 11(3)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818812

RESUMO

Nut consumption is known for its health benefits, in particular in inflammatory diseases. A possible mechanism for these effects could be their beneficial fatty acid composition. Nuts mainly contain mono- and polyunsaturated fatty acids, which have anti-inflammatory properties. However, studies investigating the effects of nut extracts on inflammatory processes on the molecular level are rare. We therefore prepared oily nut extracts after in vitro digestion and saponification of the fat-soluble constituents. Besides chromatographic analysis, cell culture experiments were performed using murine macrophages (RAW264.7) to study the capacity of different nut extracts (hazelnut, almond, walnut, macadamia, and pistachio) to modulate inflammatory processes. Oleic acid was the main fatty acid in hazelnut, almond, macadamia, and pistachio extracts. Both oily nut extracts and pure oleic acid significantly reduced the LPS-induced expression of iNos, Cox2, Tnfα, Il1ß, and Il6 mRNAs. iNos protein expression was down-regulated followed by reduced nitric oxide formation. Thus, nut extracts at concentrations achievable in the digestive tract inhibit the expression and formation of inflammatory mediators in macrophages. Hence, a beneficial contribution of nut consumption to inflammatory diseases can be assumed. We are convinced that these results provide new insights on the molecular mechanisms involved in the health-beneficial effects of nuts.


Assuntos
Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Nozes/química , Óleos Vegetais/química , Óleos Vegetais/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Células RAW 264.7
15.
Redox Biol ; 24: 101166, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30897408

RESUMO

The plant Garcinia kola is used in African ethno-medicine to treat various oxidation- and inflammation-related diseases but its bioactive compounds are not well characterized. Garcinoic acid (GA) is one of the few phytochemicals that have been isolated from Garcinia kola. We investigated the anti-inflammatory potential of the methanol extract of Garcinia kola seeds (NE) and purified GA, as a major phytochemical in these seeds, in lipopolysaccharide (LPS)-activated mouse RAW264.7 macrophages and its anti-atherosclerotic potential in high fat diet fed ApoE-/- mice. This study outlines an optimized procedure for the extraction and purification of GA from Garcinia kola seeds with an increased yield and a purity of >99%. We found that LPS-induced upregulation of iNos and Cox2 expression, and the formation of the respective signaling molecules nitric oxide and prostanoids, were significantly diminished by both the NE and GA. In addition, GA treatment in mice decreased intra-plaque inflammation by attenuating nitrotyrosinylation. Further, modulation of lymphocyte sub-populations in blood and spleen have been detected, showing immune regulative properties of GA. Our study provides molecular insights into the anti-inflammatory activities of Garcinia kola and reveals GA as promising natural lead for the development of multi-target drugs to treat inflammation-driven diseases.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Garcinia kola/química , Nozes/química , Vitamina E/análogos & derivados , Vitamina E/farmacologia , Animais , Biomarcadores , Cromatografia Líquida , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7 , Sementes , Transdução de Sinais , Espectrometria de Massas em Tandem
16.
Neuroepidemiology ; 52(3-4): 205-213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30763935

RESUMO

BACKGROUND: Traumatic spinal cord injuries (TSCI) are a neurological condition associated with reduced well-being, increased morbidity and reductions in life expectancy. Estimates of all-cause and cause-specific mortality can aid in identifying targets for prevention and management of contributors for premature mortality. OBJECTIVES: To compare all-cause and cause-specific rates of mortality to that of the Swiss general population; to identify differentials in risk of cause-specific mortality according to lesion characteristics. METHODS: All-cause and cause-specific standardized mortality ratios (SMRs) were calculated using data from the Swiss Spinal Cord Injury cohort study. Cause-specific subhazard ratios were estimated within a competing risk framework using flexible parametric survival models. RESULTS: Between 1990 and 2011, 2,492 persons sustained a TSCI, of which 379 died. Persons with TSCI had a mortality rate more than 2 times higher than that of the Swiss general population (SMR 2.32; 95% CI 2.10-2.56). Tetraplegic lesions were associated with an increased risk of mortality due to respiratory and cardiovascular diseases, infections, and accidents. Cause-specific SMRs were notably elevated for SCI-related conditions such as urinary tract infections (UTIs) and septicemia. CONCLUSIONS: Elevated SMRs due to cardiovascular disease, UTIs and septicemia-related mortality suggest the need for innovation when managing associated secondary health conditions.


Assuntos
Causas de Morte/tendências , Vigilância da População , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/mortalidade , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Vigilância da População/métodos , Traumatismos da Medula Espinal/complicações , Suíça/epidemiologia , Infecções Urinárias/diagnóstico , Infecções Urinárias/etiologia , Infecções Urinárias/mortalidade
17.
BJU Int ; 123(2): 342-352, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30113757

RESUMO

OBJECTIVE: To understand the occurrence of and risk factors for urinary tract infections (UTIs) in patients with spinal cord injury (SCI) undergoing specialized SCI rehabilitation in Switzerland. PATIENTS AND METHODS: This study used data collected from 369 patients, who participated in a nationwide rehabilitation cohort for SCI in Switzerland between 2013 and 2017. Information on UTIs as well as their potential determinants, including demographics, lesion characteristics, and time-updated data on functional independence and bladder management, was used. Multivariable regression methods were applied to perform a time-updated evaluation of determinants of UTI risk. RESULTS: The crude incidence rate (IR) of UTIs was 0.55 UTIs per 100 person-days (95% confidence interval [CI] 0.49-0.62), the cumulative IR was 43%, and the median length of stay was 122 days. The bladder emptying method at discharge was largely determined by 28 days after admission. Among those using indwelling or assisted intermittent catheterization (IC), the likelihood of self-IC at discharge was positively related to the level of self-care independence, negatively related to age at injury, and lower in women than men. Catheter users consistently had higher adjusted IRs for UTI than spontaneous voiders. The IR ratios were: indwelling catheter: 5.97 (95% CI 2.63-13.57); assisted IC: 6.05 (95% CI 2.63-13.94); self-IC: 5.16 (95% CI 2.31-11.52); test for differences across catheter groups: P = 0.82. Lesion severity and previous UTI had additional but smaller effect sizes. CONCLUSIONS: Bladder emptying method was identified as the main risk factor for UTI in patients with SCI. As spontaneous voiders had the lowest UTI rate, further research is warranted to reduce voiding dysfunction, for instance using neuromodulation procedures.


Assuntos
Cateteres de Demora/estatística & dados numéricos , Cateterismo Uretral Intermitente/estatística & dados numéricos , Bexiga Urinaria Neurogênica/complicações , Infecções Urinárias/epidemiologia , Infecções Urinárias/etiologia , Adolescente , Adulto , Idoso , Cateteres de Demora/efeitos adversos , Feminino , Humanos , Incidência , Cateterismo Uretral Intermitente/efeitos adversos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Autocuidado/efeitos adversos , Autocuidado/estatística & dados numéricos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/reabilitação , Suíça/epidemiologia , Bexiga Urinaria Neurogênica/fisiopatologia , Micção , Adulto Jovem
18.
Eur J Nutr ; 58(8): 3023-3034, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30368556

RESUMO

PURPOSE: Excessive storage of triacylglycerides (TAGs) in lipid droplets within hepatocytes is a hallmark of non-alcoholic fatty liver disease (NAFLD), one of the most widespread metabolic disorders in Western societies. For the purpose of exploring molecular pathways in NAFLD development and testing potential drug candidates, well-characterised experimental models of ectopic TAG storage in hepatocytes are needed. METHODS: Using an optimised Oil Red O assay, immunoblotting and real-time qRT-PCR, we compared the capability of dietary monosaccharides and fatty acids to promote lipid accumulation in HepG2 human hepatoma cells. RESULTS: Both high glucose and high fructose resulted in intracellular lipid accumulation after 48 h, and this was further augmented (up to twofold, as compared to basal levels) by co-treatment with the lipogenesis-stimulating hormone insulin and the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α), respectively. The fatty acids palmitic and oleic acid were even more effective than these carbohydrates, inducing significantly elevated TAG storage already after 24 h of treatment. Highest (about threefold) increases in lipid accumulation were observed upon treatment with oleic acid, alone as well as in combinations with palmitic acid or with high glucose and insulin. Increases in protein levels of a major lipid droplet coat protein, perilipin-2 (PLIN2), mirrored intracellular lipid accumulation following different treatment regimens. CONCLUSIONS: Several treatment regimens of excessive fat and sugar supply promoted lipid accumulation in HepG2 cells, albeit with differences in the extent and rapidity of steatogenesis. PLIN2 is a candidate molecular marker of sustained lipid accumulation in HepG2 cells.

19.
Pharm Dev Technol ; 24(5): 560-574, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30303440

RESUMO

The present study details the development of a small-scale spray-drying approach for the routine screening of amorphous solid dispersions (ASDs). This strategy aims to overcome the limitations of standard screening methodologies like solvent casting and quench cooling to predict drug-polymer miscibility of spray-dried solid dispersions (SDSDs) and therefore to guarantee appropriate carrier and drug-loading (DL) selection. A DoE approach was conducted to optimize process conditions of ProCept 4M8-TriX spray-drying to maximize the yield from a 100 mg batch of Itraconazole/HPMCAS-LF and Itraconazole/Soluplus 40:60 (w/w). Optimized process parameters include: inlet temperature, pump speed, drying and atomizing airflows. Identified process conditions derived from the DoE analysis were further (i) tested with Itraconazole, Naproxen and seven polymers, (ii) adapted for small cyclone use, (iii) downscaled to 20 mg batch production. Drug-polymer miscibility was systematically characterized using modulated differential scanning calorimetry (mDSC). Spray-drying was identified as a well-suited screening approach: mean yield of 10.1 to 40.6% and 51.1 to 81.0% were obtained for 20 and 100 mg ASD productions, respectively. Additionally, this work demonstrates the interest to move beyond conventional screening approaches and integrate spray-drying during screening phases so that a greater prediction accuracy in terms of SDSDs miscibility and performance can be obtained.


Assuntos
Anti-Inflamatórios não Esteroides/química , Antifúngicos/química , Dessecação/métodos , Itraconazol/química , Naproxeno/química , Polímeros/química , Varredura Diferencial de Calorimetria , Cristalização , Desenvolvimento de Medicamentos/métodos , Metilcelulose/análogos & derivados , Metilcelulose/química , Transição de Fase , Polietilenoglicóis/química , Polivinil/química , Solubilidade , Solventes/química
20.
Pharmaceuticals (Basel) ; 11(3)2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30150516

RESUMO

This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20⁻100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug⁻polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1⁻50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases.

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