Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

B-Carotene conversions and bioaccessibility as influenced by thermal processing: a case study on carrots

ß-Carotene is an important micronutrient that can be found in various plant based food products. Important health benefits have been associated with the consumption of food products that are rich in ß-carotene. Carrots (Daucus carota) are a good source of ß-carotene and they are consumed worldwide. Prior to consumption, carrots are often mechanically and/or thermally processed during preparation processes (e.g. chopping, blending, cooking and steaming) and preservation processes (e.g. pasteurisation and sterilisation processes). It is known that these food processing techniques can induce desired and undesired quality changes.Within this framework, the present work aimed at a better understanding and a quantification of the effect of thermal processing of carrot based food products on the ß-carotene content, ß-carotene conversion reactions and ß-carotene bioaccessibility. It was investigated whether changes in the ß-carotene bioaccessibility could be related to processing induced structural changes of the carrot tissue. The possibility to model ß-carotene isomerisation and ß-carotene bioaccessibility changes due to thermal processing was evaluated.ß-Carotene isomerisation reactions were shown to be rather limited during (laboratory and pilot scale) thermal processing of carrot discs. This may be an indication that the carrot matrix offers natural protection against thermal isomerisation. ß-Carotene isomerisation reactions during thermal processing of carrot puree (80 °C 150 °C) could be modelled using a fractional conversion model: after prolonged heating, the interconversion reactions between the different isomers of ß-carotene reached an equilibrium state, which was temperature dependent. Mainly for thermal sterilisation processes, isomerisation reactions of ß-carotene were pronounced, although the overall retention of all-trans-ß-carotene was substantial when compared to carotenoid losses due to isomerisation in model systems (literature data).Changes in ß-carotene bioaccessibility due to thermal processing of carrot discs (90 °C 110 °C) were shown to be related to processing induced textural changes. More specifically, an inverse correlation between carrot hardness and ß-carotene bioaccessibility was observed on laboratory as well as on pilot scale. Processing induced pectin changes were hypothesised to partially explain the processing induced ß-carotene bioaccessibility changes. In the context of thermal processing of food products containing carrot pieces, one should strive for an acceptable balance between carrot hardness retention and a high ß-carotene bioaccessibility.The ß-carotene bioaccessibility was shown to be dependent on the carrot tissue particle size. The extent of thermal processing of carrot discs prior to mechanical processing affected the relation between the carrot tissue particlesize and the ß-carotene bioaccessibility. Both for raw and gently cooked carrot tissue particles, the ß-carotene bioaccessibility was inversely correlated to the carrot tissue particle size, whereas for intensely cooked carrot samples, the ß-carotene bioaccessibility was high for all carrot tissue particle size fractions. To obtain a high ß-carotene bioaccessibility value, mechanical disintegration (i.e. in vivo mastication or mechanical processing prior to consumption (e.g. juicing, blending)) is thus required for raw or gently cooked carrots, whereas this is less essential for intensely cooked carrots. Many in vitro methods that are used today for the determination of the ß-carotene bioaccessibility only mimic gastric and intestinal digestion. Results of the present work emphasised the importance of the oral mechanical breakdown of food products for the ß-carotene bioaccessibility and a standardised method for the simulation of the oral mechanical breakdown could be designed based on results obtained from a small scale human chewing study. This in vitro mastication technique was successfully implemented in the in vitro digestion method for the determination of the ß-carotene bioaccessibility in carrot discs.From a quantitative point of view, ß-carotene bioaccessibility changes during thermal processing (90 °C 120 °C) of carrot tissue particles (500 4000 µm) could be modelled using a fractional conversion model. Steady-state conditions were thus reached after prolonged heating and the plateau values of the ß-carotene bioaccessibility were temperature dependent. Especially for processes performed at 110 °C and 120 °C, high values for the ß-carotene bioaccessibility were obtained.Taking into consideration kinetic results on both ß-carotene isomerisation and ß-carotene bioaccessibility, it can be concluded that thermal processing of carrots (90 °C 120 °C) has a beneficial effect on the selected nutritional quality markers. The loss of all-trans-ß-carotene due to isomerisation was transcended by a more pronounced increase in the ß-carotene bioaccessibility, which suggests an improved nutritional value of thermally processed carrots compared to raw carrots.status: publishe

Beta-carotene isomerisation in mango puree as influenced by thermal processing and high pressure homogenisation

The present study describes a case study on mango puree, in which focus is given to the effect of thermal processing (100–130 °C, 0–80 min) and high-pressure homogenisation (0–1300 bar) on the isomerisation of β-carotene. Both unit operations are of relevance for the production of mango puree. β-Carotene is an essential micronutrient which is present in a high amount in most mango cultivars, and it is important for human health due to its antioxidant and provitamin A capacity. It is known that these health-related properties of β-carotene are negatively affected by the conversion to cis-isomers. The results have shown that during high-pressure homogenisation of mango puree, β-carotene isomerisation was negligible. During thermal processing, on the other hand, an increase in β-carotene cis-isomer formation with increasing treatment intensity could be observed, although high temperatures and/or long treatment times were required to observe clear additional isomer formation. From a kinetic point of view, a fractional conversion model could be used to model the all-trans-β-carotene isomerisation in mango puree in the temperature and time range studied. In general, it can be concluded that a high percentage of β-carotene is present as cis-isomers in raw mango puree. Furthermore, only intense thermal processing of mango puree leads to the formation of additional cis-isomers in relevant amounts.status: publishe

Role of carotenoid type on the effect of thermal processing on bioaccessibility

Cell walls and chromoplast substructures constitute natural structural barriers governing carotenoid bioaccessibility. In order to enhance carotenoid bioaccessibility, thermal processes were applied to fractions surrounded by different levels of structural barriers. The matrices studied were orange carrots, red carrots, red tomatoes and atomic red carrots. In the case of carrots, no effect of thermal treatments on carotenoid bioaccessibility at the chromoplast level was obtained. However, in the case of tomatoes, lycopene bioaccessibility decreased upon thermal processing of chromoplasts. At the cell cluster level, low intensities of thermal processing resulted in a decrease of β-carotene and lycopene bioaccessibility. Nonetheless, at high intensities of thermal processing, only β-carotene bioaccessibility was increased. This observation was confirmed by the results obtained in the matrix rich in both types of carotenoids (atomic red carrots). It was therefore suggested, that the type of carotenoid constitutes an important factor determining the effect of thermal processing on their bioaccessibility.publisher: Elsevier articletitle: Role of carotenoid type on the effect of thermal processing on bioaccessibility journaltitle: Food Chemistry articlelink: http://dx.doi.org/10.1016/j.foodchem.2014.02.055 content_type: article copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.status: publishe

Carotene degradation and isomerization during thermal processing: a review on the kinetic aspects

Kinetic models are important tools for process design and optimization to balance desired and undesired reactions taking place in complex food systems during food processing and preservation. This review covers the state of the art on kinetic models available to describe heat-induced conversion of carotenoids, in particular lycopene and β-carotene. First, relevant properties of these carotenoids are discussed. Second, some general aspects of kinetic modeling are introduced, including both empirical single-response modeling and mechanism-based multi-response modeling. The merits of multi-response modeling to simultaneously describe carotene degradation and isomerization are demonstrated. The future challenge in this research field lies in the extension of the current multi-response models to better approach the real reaction pathway and in the integration of kinetic models with mass transfer models in case of reaction in multi-phase food systems.peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=bfsn20status: publishe

Modeling lycopene degradation and isomerization in the presence of lipids

The kinetics of thermally induced degradation and isomerization of lycopene in olive oil, fish oil, and an olive oil/tomato emulsion were studied in detail. Special attention was paid to the isomerization reactions using a multi-response modeling approach. The type of oil had a significant impact on lycopene degradation kinetics, being faster in fish oil compared with olive oil. The estimated kinetic parameters to describe lycopene degradation in olive oil were not significantly different from those in an olive oil/tomato emulsion. The overall Z-isomer formation and elimination in olive oil, fish oil, and olive oil/tomato emulsion was similar. Only the kinetic parameters for 13-Z-lycopene formation differed significantly in the two oils. Although the isomerization rate constants for the emulsion were lower than for olive oil, the isomerization reactions showed similar temperature dependency. This study shows that the kinetics of thermally induced degradation and isomerization of lycopene in oil and in an olive oil/tomato emulsion can be described using the same model. The food system, however, has an influence on the model parameters, especially on the rate constants. © 2011 Springer Science+Business Media, LLC.status: publishe

MMP-2 as a modulator of dendritic and axonal responses in the injured mammalian central nervous system

Purpose Neurons in the mammalian central nervous system (CNS) fail to regenerate their axons after injury and undergo axonal degeneration, dendritic shrinkage and eventually apoptosis. However, after inflammatory stimulation (IS), retinal ganglion cells (RGCs) are transformed into an active regenerative state. Several players essential to this regeneration-promoting effect of controlled inflammation have been identified. However, our understanding of the multiple glial- or macrophage-derived factors that may synergistically contribute or potentiate the beneficial effects of IS, is still incomplete. Multiple research lines suggest that matrix metalloproteinases (MMPs) are important players in CNS development, where they contribute to axonal navigation, dendritic tree refinement, etcâ ¦ However, their in vivo functions during de- and regeneration in the adult mammalian brain remain largely elusive. Here, we investigated the effect of MMP-2 downregulation on dendrite remodeling and axonal regeneration after optic nerve crush (ONC) injury (degeneration model) and ONC combined with IS (regeneration model) in the mouse visual system. Methods IS, induced via intravitreal injections of zymosan or Pam3Cys, was used to induce axonal regeneration after ONC in both wild-type and Mmp-2-/- mice. Dendritic remodeling was examined via optical coherence tomography (OCT), (immune)histological stainings on retinal sections and western blots for microtubule associated protein (MAP)-2. In addition, axonal regeneration was assessed by quantifying fluorescently labelled cholera toxin beta (CTB-alexa 488)-positive axons in optic nerve sections. Results Our results revealed that, of all paradigms tested, Pam3Cys combined with cAMP form the best method to induce axonal regeneration. OCT- and histological analyses showed thinning of the inner plexiform layer (IPL), containing the RGC dendrites, upon injury. Strikingly, MAP-2c, typically expressed in the developing CNS, becomes upregulated in the IPL, while MAP 2a+b, normally present in the adult CNS, is downregulated. After injury, MMP-2 expression was highly increased in the inner retina, where it is localized in Muller glia, and in infiltrating immune cells in the vitreous. Interestingly, IPL shrinkage could not be observed in the retina of Mmp-2-/- mice. In addition, also a lower number of CTB+ regenerating axons was found in the optic nerves of Mmp-2-/- mice, as compared to wild-type animals. Conclusion Taken together, our results suggest that MMP-2 plays a beneficial role during axonal regeneration and affects both dendritic and axonal processes in the injured mouse retina/optic nerve. Furthermore, its expression by invading immune cells puts MMP-2 forward as a molecule linking inflammatory stimulation to enhanced axonal regeneration. Additional research is needed to unravel the presumed pleiotropic function of MMP-2 during these regenerative processes.status: publishe

MMP-2 as a modulator of dendritic shrinkage and axonal regeneration: neuroinflammation as the driving force

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Influence of pilot scale in pack pasteurization and sterilization treatments on nutritional and textural characteristics of carrot pieces

The current work presents a pilot scale study in which the effect of in pack thermal preservation processes in a retort system on particular carrot quality aspects, more specifically nutritional and textural characteristics, was investigated. Pasteurization as well as sterilization processes with different intensities were included. The carrot hardness, analyzed by a compression test, and the β-carotene bio-accessibility, analyzed by an in vitro digestion method, were the main quality markers. As a main conclusion, it can be stated that the results of this pilot scale study are a good validation of results obtained during previous laboratory scale experiments on carrot nutritional and textural characteristics. The processes applied in this study only resulted in limited conversion of all-trans-β-carotene to its cis-isomers. Furthermore, it was shown that intense thermal processing is required to observe a significant increase in the β-carotene bio-accessibility. However, this was accompanied with a clear degradation of the hardness. When thermal processing was preceded by low temperature blanching, a technique to improve texture retention of thermally processed plant-based foods, a lower β-carotene bio-accessibility was observed. Both observations clearly illustrated the inverse correlation between textural and nutritional characteristics of (processed) carrots. Statistical analyses confirmed the trends observed. For process design, the choice of the process intensity was identified to be crucial: the required product safety needs to be achieved, while still reaching an acceptable structural and nutritional quality. Exploring strategies to enhance the β-carotene bio-accessibility while ensuring an acceptable carrot texture can therefore be useful.status: publishe