21 research outputs found
Using Reduced Kinetic Model for the Multi-Objective Optimization of Thermal Section of the Claus Process Leading to a More Cost-Effective and Environmentally Friendly Operation
No full textThe Claus process is a sulfur recovery unit wherein hydrogen sulfide is converted into the elemental sulfur. This study aims to model the thermal section of the Claus process, which consists of a reaction furnace and a waste heat boiler, as a configuration of two reactors, and subsequently optimize the entire section. Two different reduced kinetic schemes were provided for both units. Using the validated kinetics, mathematical models were developed. The waste heat boiler was modeled as a plug flow reactor with heat transfer, instead of a heat exchanger. The main objective was to maximize the amount of elemental sulfur at the end of the thermal section. Additionally, maximizing the amount of steam generated in the WHB was considered as a secondary objective, and the multi-objective optimization problem was solved. The sulfur production was improved 14.1% and 30% as a result of single- and multi-objective optimization studies. In addition, as an alternative, the Taguchi method was also used for optimization studies, and optimum values were determined. Using the Taguchi method, we determined that an increase in sulfur production by 24% is possible
Seismic data reveal eastern Black Sea Basin structure
No full textRifted continental margins are formed by progressive extension of the lithosphere. The development of these margins plays an integral role in the plate tectonic cycle, and an understanding of the extensional process underpins much hydrocarbon exploration. A key issue is whether the lithosphere extends uniformly, or whether extension varies\ud
with depth. Crustal extension may be determined using seismic techniques. Lithospheric extension may be inferred from the waterloaded subsidence history, determined from\ud
the pattern of sedimentation during and after rifting. Unfortunately, however, many rifted margins are sediment-starved, so the subsidence history is poorly known.\ud
To test whether extension varies between the crust and the mantle, a major seismic experiment was conducted in February–March 2005 in the eastern Black Sea Basin (Figure 1), a deep basin where the subsidence history is recorded\ud
by a thick, post-rift sedimentary sequence. The seismic data from the experiment indicate the presence of a thick, low-velocity zone, possibly representing overpressured sediments. They also indicate that the basement and\ud
Moho in the center of the basin are both several kilometers shallower than previously inferred. These initial observations may have considerable impact on thermal models of the petroleum system in the basin. Understanding\ud
the thermal history of potential source rocks is key to reducing hydrocarbon exploration risk. The experiment, which involved collaboration between university groups in the United Kingdom, Ireland, and Turkey, and BP and\ud
Turkish Petroleum (TPAO), formed part of a larger project that also is using deep seismic reflection and other geophysical data held by the industry partners to determine the subsidence history and hence the strain evolution of\ud
the basin
Docetaxel combined with oral etoposide as second-line treatment for advanced gastric carcinoma after failure of platinum- and fluoropyrimidine-based regimens
No full textBackground. Platinum, antracyline, and fluoropyrimidine combination chemotherapy has been widely used as a first-line treatment for advanced gastric cancer (AGC). In the present study, we determined the efficacy and the safety of docetaxel and oral etoposide as second-line combination chemotherapy after failure of commonly used combination regimens in AGC. Methods. Patients with histologically proven gastric cancer and measurable metastatic disease received docetaxel 75 mg/m2 as a 1-h intravenous infusion on day 1, and oral etoposide 50 mg/m2 once daily on days 1-5, every 3 weeks until disease progression or unacceptable toxicities. Results. Between June 2006 and September 2008, 32 patients, of median age 60 years (range 32-77 years) were included in the study. Overall response rate was 9.4% and 31.3% of patients achieved a stable disease. Median progression-free survival was 3 months (95% CI, 2.5-3.5). Median overall survival was 6 months (95% CI, 3.8-8.2) with 16.9% 1-year survival rate. Grade 3-4 toxicities included neutropenia (28.8%), febrile neutropenia (18.8%), thrombocytopenia (3.1%), nausea and vomiting (15.6%), diarrhea (9.4%), and mucositis (6.2%). Conclusion. Docetaxel and oral etoposide combination was moderately effective and safe in appropriately selected AGC patients after failure of platinum- and fluoropyrimidine-based combination regimens. © The Author(s), 2010
Does re-design of the policies on housing finance and supply help to solve housing question of Turkey?
No full textHousing is one of the major socio-economic problems in Turkey. Widespread spontaneous settlements in urban area may be accepted as the sufficient criterion for the level of housing question in Turkey. Additionally, there are important quality problems in existing housing units. This problematic structure may be also explained by the lack of efficient housing policies and housing finance system. It seems after 2003 that housing policy of Turkey is essentially based on the Housing Development Administration‟s (HDA) pragmatic approaches. In this context, we may argue that the current housing policy is one-dimensional and also would be unsustainable in some perspectives. In this experimental research, the author attempts to analyze limitations and clear/potential problems of the housing policies of HDA. We basically analyze whether affordable housing problem is minimize with alternative policies and required incentives. In this context, we review housing subsidies and PPPs as the instruments of alternative social/private rental housing supply models. In a broader perspective, the original contribution of this paper is to examine private rental housing, social rental housing, urban renewal, micro-finance and housing production of REITs as the alternative housing supply/finance models to improve affordable housing. We conclude that these alternative housing supply/finance models may improve housing affordability and hence minimize the housing question in Turkey, if they can optimally design and required incentives may meet by the central/local governments.Housing finance, affordable housing, Turkish housing policies, TOKI (Housing Development Administration)
A possible role of the locus coeruleus in complex regional pain syndrome
No full textHeightened sensitivity to painful stimulation commonly spreads from the affected limb to the ipsilateral forehead in patients with complex regional pain syndrome (CRPS). In addition, acoustic startle evokes greater auditory discomfort and increases in limb pain when presented on the affected than unaffected side. In contrast, limb pain ordinarily evokes analgesia in the ipsilateral forehead of healthy participants, and acoustic startle suppresses limb pain. Together, these findings suggest that hemilateral and generalized pain control mechanisms are disrupted in CRPS, and that multisensory integrative processes are compromised. Failure to inhibit nociceptive input from the CRPS-affected limb could sensitize spinal and supraspinal neurons that receive convergent nociceptive and auditory information from hemilateral body sites. Somatosensory, auditory and emotional inputs may then aggravate pain by feeding into this sensitized nociceptive network. In particular, a disturbance in hemilateral pain processing that involves the locus coeruleus could exacerbate the symptoms of CRPS in some patients
Association between Tetrodotoxin Resistant Channels and Lipid Rafts Regulates Sensory Neuron Excitability
No full textPubMed ID: 22870192This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
COCHRANE BVS BIREME OPAS OMS Imprimir | Fechar CLEAVAGE STAGE VERSUS BLASTOCYST STAGE EMBRYO TRANSFER IN ASSISTED REPRODUCTIVE TECHNOLOGY P L A I N L A N G U A G E S U M M A R Y
No full textA B S T R A C T Background Recent advances in cell culture media have led to a shift in IVF practice from early cleavage embryo transfer to blastocyst stage transfer. The rationale for blastocyst culture is to improve both uterine and embryonic synchronicity and self selection of viable embryos thus resulting in higher implantation rates. Objective To determine if blastocyst stage embryo transfers (ETs) affect live birth rate and associated outcomes compared with cleavage stage ETs and to investigate what factors may influence this. Criteria for considering studies for this review Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Controlled Trials Register (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and Bio extracts. The last search date was January 2007. Selection criteria Trials were included if they were randomised and compared the effectiveness of early cleavage versus blastocyst stage transfers. Data collection and analysis Of the 50 trials that were identified, 18 randomised controlled trials (RCTs) met the inclusion criteria and were reviewed. The primary outcome was rate of live birth. Secondary outcomes were rates per couple of clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos and cryopreservation. Quality assessment, data extraction and meta-analysis were performed following Cochrane guidelines. Main results Evidence of a significant difference in live-birth rate per couple between the two treatment groups was detected in favour of blastocyst culture (9 RCTs; OR 1.35, 95% CI 1.05 to 1.74 (Day 2/3: 29.4% versus Day 5/6: 36.0%)). This was particularly for trials with good prognosis patients, equal number of embryos transferred (including single embryo transfer) and those in which the randomisation took place on Day 3. Rates of embryo freezing per couple was significantly higher in Day 2 to 3 transfers (9 RCTs; OR 0.45, 95% CI 0.36 to 0.56). Failure to transfer any embryos per couple was significantly higher in the Day 5 to 6 group (16 RCTs; OR 2.85, 95% CI 1.97 to 4.11 (Day 2/3: 2.8% versus Day 5/6: 8.9%)) but was not significantly different for good prognosis patients (9 RCTs; OR 1.50, 95% CI 0.79 to 2.84). Authors' conclusions This review provides evidence that there is a significant difference in pregnancy and live birth rates in favour of blastocyst transfer with good prognosis patients with high numbers of eight-cell embryos on Day three being the most favoured in subgroup for whom there is no difference in cycle cancellation. There is emerging evidence to suggest that in selected patients, blastocyst culture maybe applicable for single embryo transfer. 25/08/11 07:28 http://cochrane.bireme.br/cochrane/show.php?db=reviews&mfn=1146&id=CD002118&lang=pt&dblang=&lib=COC&print=yes Página 2 de 23 P L A I N L A N G U A G E S U M M A R Y Keeping embryos a few days longer in the laboratory before transfer has not been shown to lead to more pregnancies than regular IVF In vitro fertilisation (IVF) is fertilisation (egg and sperm creating an embryo) in a laboratory (in a 'test tube'). With regular IVF, embryos are transferred into the woman's uterus two to three days after fertilisation (at the cleavage stage). An alternative technique delays transferal until five to six days after fertilisation (at blastocyst stage). This may be better timing and allow choice of more viable embryos. The review of trials found evidence that more women will have a pregnancy and baby with blastocyst transfer than with regular IVF. There was however, a higher risk that a women would have fewer embryos to freeze and no embryos available for transfer. W H A T ' S N E W What's new Last assessed as up-to-date: 22 July 2007. Date Event Description 20 September 2010 Amended Contact details updated. B A C K G R O U N D The fledgling era of in vitro fertilisation (IVF) from 1980 to the mid 1990s, was characterised by relatively static success rates of around 20% pregnancy rates. The past decade however, has given rise to exciting advances in ovarian stimulation, cell culture and embryo transfer techniques that have culminated in significant overall improvements in successful pregnancies. This is evident in the annual statistical reports from different areas of the globe. One such report for example, has demonstrated a doubling of pregnancy rate per embryo transfer cycle from 1994 to 2003 despite a decrease in the mean number of embryos transferred ( Waters 2006 ). The contribution of embryo culture to these improvements is the focus of this Cochrane review of cleavage stage versus blastocyst stage transfer. With the introduction of a variety of commercial preparations of sequential media in the late 1990s, the IVF industry witnessed an explosion of worldwide interest in blastocyst culture, with most clinics conducting research into its application in their own setting. As a result a substantial volume of publications followed. These included conflicting trials and debates about the merits and drawbacks of extended culture. A lack of strong consensus about the best practice for blastocyst culture has not aided by the fact that many of the trials were not prospectively randomised and/or were underpowered. The need for an evidence-based approach using meta-analysis of small trials was, therefore, required to assist in deciphering the overall affect of blastocyst culture to help identify patient subsets and practices that might best benefit from this approach. Blastocyst culture is not novel; indeed, the very first report of an IVF pregnancy was from a transferred blastocyst There are two central arguments why blastocyst culture has purported advantages over traditional cleavage stage transfer. Firstly, it has long been recognised that it is physiologically premature to expose early-stage embryos to the uterine environment, particularly one that has been subjected to superovulation and thus high levels of oestrogen The second argument for blastocyst culture is in their innately higher implantation potential compared with early cleavage embryos. As a consequence of self selection, it is postulated that only the most viable embryos are expected to develop into blastocysts. It is widely acknowledged that the morphological criteria used for selection of the best embryos on Day 2 to 3 is limited. Many published studies that debate the correlation of morphological features with pregnancy rates can be found in the literature Arguments against blastocyst culture are largely related to this process of self selection. Couples undergoing blastocyst culture are expected to have a higher incidence of: a) being cancelled due to failed embryo development There is also the question of how scientists can be so certain that any given Day 3 embryo has the ability to become a viable blastocyst in vivo, but not in vitro. Based on the very wide range of basculation rates reported, there is evidence that not all clinical and laboratory environments are equal, despite identical sequential media being used. This is an obvious compounding factor when performing a meta-analysis. Variables such as number of incubators, gas mix, culture ware quality control ( Gardenr 2003b ), and the superovulation regimen ( Bukulmez 2007 ; Other negative outcomes reported to be associated with blastocyst culture include a higher incidence of monozygotic twinning and altered sex ratio in favour of males The niche of blastocyst culture is unfolding against a backdrop of evolving regulatory and community pressures. Until relatively recently it was been widely accepted that in order to achieve acceptable pregnancy rates, several embryos were required to be replaced in the uterus ( Edwards 1983 ). However, pressure on the assisted reproductive technology (ART) industry to reduce the multiple-birth rate and high order birth rates (more than two fetal sacs) over the past decade has seen a steady decline in the number of embryos transferred. Single embryo transfers for selected patient groups are now considered standard practice in many clinics throughout the world Advocates of blastocyst culture are confident that only the most viable embryos will survive the extended culture to Day 5 to 6. This would result in a higher probability of implantation and require fewer embryos to be transferred, thereby lowering the costly multiple-birth rate O B J E C T I V E S The primary aim of this review was to compare the outcomes of cleavage stage with blastocyst stage embryo transfers in subfertile couples. M E T H O D S O F T H E R E V I E W C R I T E R I A F O R C O N S I D E R I N G S T U D I E S F O R T H I S R E V I E W Types of studies All randomised controlled trials (RCTs) comparing early-stage embryo transfers (Day 2 to 3) with blastocyst stage 25/08/11 07:28 http://cochrane.bireme.br/cochrane/show.php?db=reviews&mfn=1146&id=CD002118&lang=pt&dblang=&lib=COC&print=yes Página 4 de 23 transfers (Day 5 to 6) were considered. Quasi-randomised controlled trials (trials that stated they used random allocation but allocation was, for example, the day of the week, which is not truly random) were excluded and withdrawn from the previous versions of the review. Types of participants Inclusion criteria Couples undergoing in vitro fertilization (IVF) or (ICSI) for therapeutic reasons or for oocyte donation within all patient prognosis groups. Patient prognosis groups (patient subsets or populations) is a term used to describe the categories that couples are assigned to based on several factors such as their age, type of infertility, ovarian response to the superovulation drugs and number of previous failed attempts. See the subgroup analysis section in the 'Methods of the review' below for the categories. Exclusion criteria Couples whose IVF or ICSI cycle, or both, has involved in vitro matured oocytes or pre-implantation diagnosis. Types of intervention Inclusion criteria Single and sequential media culture methods for IVF and ICSI where the embryos were grown for between 2 to 6 days in vitro prior to embryo transfer and where Day 2 to 3 transfers were compared with Day 5 to 6 transfers. Exclusion criteria Co-culture methods. Types of outcome measures Primary outcome Live-birth rate per couple (number of live-births per couple). Secondary outcomes Clinical pregnancy rate per couple: number of couples achieving a clinical pregnancy (defined by the demonstration of fetal heart activity on ultrasound scan). Multiple-pregnancy rate per couple: number of multiple pregnancies per couple. High order multiple-pregnancy rate per couple: three or more fetal heartbeats per couple. Miscarriage rate: number of occurrences per couple and per pregnant woman. Embryo freezing rate: number of couples that had embryos frozen per couple. Failure to have any embryo transfer rate: percentage of couples that did not have an embryo transfer. Additional outcomes not appropriate for statistical pooling Data per cycle or per embryo transfer (ET) or per ovum pick up (OPU) were not able to be pooled S E A R C H M E T H O D S F O R I D E N T I F I C A T I O N O F S T U D I E S Search methods for identification of studies All reports that described (or might have described) randomised controlled trials comparing early-stage embryo transfer and blastocyst stage transfer in the treatment of subfertility, using IVF or ICSI, were obtained using the search strategy developed by the Menstrual Disorders and Subfertility Group. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (1966 to Jan 2007, EMBASE (1980( to Jan 2007 and Bio extracts using the Cochrane highly sensitive search strategy and the following keywords: blastocyst/embryo or embryo transfer/cleavage stage, ovum/culture media or embryo culture/sequential culture/co-culture. See Appendix 1 . The National Research Register (NRR), a register of ongoing and recently completed research projects funded by or of interest to the United Kingdom's National Health Service, entries from the Medical Research Council Clinical Trials Register, and details on reviews in progress collected by the NHS Centre for Reviews and Dissemination, were searched. The Clinical Trials register (clinicaltrials.gov), a registry of both federally and privately funded US and other clinical trials, was also searched. 25/08/11 07:28 http://cochrane.bireme.br/cochrane/show.php?db=reviews&mfn=1146&id=CD002118&lang=pt&dblang=&lib=COC&print=yes Página 5 de 23 The search was performed on titles, abstracts and keywords of the listed articles. The citation lists of relevant publications review articles, and included studies were also searched. Relevant conference abstracts were hand searched. D A T A C O L L E C T I O N A N D A N A L Y S I S Data collection and analysis Two review authors (DB, NJ or CF) performed the selection of trials for inclusion in the review after employing the search strategy described previously. Excluded articles were detailed in the Characteristics of excluded studies and Included trials were analysed for the quality criteria and methodological details outlined below see . This information is presented in a Characteristics of included studies and provides a context for assessing the reliability of results. Trial characteristics 1. Allocation of concealment: a) a third party (telephone) or trialist (computer, sealed envelope or register); b) not stated. Characteristics of the study participants 1. Baseline characteristics: a) age; b) primary or secondary infertility; c) cause and duration of infertility; d) previous treatment. 2. Other subgroup criteria, women: a) undergoing IVF or ICSI, or both; b) over the age of 37 undergoing IVF or ICSI, or both; c) with high basal follicle stimulating hormone (FSH) (more than 15 on Day 3) undergoing IVF or ICSI, or both; d) with greater than 10 follicles one day prior to egg retrieval; e) with less than five oocytes on the day of egg retrieval; f) with repeated implantation failure (more than two failed stimulation cycles with ET). 2. Secondary: a) clinical pregnancy (per couple randomised); b) multiple pregnancy (per couple randomised); c) high order pregnancy rate (three or more fetal heart beats per couple randomised). a) miscarriage; d) embryo freezing; e) failure to transfer any embryos; f) implantation 3. Additional outcomes not appropriate for statistical pooling: a) cycle data per ovum pick up (OPU) and embryo transfer (ET) Subgroup analysis The following subgroup analyses were planned. Subgroup A: studies where the policy for the number of embryos replaced was equal in both Day 2 to 3 and Day 5 to 6 groups (includes studies where there was a policy of single embryo transfer) versus studies where fewer Day 5 to 6 than Day 2 to 3 embryos were replaced. Subgroup B: studies that actively selected for good prognosis participants (for example four or more zygotes, first two cycles, more than 10 follicles, young population, no male-factor individuals) versus participants with poor prognostic factors (for example previous failed ART cycles or poor response to ovulation stimulation) versus studies with unselected participants. Subgroup C: studies that randomised at the start of the cycle (that is prior to ovarian stimulation) were compared with the days immediately prior and post OPU (that is day of final ultrasound scan and prior to HCG trigger up to and including the day of fertilisation check, when numbers of oocytes are anticipated). Sensitivity analysis The following sensitivity analyses were planned: studies that used concealment of allocation, reported were the randomisation method and the day of randomisation was considered. Information was independently extracted on methodological quality and outcome data by two review authors (DB, NJ) using forms designed according to Cochrane guidelines. Another co-author (CF) was available to resolve any discrepancies. Additional information on trial methodology or actual original trial data were sought from the principal author of trials that appeared to meet eligibility criteria but were unclear in aspects of methodology, or where the data was in a form unsuitable for meta-analysis. Reminder correspondence was sent when a reply was not received within three weeks. Statistical analyses were performed in accordance with the guidelines for statistical analysis developed by the Cochrane Menstrual Disorders and Subfertility Group. Heterogeneity between the results of different studies was examined by inspecting the scatter of data points, the overlap in their confidence intervals and more formally by checking the results of the chi squared tests. A priori, it was planned to look at the possible contribution of differences in trial design to the heterogeneity identified. Where possible, the outcomes were pooled statistically. Where possible the data were analysed using an intention to treat analysis. We used the number of women randomised as the denominator even if the authors did not. For dichotomous data (for example clinical pregnancy rate), results for each study were expressed as odds ratios (OR) with 95% confidence intervals and combined for meta-analysis with RevMan software using the Peto-modified MantelHaenzel method. The data were entered on the graphs so that in positive outcomes (for example pregnancy) points to the left of the line of no effect favour Day 5 to 6 transfer, and in negative outcomes (for example miscarriage) points to the right of the line of no effect favour Day 5 to 6 transfer. A search for new trials is conducted bi-annually and the review updated as and when new trials to be incorporated are found. M E T H O D O L O G I C A L Q U A L I T Y R E S U L T S Results Description of studies 25/08/11 07:28 http://cochrane.bireme.br/cochrane/show.php?db=reviews&mfn=1146&id=CD002118&lang=pt&dblang=&lib=COC&print=yes Página 7 de 23 See: Characteristics of included studies ; Characteristics of excluded studies . Fifty trials were identified as providing data comparing early cleavage stage and blastocyst stage embryo transfer outcomes, dating back to 1991. Eighteen trials met the inclusion criteria and were fully reviewed. Excluded studies Thirty-two studies failed to meet the inclusion criteria for reasons outlined in the table 'Characteristics of excluded studies'. In accordance with the policy of the Cochrane Menstrual Disorders and Subfertility Group, all quasi-randomised trials that had previously been included in the original Cochrane Review in 2000 have now been excluded from this update Included studies Eighteen studies met the inclusion criteria. One of the studies had been published or presented on separate dates and both sets of data appear in the table 'Characteristics of included studies' within single entries. Fifteen trials used sequential media, of which nine used Vitro life G1/G2 while the remaining media were combinations of brands or made in house. Three did not state the media used ( in additional tables). Risk of bias in included studies See the 'Additional tables' for a summary of the quality of the included studies. The length of culture and the day of embryo transfer was different for each of the experimental groups making it impossible to blind which group a participant was in for the doctor, scientist, nurse and participant. There was no evidence to suggest that the statistician in any trial was blinded to the assignment status. Intention to treat, withdrawals and dropouts Only the two most recent trials stated that they performed an intention-to-treat analysis ( Papanikolaou 2005 ; Papanikolaou 2006 ). The latter trial also performed an interim analysis and was terminated after 50% of the intended patients were enrolled due to a significant difference being detected. Identification of participants failing to have an embryo transfer was not stated, or unclear, in some trials. Coskun 2000 implied that a 100% embryo transfer rate was achieved in both Day 2 to 3 and Day 5 to 6 groups, which is unexpectedly high and is possibly explained by transferring embryos of a lesser stage when blastocysts were not available. Where the number of couples and the number of ETs were different, the number of couples was used as the denominator even when exclusions took place post randomisation, assuming no pregnancies occurred. For example, Frattarelli 2003 excluded eight couples including four for embryo quality. These eight couples were able to be added to the denominator and, therefore, an intention-to-treat analysis was possible. Emiliani 2003 excluded 10 women because of protocol violations. Livingstone 2002 excluded 20 women post randomisation on the basis of study quality and no further data on these were available. Van der Auwera 2002 excluded seven women post-randomisation as three couples randomised to Day 2 requested blastocyst transfer and four couples requested Day 2 transfer. These numbers were added to the denominator, assuming they did not conceive. For the remaining studies, the Day 5 to 6 ET rate ranged from 71% to 96%. Attempts were made to obtain additional information regarding all aspects of randomisation, blinding, power analysis and intention to treat from all trial authors. Effects of interventions Live birth per couple Evidence of a significant difference was detected between the two treatment groups for live-birth rate per couple (9 RCTs; OR 1.35, 95% CI 1.05 to 1.74 (Day 2/3: 29.4% versus Day 5/6: 36.0%)). There was no heterogeneity det
The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis.
No full textObjectives: To review the evidence for an association of white matter hyperintensities with risk of stroke, cognitive decline, dementia, and death.
Design: Systematic review and meta-analysis.
Data sources: PubMed from 1966 to 23 November 2009.
Study selection: Prospective longitudinal studies that used magnetic resonance imaging and assessed the impact of white matter hyperintensities on risk of incident stroke, cognitive decline, dementia, and death, and, for the meta-analysis, studies that provided risk estimates for a categorical measure of white matter hyperintensities, assessing the impact of these lesions on risk of stroke, dementia, and death.
Data extraction: Population studied, duration of follow-up, method used to measure white matter hyperintensities, definition of the outcome, and measure of the association of white matter hyperintensities with the outcome.
Data synthesis: 46 longitudinal studies evaluated the association of white matter hyperintensities with risk of stroke (n=12), cognitive decline (n=19), dementia (n=17), and death (n=10). 22 studies could be included in a meta-analysis (nine of stroke, nine of dementia, eight of death). White matter hyperintensities were associated with an increased risk of stroke (hazard ratio 3.3, 95% confidence interval 2.6 to 4.4), dementia (1.9, 1.3 to 2.8), and death (2.0, 1.6 to 2.7). An association of white matter hyperintensities with a faster decline in global cognitive performance, executive function, and processing speed was also suggested.
Conclusion: White matter hyperintensities predict an increased risk of stroke, dementia, and death. Therefore white matter hyperintensities indicate an increased risk of cerebrovascular events when identified as part of diagnostic investigations, and support their use as an intermediate marker in a research setting. Their discovery should prompt detailed screening for risk factors of stroke and dementia
Targeted delivery of advanced functionality by nanomaterials : focus on nucleic acids delivery by novel block copolymers
No full textAbstract: Smart drug delivery systems are versatile examples of successful nanomedicine with
potential in diagnostics and medical therapy. The thesis presents selected
approaches in current drug delivery systems in the (pre-)clinical trials, and deals with
potential side effects, including complement activation and hypersensitivity reactions
as well as the design requirements of the delivery systems. Furthermore, it presents
approaches of cationic block copolymers, which are capable to condense negatively
charged nucleic acid molecules such as plasmid deoxyribonucleic acid (pDNA) and
small interfering ribonucleic acid (siRNA) with the aim of efficient cell gene delivery
and specific gene suppression, respectively.
The first part addresses the transfection efficiency of circular versus linearized
plasmid DNA using a green fluorescent protein expressing vector with Lipofectamine
2000 and linear 25 kDA polyethylenimine (PEI). These results show a considerably
improved transfection efficiency with the circular compared to the linearized DNA for
the two transfection reagents. The electron microscopy images with Lipofectamine or
PEI demonstrate that the circular DNA gives rise to random coil appearance of
compact, spherical shape, while linearized DNA appear as worm-like strands.
Particle size and shape are important in the cell biology of endocytosis and
phagocytosis. The findings indicate that the shape of the transfection particle is vital
for successful gene transfer.
To develop a delivery system for gene therapy, two cationic diblock copolymers
consisting of primary and tertiary amines were synthesized and analyzed with
respect to DNA condensation properties, morphology of the condensed plasmid DNA
and transfection efficiency using two cell lines. This study revealed proof-of-concept
showing an order of magnitude lower transfection efficiency of primary amine diblock
copolymers compared to PEI after 48 h with increasing plasmid DNA concentration.
Furthermore, primary amines compared to tertiary ones show much stronger binding
to DNA and improved transfection efficiency. Transmission electron and atomic force
microscopy data revealed morphologies of primary and tertiary amines regarding the
condensation of the plasmid DNA, in agreement with the transfection efficiency.
In a second part the design and characterization of pentablock-based polyplexes
based on the combination of cationic pentablock copolymers with folic acid
functionalized copolymers for targeted specific siRNA delivery is described. The
achieved 31 % knockdown efficiency shows its potential regarding cancer gene
therapy. The pentablock architecture allows the formation of highly stable
micelleplexes of (21 ± 3) nm in 10 mM PBS buffer solution with a neutral surface
charge, excellent siRNA condensation properties, outstanding colloidal stability in
10 % serum over 24 h and biocompatibility deduced from the absence of
considerable cytotoxicity even after 48 h incubation. Furthermore, selective delivery
of the siRNA could be proven by the introduction of a ligand-linked block copolymer,
resulting in 31 % compared to 8 % gene suppression for targeted a non-targeted
micelleplexes. This pentablock-based delivery system might yield impact to future
delivery systems as well as being a potential platform to be applied in vivo for cancer
gene therapy. ---------- Zusammenfassung
Innerhalb des Bereichs der Nanomedizin weisen intelligente Wirkstoffabgabesysteme
ein großes Potenzial auf, sowohl hinsichtlich der Diagnostik wie auch der
medizinischen Therapie. Die vorliegende Arbeit stellt im Rahmen einer
Literaturrecherche ausgewählte Wirkstoffabgabesysteme vor, welche sich in (vor-)
klinischen Studien befinden, den Nebenwirkungen welche durch diese entstehen
können, im speziellen der Komplementaktivierung und Überempfindlichkeitsreaktionen,
sowie deren Konstruktionsanforderungen. Des weiteren werden in einem
experimentellen Teil kationische Block-Kopolymere präsentiert, welche in der Lage
sind, negativ geladene Nukleinsäuremoleküle zu binden - wie etwa Plasmid
Desoxyribonukleinsäure (pDNA) und kleine interferierende Ribonukleinsäuren
(siRNA) - mit dem Ziel der Transfektion von fremder DNA in die Wirtszellen und
damit der spezifischen Unterdrückung der Genexpression.
Der erste Teil der experimentellen Arbeit untersucht die Transfektionseffizienz von
zirkulärer gegenüber linearisierter Plasmid-DNA mittels eines Vektors, welcher ein
grün fluoreszierendes Protein exprimiert. Transfiziert wurde einerseits mit
Lipofectamine 2000 und andererseits mit linearem 25 kDa Polyethylenimin (PEI),
zwei etablierten Transfektionsreagenzien. Die Ergebnisse zeigen eine wesentlich
verbesserte Transfektionseffizienz der zirkulären, verglichen mit der linearisierten
DNA für beide Transfektionsreagenzien. Die elektronenmikroskopischen Bilder von
Lipofectamine sowie PEI komplexiert mit DNA zeigen, dass die zirkuläre DNA
zufällige, kompakte Kugelformen bildet, während die linearisierte DNA wurmartige
Stränge aufweist. Partikelgröße und -form spielen in der Zellbiologie eine wichtige
Rolle bei der Endozytose und Phagozytose. Die Ergebnisse legen die Vermutung
nahe dass die Form der zu transfizierenden DNA-Transfektions-Komplexen eine
wichtige Rolle einnimmt für einen erfolgreichen Gentransfer.
Für die Entwicklung eines intelligenten Wirkstoffabgabe-Systems für die Gentherapie
wurden zwei kationische Diblock-Kopolymere, die aus primären und tertiären Aminen
bestehen synthetisiert und im Hinblick auf deren DNA-Kondensationseigenschaften,
Morphologie der kondensierten Plasmid-DNA sowie Transfektionseffizienz unter
Verwendung von zwei Zelllinien analysiert. Die Studie bestätigt trotz einer um den
Faktor 10 schwächeren Transfektionseffizienz der primären Amin-DiblockKopolymeren
im Vergleich zu PEI nach 48 h mit zunehmender pDNA Konzentration
eine Bestätigung des Konzepts. Außerdem weisen die primären Amin-Block-
Kopolymere im Vergleich zu den tertiären eine viel stärkere Komplexbildung der DNA
auf - wie transmissions-elektronen- und rasterkraft-mikroskopische Daten ergaben -
als auch eine verbesserte Transfektionseffizienz. Diese physikalischmorphologischem
Erkenntnisse über die Kondensation der primären und tertiären
Amine mit Plasmid-DNA konnten mittels der biologischen Transfektionseffizienzdaten
validiert werden.
Der zweite Teil der experimentellen Arbeit befasst sich mit dem Design sowie der
Charakterisierung von pentablock-basierten Polyplexen für einen gezielten siRNA
Transport. Diese Polyplexe beruhen auf einer Kombination von kationischen
Pentablock-Kopolymeren mit folsäure-funktionalisierten Kopolymeren. Die erreichten
31% Gen-Suppression in einem Krebszellkulturmodell, zeigen das Potenzial des
Wirkstoffabgabesystems in Bezug auf eine Krebstherapie auf. Die Architektur
ermöglicht die Bildung von sehr stabilen Mizellen mit einer Grösse von (21 ± 3) nm in
10 mM PBS Pufferlösung, eine neutrale Oberflächenladung, ausgezeichneten siRNAKondensationseigenschaften,
hervorragender kolloidaler Stabilität in
Zellkulturmedium supplementiert mit 10 % Serum über 24 h, sowie guter
Biokompatibilität aufgrund fehlender erheblicher Zytotoxizität auch nach 48 h
Inkubation in einem Zellkulturmodell. Ferner konnte durch die Einführung eines
liganden-gebundenen Block-Kopolymers der selektive Transport der siRNA
nachgewiesen werden, was zu einer Gen Suppression von 31% gegenüber 8% nicht
funktionalisierter Polyplexen führte. Das in dieser Arbeit eingeführte und
charakterisierte pentablock-basierte Wirkstoffabgabesystem könnte Auswirkungen
auf das Design zukünftiger Wirkstoffabgabesystem haben als auch als eine
potentielle Plattform für in vivo-Krebsgentherapien angewendet werden
The Market Maven, a new ally in the diffusion of innovations process
No full textThe initial motive for undertaking this research, was a desire to better understand those
factors which were said to affect the diffusion of ethnic foods. In attempting to develop
the general methodology for this study, the author revisited seminal studies on
diffusion of innovations, word-of-mouth, opinion leadership, and innovator / early
adopter influence. During this process, the author discovered Feick and Price's (1987),
emergent "Market Maven", theory. Said to be distinctly different from opinion leaders
and early adopters, market mavens were not only believed to have a higher awareness
of general marketplace information, but also more source credibility than other word-
of-mouth influencers. Employing a replication study approach, a telephone survey of
400 households in urban, suburban and rural north Bedfordshire was undertaken. The
author found that the market maven construct was not a purely US phenomenon, but
was also present in the UK. Developing further Feick and Price's (1987) preliminary
investigations, this study confirmed that (in common with related opinion leadership
studies), it had not been possible to identify market mavens using demographic / socio-
economic variables. VAiilst classifying market mavens remained problematic, the
author was nonetheless able to confirm Feick and Price's (1987) earlier findings, that
market mavens had an inherently increased propensity for general marketplace
information gathering. As this behaviour was considered by the author to be unique to
market mavens, the construct was employed to test those factors, said to affect ethnic
food diffusion, with interesting, if largely inconclusive results.
The author concluded, that the potential of the market maven construct in the diffusion
of innovations process was significant, particularly as a conduit for internal word-of-
mouth information in the business-to-business / industrial marketing context. In that
situation, market mavens' heightened awareness of, and active search for, general
marketplace information, would make them ideal targets for the type of marketing
communication message that innovators and opinion leaders alike, reputedly ignore
