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BACKGROUND AIMS: Autologous macrophage therapy represents a potentially significant therapeutic advance for the treatment of severe progressive liver cirrhosis. Administration of macrophages has been shown to reduce inflammation and drive fibrotic scar breakdown and tissue repair in relevant models. This therapeutic approach is being assessed for safety and feasibility in a first-in-human trial (MAcrophages Therapy for liver CirrHosis [MATCH] trial).METHODS: We outline the development and validation phases of GMP production. This includes use of the CliniMACS Prodigy cell sorting system to isolate CD14(+) cells; optimizing macrophage culture conditions, assessing cellular identity, product purity, functional capability and determining the stability of the final cell product.RESULTS: The GMP-compliant macrophage products have a high level of purity and viability, and have a consistent phenotypic profile, expressing high levels of mature macrophage markers 25F9 and CD206 and low levels of CCR2. The macrophages demonstrate effective phagocytic capacity, are constitutively oriented to an anti-inflammatory profile and remain responsive to cytokine and TLR stimulation. The process validation shows that the cell product in excipient is remarkably robust, consistently passing the viability and phenotypic release criteria up to 48 hours after harvest.CONCLUSIONS: This is the first report of validation of a large-scale, fully Good Manufacturing Practice-compliant, autologous macrophage cell therapy product for the potential treatment of cirrhosis. Phenotypic and functional assays confirm that these cells remain functionally viable for up to 48 h, allowing significant flexibility in administration to patients.

Background: Open surgical closure and small-bore suture-based preclosure devices have limitations when used for transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, or percutaneous thoracic endovascular aortic aneurysm repair. The MANTA vascular closure device is a novel collagen-based technology designed to close large bore arteriotomies created by devices with an outer diameter ranging from 12F to 25F. In this study, we determined the safety and effectiveness of the MANTA vascular closure device. Methods and Results: A prospective, single arm, multicenter investigation in patients undergoing transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, or thoracic endovascular aortic aneurysm repair at 20 sites in North America. The primary outcome was time to hemostasis. The primary safety outcomes were accessed site-related vascular injury or bleeding complications. A total of 341 patients, 78 roll-in, and 263 in the primary analysis cohort, were entered in the study between November 2016 and September 2017. For the primary analysis cohort, transcatheter aortic valve replacement was performed in 210 (79.8%), and percutaneous endovascular abdominal aortic aneurysm repair or thoracic endovascular aortic aneurysm repair was performed in 53 (20.2%). The 14F MANTA was used in 42 cases (16%), and the 18F was used in 221 cases(84%). The mean effective sheath outer diameter was 22F (7.3 mm). The mean time to hemostasis was 65±157 seconds with a median time to hemostasis of 24 seconds. Technical success was achieved in 257 (97.7%) patients, and a single device was deployed in 262 (99.6%) of cases. Valve Academic Research Consortium-2 major vascular complications occurred in 11 (4.2%) cases: 4 received a covered stent (1.5%), 3 had access site bleeding (1.1%), 2 underwent surgical repair (0.8%), and 2 underwent balloon inflation (0.8%). Conclusions: In a selected population, this study demonstrated that the MANTA percutaneous vascular closure device can safely and effectively close large bore arteriotomies created by current generation transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, and thoracic endovascular aortic aneurysm repair devices. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02908880.

Cell transplantation therapy aspires to repair and restore lost function while minimizing the risk of harm. The potential for harm arises from cell instability, variability, inappropriate behavior, and/or transmission of adventitious pathogens. Quality assured and controlled assessment and production of human cells for clinical use ensures that the risk of harm is minimized. Application of quality standards requires thorough planning and consultation with regulatory authorities on process and product specifications, as early as possible at the research and development (R&D) stage. Here we outline considerations applicable to all human cells in relation to regulatory governance, the route to the clinic and Cell Therapy Product (CTP) characterization, with special emphasis on human pluripotent stem cells (hPSC).

Cellular therapeutics are a fast-growing, highly innovative area of medicine. This field encompasses well-established immune therapies for infection and cancer, as well as newer cell therapies aimed at regenerating diseased tissue. Flow cytometry is arguably the most important tool in the development of advanced cellular therapeutics and plays a role in many aspects of manufacturing. Quality control of raw materials, assessing rates of cellular growth during complex in vitro culture processes, differentiation status, as well as final product characterization, viability, and product stability are all essential data to be collected and documented. This requires robust and validated flow cytometric analysis. In this review, we discuss flow cytometer set up; design and use of assays to maintain quality control in cell processing, and the building of a robust set of release criteria. The use of flow cytometric assays as surrogates of functional assays to allow comparison and release of cellular products for clinical use are reviewed with reference to monocyte-derived and T cell products.

SUMMARY Background and objectives Irradiation of red cell concentrates RCCs) can lead to well-documented elevated extracellular potassium concentrations. Transfusion of these products has the potential, if given as a massive/rapid transfusion, to lead to transient hyperkalemia. A potassium absorption filter (PAF) has recently been developed and has been proven to effectively remove excess K+. However, data are lacking on the red cell quality parameters over storage after irradiation. Methods Thirty RCCs were pooled and split into 3 groups of 10. All RCCs were irradiated on day 14 and filtered on day 28 (group 1 control), day 15 (group 2) or day 17 (group 3). Pre-irradiation, pre- and post-filtration and day 28 samples were taken for each study. Standard red cell quality parameters were measured over storage at the above time points. Results Losses for haemoglobin, haematocrit and volume were minimal after filtration with all units containing >40 g Hgb unit−1. Statistically, significant differences were observed for K+ and Na+ levels in groups filtered at either 24 or 72 h post-irradiation, and this was observed directly after filtration and remained by day 28. Filtration had no significant impact on any other parameters measured. Conclusions PAF effectively removed supernatant potassium (93%) from all RCC units. Early removal of K+ at either day 15 or 17 on RCCs subsequently stored to day 28 had no measurable effect on red cell quality, suggesting this may be a useful device to ensure further safety for at-risk immunocompromised patient groups requiring irradiated RCCs.

Blood transfusion is a mainstay of modern medical practice. In many parts of the world the use of this life-saving therapy is hampered by issues of supply and the potential for transfusion transmitted infections. Accordingly, there are many studies seeking to find an alternative to donated red blood cells (RBCs) for transfusion, including large-scale production from adult and pluripotent stem cells, or erythroid cell lines. Translating basic studies, using any cell lineage, into protocols that are suitable for the generation of cellular therapies requires a wide range of biological and regulatory procedures to be put in place. Additionally, there are specific challenges for the production of RBCs caused by the number of cells needed for a single dose (approx. 1-2 × 10

Blood transfusion is a mainstay of modern medical practice. In many parts of the world the use of this life-saving therapy is hampered by issues of supply and the potential for transfusion transmitted infections. Accordingly, there are many studies seeking to find an alternative to donated red blood cells (RBCs) for transfusion, including large-scale production from adult and pluripotent stem cells, or erythroid cell lines. Translating basic studies, using any cell lineage, into protocols that are suitable for the generation of cellular therapies requires a wide range of biological and regulatory procedures to be put in place. Additionally, there are specific challenges for the production of RBCs caused by the number of cells needed for a single dose (approx. 1-2 × 1012). In this chapter, we will review critical areas in the development and good manufacturing practice (GMP) translation of cellular therapeutics through to early phase clinical trials and how this learning can be applied to in vitro RBC therapies.

The promise of human pluripotent stem cells to serve as a scalable and renewable starting material for "off the shelf" therapeutic cell products to repair or replace cells and tissues damaged by disease or injury is unparalleled. Whether originating from embryos or the genetic manipulation of adult tissue-derived cells, this prospective impact dictates a comprehensive yet practicable standard of quality assured characterization, blending existing and bespoke standards and considerations. Here, we provide a guide to qualifying the suitability of this resource for human clinical application.

Summary T cell lines with defined cytokine profiles are an invaluable tool for assessing the control of immune responses both in vitro and in vivo. Production of such cell lines can be complex and time-consuming. Here we present a powerful technique to assay the cytokines produced by T cells activated polyclonally or with specific antigens. This paper presents a detailed methodology for the identification and isolation of cytokine-producing T cells activated with the artificial superantigen, CytoStim, or viral and fungal antigens. These cells can be analysed for different cytokines simultaneously, or cultured further to rapidly establish T cell lines making known cytokine types. We highlight the enumeration, isolation and phenotype of interleukin-17-producing T cells, and the rapid generation of virus-specific Th1 T cell lines.

Irradiation of red cell concentrates RCCs) can lead to well-documented elevated extracellular potassium concentrations. Transfusion of these products has the potential, if given as a massive/rapid transfusion, to lead to transient hyperkalemia. A potassium absorption filter (PAF) has recently been developed and has been proven to effectively remove excess K(+) . However, data are lacking on the red cell quality parameters over storage after irradiation.Thirty RCCs were pooled and split into 3 groups of 10. All RCCs were irradiated on day 14 and filtered on day 28 (group 1 control), day 15 (group 2) or day 17 (group 3). Pre-irradiation, pre- and post-filtration and day 28 samples were taken for each study. Standard red cell quality parameters were measured over storage at the above time points.Losses for haemoglobin, haematocrit and volume were minimal after filtration with all units containing40 g Hgb unit(-1). Statistically, significant differences were observed for K(+) and Na(+) levels in groups filtered at either 24 or 72 h post-irradiation, and this was observed directly after filtration and remained by day 28. Filtration had no significant impact on any other parameters measured.PAF effectively removed supernatant potassium (93%) from all RCC units. Early removal of K(+) at either day 15 or 17 on RCCs subsequently stored to day 28 had no measurable effect on red cell quality, suggesting this may be a useful device to ensure further safety for at-risk immunocompromised patient groups requiring irradiated RCCs.

Summary Background There is a need to understand what affects the success of in-vitro fertilisation (IVF) and the rate of resulting twin births so that pregnancy rates can be improved and multiple gestations avoided. Our aim was to assess the role of B vitamins and genetics. Methods We did a prospective cohort study of 602 women undergoing fertility treatment. We assessed intake of folate and vitamin B12 with a questionnaire and measured their plasma and red-blood-cell concentrations by radioimmunoassay. We measured five B-vitamin-related gene variants in women who received treatment and in 932 women who conceived naturally. Findings The likelihood of a twin birth after IVF rose with increased concentrations of plasma folate (1·52, 1·01–2·28; p=0·032) and red-cell folate (1·28, 1·00–1·65; p=0·039). There was no association between folate and vitamin B12 levels and likelihood of a successful pregnancy. Women homozygous for the 1298 CC variant of methylenetetrahydro-folate reductase ( MTHFR ), rather than the AA variant, were less likely to produce a livebirth after IVF (0·24, 0·08–0·71; p=0·003) or to have had a previous pregnancy (0·42, 0·21–0·81; p=0·008). Interpretation Our findings suggest that MTHFR genotype is linked to a woman's potential to produce healthy embryos (possibly through interaction with genes related to DNA methylation). In women likely to have a successful IVF pregnancy, high folate status increases the likelihood of twin birth after multiple embryo transfer. Proposals to fortify the UK diet with folic acid could lead to an increase in the number of twins born after IVF.

Background Women who deliver by caesarean section have been shown to be less likely to have a subsequent pregnancy. It is not clear whether this is due to a direct effect of the procedure on future fertility or due to deliberate avoidance of a future pregnancy. Objective To investigate whether absence of conception following caesarean section is voluntary or involuntary. Design Follow up of a population-based retrospective cohort. Setting Grampian region, Scotland. Population Women who had no further viable pregnancies within 5 years of an initial delivery. Methods Cases included women who delivered their first child by caesarean section between 1980 and 1995 but had no further viable pregnancies by December 2000. Controls included women who delivered their first child during the same period, by means of either spontaneous vaginal delivery (SVD) or instrumental vaginal delivery (IVD), and who had no further viable pregnancies by December 2000. Eligible women were identified from the Aberdeen Maternity and Neonatal Databank (AMND) and sent postal questionnaires to determine the extent to which not conceiving after first delivery was voluntary and the reasons for avoiding further pregnancies. Characteristics of the different mode of delivery groups were compared using univariate techniques. Main outcome measures Extent to which absence of conception following an initial delivery by caesarean section is voluntary. Results Questionnaires were returned by 3204 (60%) of 5300 women identified from the AMND. Of these, 1675 women had not conceived at all during the follow-up period (median duration = 13 years). Absence of conception was voluntary in 488 (69%; 95% CI 66–73%) women following caesarean section, 340 (71%; 95% CI 67–76%) following SVD and 354 (72%; 95% CI 68–76%) following IVD. Few women considered seeking fertility treatment (caesarean section = 72 [10%], SVD = 50 [11%], IVD = 39 [8%]). Of the women who decided to delay or avoid a further pregnancy, fewer women who delivered by SVD reported that the birth experience influenced their decision (caesarean section = 163 [32%], SVD = 67 [18%], IVD = 136 [35%]; P < 0.001). Conclusions Irrespective of mode of delivery, not conceiving following the birth of the first child is mainly voluntary. The experience of the previous birth is one of several factors affecting women's decisions to avoid a subsequent pregnancy.

Aims/hypothesis Type 1 diabetes complicated by hypoglycaemia is prevalent in socioeconomically deprived populations. Islet transplantation is of proven efficacy in type 1 diabetes complicated by hypoglycaemia, but it is not known if nationally funded programmes reach the socioeconomically deprived. Our aim was to determine: (1) socioeconomic indices in participants referred to our nationally funded programme; and (2) if metabolic outcomes in our transplant recipients were improved. Methods Participants referred (n = 106) and receiving transplants (n = 18; 32 infusions) were examined with respect to socioeconomic status (deprivation category score) and their ability to work and drive. In participants followed for ≥12 months after transplantation, metabolic and anthropometric measurements (n = 14) were recorded pre- and post-transplant (assessed ~1, ~3, ~6 and ~12 months with mixed-meal tolerance tests and 6 day continuous glucose monitoring assessments). Donor data was also examined. Results There was a greater prevalence of socioeconomic deprivation in referred and transplant recipients than the general population (p

In this paper we investigate the motion of small particles suspended in a fluid through which an ultrasound field is propagating. The application of the lattice Boltzmann model to this problem is considered using a two dimensional model. Particles in an ultrasound field are observed to move with a mean particle motion. Further, the time-averaged force on a fixed cylinder is computed and found to be in good agreement with a theoretical expression for the radiation force. Simulations are performed with a single particle, although the approach can equally be applied for a larger number of particles.

Objective To examine the psychometric properties of the Screen for Child Anxiety Related Emotional Disorders (SCARED) for a community sample of African-American high school students. Method The 41-item SCARED was administered to 111 adolescents (57 girls; mean age 15.75) in an urban parochial school. Item frequency, internal consistency, test-retest reliability, and construct validity were assessed. Results Approximately 30% of the sample had scores high enough to warrant further assessment for anxiety disorders, and girls reported significantly higher anxiety symptoms than boys. Internal consistency (α = .89) and test-retest reliability ( r = 0.47) over 6 months for the SCARED's total score were good. The SCARED's total score was positively correlated with other measures of anxiety symptoms and inattention and was negatively correlated with perceived self-worth. Unlike the five-factor structure reported for primarily white samples, only three factors emerged for this African-American sample. Conclusions The SCARED shows utility as a self-report anxiety screening instrument in a community sample of African-American youths.

This paper considers the measurement of the internal radius of a number of similar, short, tubular leadpipes using pulse reflectometry. Pulse reflectometry is an acoustical technique for measuring the internal bore of a tubular object by analysing the reflections which occur when an acoustical pulse is directed into the object. The leadpipes are designed to form the initial, or lead, part of a trumpet or cornet and their internal radii differ by less than 0.1 mm between similar pipes. The ability of the reflectometer to detect these small differences, which are considered by players to produce a noticeable difference in the sound of an instrument, are investigated. It is seen that the pulse reflectometer is able to distinguish between leadpipes with different nominal radii varying by as little as 0.03 mm, demonstrating its potential in the study of musical instruments and showing that it can be used as a diagnostic tool by the instrument manufacturer to detect defects which are significant enough to acoustically alter performance. The absolute accuracy of the radius measurements is also considered at the end of the leadpipe, where the uncertainty is ±0.05 mm.

Control of Theileria annulata is currently best achieved by the use of live attenuated cell line vaccines. However, the mechanisms underlying attenuation are unclear and there is a need to rapidly produce new cell line vaccines, which could safely and effectively vaccinate cattle against tropical theileriosis. There is increasing evidence to suggest that proinflammatory cytokines produced by T. annulata infected cells play a central role in both pathology and immune evasion. This study aimed to test this hypothesis and to evaluate cytokine expression as a marker of virulence. The pathogenicity and protective efficacy of cloned T. annulata cell lines that expressed different levels of proinflammatory cytokines were compared. In two independent trials using different stocks of T. annulata, cell lines that expressed higher levels of proinflammatory cytokines induced severe reactions, and in some cases death, when used to vaccinate groups of cattle. In contrast, low cytokine expressing lines induced low post-vaccinal reactions. The results clearly demonstrated that cytokine expression by T. annulata infected cells could be used as a marker of virulence and provided strong evidence to support a role for cytokines in the induction of pathology. Both high and low cytokine expressing cell lines protected cattle against heterologous challenge infection, offering the possibility of using cytokine expression to rapidly select new safe, potent vaccines against tropical theileriosis without the need for culture attenuation.

A musical wind instrument transforms a constant pressure input from the player's mouth into a fluctuating pressure output in the form of a radiating sound wave. In reed woodwind and brass instruments, this transformation is achieved through a nonlinear coupling between two vibrating systems: the flow control valve formed by the mechanical reed or the lips of the player, and the air column contained by the pipe. Although the basic physics of reed wind instruments was developed by Helmholtz in the nineteenth century, the application of ideas from the modern theory of nonlinear dynamics has led to recent advances in our understanding of some musically important features of wind instrument behaviour. As a first step, the nonlinear aspects of the musical oscillator can be considered to be concentrated in the flow control valve; the air column can be treated as a linear vibrating system, with a set of natural modes of vibration corresponding to the standing waves in the pipe. Recent models based on these assump...

We consider the application of the lattice Boltzmann BGK model to simulate sound waves in situations where the density variation is small compared to the mean density. Linear sound waves are simulated in two different situations: a plane wave propagating in an unbound region; and a wave in a tube. For both cases the behaviour of the simulated waves is found to be in good agreement with analytic expressions. Non-linear sound waves are also simulated and are seen to display the expected features.

CattleDRA andDRB genes, cloned by reverse-transcription polymerase chain reaction, were transfected into mouse L cells. The cattle DR-expressing L-cell transfectant generated was analyzed serologically, biochemically, and functionally. Sequence analysis of the transfectedDRB gene clearly showed showed that it wasDRB3 alleleDRB3 *0101, which corresponds to the 1D-IEF-determined alleleDRBF3. 1D-IEF analysis of the transfectant confirmed that the expressed DR product was DRBF3. Functional integrity of the transfected gene products was demonstrated by the ability of the transfectant cell line to present two antigens (the foot-and-mouth disease virus-derived peptide FMDV15, and ovalbumin) to antigenspecific CD4+ T cells from both the original animal used to obtain the genes, and also from an unrelated DRBF3+ heterozygous animal. Such transfectants will be invaluable tools, allowing us to dissect the precise contributions each locus product makes to the overall immune response in heterozygous animals, information essential for rational vaccine design.

The partial doubly differential cross sections (PDDCS) for the ions , , , , (, ), , , and resulting from the dissociative ionization of the molecule by electron impact employing the ejected-electron and produced-ion coincidence technique have been measured. Measurements have been made for incident electron energies of 100 and 200 eV and for ejected electron energies of 30, 50, 65, 100 and 150 eV. The angular range for the detection of the ejected electron is between and . No trace of ions is found at any energy used. No previous data or theoretical predictions exist with which to make comparisons.

We present data on the spin polarization P and quantum yield Y of electrons photoemitted from negative electron affinity semiconductors, including GaAs(100), GaAsP(100) alloy, and strained GaAs layer epitaxially grown on a GaAsP(100) buffer. Near photothreshold the following values for P(Y) are, respectively, obtained: 26% (2.5×10−2), 40% (1×10−3), and 60% (1.5×10−4). We describe in detail the apparatus used containing a low energy (10–25 keV) Mott polarimeter. The system, completely fitted in a small volume (∼104 cm3) ultrahigh vacuum chamber, is intended as a test facility for characterizing candidate photocathode materials for spin polarized electron sources.

Objective To determine if large loop excision of the transformation zone affects subsequent fertility and pregnancy outcome. Design A case-control study. Setting A teaching hospital serving a regional population. Subjects One thousand women who had undergone large loop excision of the transformation zone (LLETZ) for the treatment of cervical intraepithelial neoplasia (CIN) between 1989 and 1991. Two controls were matched for each of the 149 women who had a singleton pregnancy progressing beyond 20 weeks of gestation following treatment, with regard to age, parity, height, husband's or partner's social class and smoking habits to account for common independent risk factors for adverse obstetric outcome and cervical intraepithelial neoplasia. Main outcome measures Intention to conceive, number of pregnancies, gestation, low birthweight, mean birthweight, mode of delivery, and duration of labour. Results Out of a cohort of 1000 women who underwent LLETZ for the treatment of CIN, 653 women replied to a postal questionnaire. When asked up to 54 months after treatment, 130 women (19.9%) had become pregnant and 47 (7.2%) had tried to become pregnant. A total of 199 pregnancies from 178 women was identified from the cohort of women. For the 149 women from the case cohort, the mean birthweight was 3380 g compared with 3373 g in the control group (P= 0.88). The incidence of low birthweight in pregnancies progressing to at least 37 weeks of gestation was 3.1% in the treated group, compared with 3.2% in the control group (P= 098). Following LLETZ, 94% of deliveries were preterm (< 37 weeks of gestation), compared with 50% in the control group (P= 0.12). There was no significant difference in mean gestation, mode of delivery, indication for caesarean section or duration of labour between the women who had undergone LLETZ and the controls. Conclusion When socio-epidemiological factors associated with the development of cervical intraepithelial neoplasia are controlled for, LLETZ does not appear to exert an independent adverse effect on subsequent pregnancy outcome.

A beam of unpolarized electrons is crossed at right angles with a beam of partially polarized sodium or potassium atoms (degree of polarization PA approximately=21%) and resonance lines from the excited 2P3/2, 1/2 states are observed in a direction perpendicular to both the atom and electron beams for electron energies from threshold to 200 eV. The polarization of the emitted photons is measured in the form of the Stokes parameters P1, P2 and P3. The present measurements for sodium atoms are in better agreement with the theoretical values than the previously published experimental results. No other experimental or theoretical results are available for potassium atoms.

Tropical instability waves have been shown to have a major impact on the variability of temperature and nutrients along the equatorial wave guide. In order to assess the impact of these features on carbon species distributions during an ENSO event, sea surface temperature, salinity, sigma-t, nitrate, CO[sub 2] fugacity, total inorganic carbon, total alkalinity, and pH along the equator were measured from 130[degrees]W to 100[degrees]W during 8-15 May 1992. Concurrent moored measurements of surface currents and temperature were also made at 0[degrees], 110[degrees]W. Results indicate that tropical instability waves, with periods of 15 to 20 days and zonal wavelengths of 700-800 km, controlled the observed spatial variability of the CO[sub 2] species, nitrate and hydrographic parameters at the equator. 37 refs., 3 figs.

Improved survival of patients with acute lymphoblastic leukemia (ALL) has emerged from identifying new prognostic markers; however, 20% of children still suffer recurrence. Previously, the altered expression of Fat1 cadherin has been implicated in a number of solid tumors. In this report, in vitro analysis shows that Fat1 protein is expressed by a range of leukemia cell lines, but not by normal peripheral blood (PB) and bone marrow (BM) cells from healthy donors. In silico analysis of expression of array data from clinical leukemias found significant levels of Fat1 transcript in 11% of acute myeloid leukemia, 29% and 63% of ALL of B and T lineages, respectively, and little or no transcript present in normal PB or BM. Furthermore, in two independent studies of matched diagnosis-relapse of precursor B-cell (preB) ALL pediatric samples (n=32 and n=27), the level of Fat1 mRNA expression was prognostic at the time of diagnosis. High Fat1 mRNA expression was predictive of shorter relapse-free and overall survival, independent of other traditional prognostic markers, including white blood cell count, sex and age. The data presented demonstrate that Fat1 expression in preB-ALL has a role in the emergence of relapse and could provide a suitable therapeutic target in high-risk preB-ALL.

Identification of ischaemic stroke subtype currently relies on clinical evaluation supported by various diagnostic studies. The authors sought to determine whether specific diffusion-weighted MRI (DWI) patterns could reliably guide the subsequent work-up for patients presenting with acute ischaemic stroke symptoms.273 consecutive patients with acute ischaemic stroke symptoms were enrolled in this prospective, observational, single-centre NIH-sponsored study. Electrocardiogram, non-contrast head CT, brain MRI, head and neck magnetic resonance angiography (MRA) and transoesophageal echocardiography were performed in this prespecified order. Stroke neurologists determined TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification on admission and on discharge. Initial TOAST stroke subtypes were compared with the final TOAST subtype. If the final subtype differed from the initial assessment, the diagnostic test deemed the principal determinant of change was recorded. These principal determinants of change were compared between a CT-based and an MRI-based classification schema.Among patients with a thromboembolic DWI pattern, transoesophageal echocardiography was the principal determinant of diagnostic change in 8.8% versus 0% for the small vessel group and 1.7% for the other group (p0.01). Among patients with the combination of a thromboembolic pattern on MRI and a negative cervical MRA, transoesophageal echocardiography led to a change in diagnosis in 12.1%. There was no significant difference between groups using a CT-based scheme.DWI patterns appear to predict stroke aetiologies better than conventional methods. The study data suggest an MRI-based diagnostic algorithm that can potentially obviate the need for echocardiography in one-third of stroke patients and may limit the number of secondary extracranial vascular imaging studies to approximately 10%.

The ever increasing load demands placed on existing theaters by modern live entertainment pose unique challenges for the structural engineer. One of the more difficult aspects for the engineer is the fact that many of the older theaters have limited, or no, design/construction documentation in existence. In the absence of drawings, investigations must be based solely on surveys of the existing conditions of the stage supporting structures and the grid-iron and fly systems. Typically, one finds that structural modifications have been made over the years for various shows without the benefit of engineering reviews. The Hammerstein Ballroom Theater (circa 1906) and the Howard Gilman Opera House at the Brooklyn Academy of Music (circa 1908) are two particularly interesting examples of old theaters requiring structural reviews for recent productions of new shows whose loads would impose a high demand on the existing structures.

Objectives: Establish metric properties of the Neighborhood Inventory for Environmental Typology (NIfETy). Method: A total of 919 residential block faces were assessed by paired raters using the NIfETy. Reliability was evaluated via interrater and internal consistency reliability; validity by comparing NIfETy data with youth self-reported violence, alcohol, and other drug exposure and crime statistics. Results: Validity and reliability metrics were moderate to exemplary for the total scale and subscales. NIfETy data correlated strongly with crime data and youth self-reported exposure. Conclusions: The NIfETy is valid and reliable. Future investigations will explore its use in other urban centers and association to other health outcomes.

This study analyzed the clinical outcome in endovascular aneurysm repair (EVAR) patients with an angulated aortic neck. Two hundred thirty-eight EVAR patients underwent postoperative duplex ultrasonography and/or computed tomographic angiography, which was repeated every 6 to 12 months. Aortic neck angle was classified into < 45° (A1, n= 129), ≥ 45 to < 60° (A2, n = 43), and ≥ 60° (A3, n = 42). The perioperative complication rates for groups A1, A2, and A3 were 13%, 5%, and 29%, respectively ( p = .006). Proximal type I early endoleaks occurred in 9%, 33%, and 38% in groups A1, A2, and A3, respectively ( p < .0001). Intraoperative proximal aortic cuffs were needed in 7%, 28%, and 33% in groups A1, A2, and A3, respectively ( p < .0001). However, the rate of late reintervention was comparable in all groups. Postoperatively, the size of abdominal aortic aneurysm decreased or remained unchanged in 97%, 95%, and 84% in A1, A2, and A3, respectively ( p = .0147). The rates of freedom from late type I endoleak at 1, 2, and 3 years were 90%, 85%, and 85% for A1; 74%, 74%, and 68% for A2; and 64%, 64%, and 53% for A3 ( p = .0013). EVAR can be used for patients with an angulated aortic neck but was associated with a higher rate of early and late type I endoleaks and early interventions.

It has been proposed that altered epigenetic status at imprinted loci may play a role in the early programming of disease susceptibility (1) . The ultimate methyl donor for methylation reactions is the folate-methylation cycle and feeding pregnant dams diets deficient in methyl donors results in altered regulation of specific genes in the offspring which are under imprinting control (2) . The aim of this study was to determine whether a similar phenomenon may occur in human pregnancy. The study was approved by Grampian Research Ethics Committee and all participants gave informed written consent. We collected data on dietary and supplement intake and cord blood DNA from pregnancies sequentially recruited at Aberdeen Maternity Hospital. Energyadjusted intake of the B-vitamins (thiamine, niacin, biotin, riboflavin, folate, B6 and B12) from the diet was assessed at 19 weeks gestation using a self-administered food frequency questionnaire (3) . The use of folic acid supplements (type/brand, amount per day, timing and duration of consumption in relation to stage of pregnancy) were also recorded. Multiple methylation sites were measured in three imprinted genes (IGF2, n 374; SNRPN, n 363; PEG3, n 377) and LINE1 (n 372) which was thought to contribute to the differential expression of paternally and maternally imprinted genes. Methylation was determined by pyrosequencing using a PyroMark MD system (Qiagen, Crawley, UK) after bisulphite conversion of DNA using Epitect Bisulfite kits (Qiagen, Crawley, UK). Statistical analysis was carried out using STATA 11MP (Stata Corp, College Station, TX, USA). All the B vitamins from diet were included in the regression model. There was no evidence that dietary intake of B vitamins was related to LINE1 or SNRPN methylation. Dietary intake of riboflavin, vitamin B6 and folate were associated with the average methylation status of both IGF2 (riboflavin, P = 0.012; vitamin B6, P = 0.047; folate, P = 0.024; model r 2 = 3.9%) and PEG3 (riboflavin, P = 0.016; vitamin B6, P = 0.014; folate, P = 0.001; model r 2 = 2.6%). Although responsive to the same nutrients, there were differences between PEG3 and IGF2 in the sign of the response. Separate analysis of supplement use provided no evidence for an effect on the methylation of folic acid intake in line with current advice. The way in which parental diet influences the methylation of individual genes and the health consequences for the offspring merit further study. Further work on this phenomenon in larger numbers of pregnancies is proposed.

The main goal of this study is to extend the dynamic range of isomerization rates for cyclohexane in order to determine with high accuracy whether the barrier height to isomerization is pressure dependent. Therefore, the effect of pressure and temperature on the conformational isomerization of cyclohexane in carbon disulfide solvent has been investigated using the NMR (nuclear magnetic resonance) rotating frame relaxation technique. This technique, used for the first time in pressure studies of chemical exchange, allows the measurement of isomerization dynamics over a wide range of pressures and temperatures. By combining the rotating frame and NMR line shape techniques and generating the isoviscosity plots, it is shown that the barrier height to isomerization is independent of pressure. Since the experimental isomerization rate is accelerated by pressure, the viscosity dependence of the reduced transmission coefficient shows that the isomerization falls into the energy controlled (inertial) regime of the...

SummarySummaryIntra-uterine growth retardation (IUGR) is the main contributory factor in the increased perinatal morbidity and mortality associated with pregnancy induced hypertension. Seventy-six primigravidae and 38 parous women with non-proteinuric hypertension (diastolic blood pressure >90mmHg) and singleton pregnancies were allocated at random to receive either labetalol or no anti-hypertensive treatment. At recruitment maternal age, blood pressure and gestational age were similar in both treatment and control groups. For primigravidae 16 per cent (7/45) of the controls delivered a baby with weight less than the 10th centile for gestational age compared with 19 per cent (6/31) in the labetalol treated group. A birth weight less than the 10th centile for gestational age occurred in 2 out of 18 multigravid controls and 4 out of 20 of the multigravid labetalol treated group. There were more admissions to the neonatal unit for the babies of labetalol treated mothers.A limited meta-analysis of the results...

Hereditary angioedema (HAE) is a rare but potentially life-threatening condition caused by deficiency of C1 esterase inhibitor. It is characterized by subcutaneous swelling in any part of the skin, gastrointestinal and respiratory tracts. We present the case of a pregnant woman with known HAE that deteriorated during pregnancy with frequent attacks that were managed successfully with danazol, tranexamic acid and regular intravenous administration of C1 esterase inhibitor.