Malignant hypertension in the transgenic Ren-2 rat

The transgenic rat line TGR(mREN2)27 has been previously shown to develop severe hypertension as a consequence of over -expression of the mouse Ren -2 renin gene (Mullins et al 1990). It was observed that an alteration in phenotype occurred in hybrids (HanRen2/Edin --) derived from crossing homozygous Ren -2 transgenic rats with the Edinburgh Sprague -Dawley strain of rats. Investigations into this phenotypic change revealed it to be due to spontaneous development of malignant phase hypertension. Furthermore the incidence of the malignant hypertensive phenotype was altered by the genetic background into which the transgene was introduced.The introduction of this thesis has reviewed the literature on the genetics of human essential hypertension and rat models of genetic hypertension, the role of the kidney in essential hypertension and the pathogenesis of malignant hypertension. Techniques in molecular biology which include transgenesis have been used to investigate the role of individual genes in blood pressure regulation. In this context the literature concerning the transgenic rat line TGR(mREN2)27 was extensively reviewed.The heterozygote cross HanRen2/Edin -- was found to develop malignant phase hypertension within a relatively narrow age range. Seventy -three percent of male and 52% of female HanRen2/Edin -- developed malignant hypertension. In contrast, other heterozygote crosses HanRen2/Han-- and HanRen2/Lew -- had an incidence in males of 18% and 0% and in females of 4% and 0% respectively. Telemetry was used to record blood pressure continuously in unrestrained conscious rats and demonstrated an accelerated rise in blood pressure in rats with clinical features of malignant phase hypertension. Histopathology showed fibrinoid necrosis and myo- intimal proliferation of afferent arterioles and small renal arteries. An associated deterioration in renal function occurred with a rise in plasma urea and creatinine. TGR(mREN2)27 normally have a suppressed renal renin -angiotensin system but in malignant phase affected animals had a significant elevation of plasma renin, angiotensin II and aldosterone. Immunohistochemistry demonstrated increased renin at the site of the afferent arterioles near the vascular poles of glomeruli. Blood films demonstrated a microangiopathic haemolytic anaemia. A genetic basis for the differing incidence of malignant phase between the three heterozygote crosses was further supported by the results of an analytical cross set up to segregate Edinburgh Sprague -Dawley alleles. Results suggested that malignant phase hypertension complicated benign hypertension due to the effects of one or possibly two genetic loci.A further study looked at the role of endothelin in malignant hypertension. Previous investigators had suggested that endothelin may be involved in the pathogenesis of malignant phase hypertension. RNase protection assays demonstrated increased expression of endothelin- 1 mRNA in kidneys from malignant hypertensive rats. Chronic inhibition of endothelin receptors using an oral non -specific endothelin receptor antagonist (Bosentan) did not prevent or reduce the transition from benign to malignant phase hypertension. It would therefore appear that endothelin synthesis occurs in response to the transition to malignant hypertension but it is not a central initiating factor.In conclusion, this is a representative model showing many of the characteristics of malignant phase hypertension in humans. The differing incidence between transgenic Ren -2 crosses appeared to be a consequence of genetic factor(s). This may therefore be another example of a genetic pre -disposition to develop target organ damage from hypertension

Teamwork Makes the Dream Work: Using Team-Based Learning in the Science Classroom

With an overwhelming amount of research and a demand for collaborative learning in the classroom, teachers are tackling challenges at all educational levels that often accompany the social aspects of group work. Team-Based Learning (TBL) is an instructional sequence that shifts instruction from teacher lecture to small-group learning. Through the use of teams and social learning, students are actively engaged and learning through critical-thinking tasks. College students can take responsibility both for their own learning and for each other as learners and fellow human beings. TBL allows the instructors to design opportunities for students to demonstrate what they know and can do in the classroom with the content. This study qualitatively examines students’ perceptions of the pedagogical strategy TBL in an undergraduate science course. TBL practices enabled instructors to prepare students for classes in advance and assist students in deeply learning the material through application of course concepts, allowing them to solve interesting, complex, and real-world problems that are relevant to the teaching profession

TEM8/ANTXR1-specific CAR T cells mediate toxicity in vivo

Engineering T-cells to express receptors specific for antigens present on tumour tissue is proving a highly effective treatment for some leukaemias. However, extending this to solid tumours requires antigens that can be safely and effectively targeted. TEM8, a marker overexpressed on the vasculature of some solid tumours, has been proposed as one such target. A recent report stated that T-cells engineered to express a TEM8-specific chimeric antigen receptor (CAR), when injected into mouse models of triple negative breast cancer, are both safe and effective in controlling tumour growth. Here we report contrasting data with a panel of TEM8-specific CAR-T-cells including one generated from the same antibody used in the other study. We found that the CAR-T-cells demonstrated clear TEM8-specific cytotoxic and cytokine release responses in vitro, but when injected into healthy C57BL6 and NSG mice they rapidly and selectively disappeared from the circulation and in most cases caused rapid toxicity. Infusing CAR-T-cells into a TEM8-knockout mouse indicated that selective loss of cells from the circulation was due to targeting of TEM8 in healthy tissues. Histological analysis of mice treated with a TEM8-specific CAR revealed evidence of inflammation in the lung and spleen with large collections of infiltrating neutrophils. Therefore our data raise concerns over potential on-target off-tumour toxicity with CARs targeting TEM8 and these should be considered carefully before embarking upon clinical trials with such agents

Stillbirth 2010-2018: A prospective, population-based, multi-country study from the global network

Background: Stillbirth rates are high and represent a substantial proportion of the under-5 mortality in low and middle-income countries (LMIC). In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented cause of stillbirths or the trends in rate of stillbirth over time.Methods: We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, Democratic Republic of Congo, India, Pakistan, and Guatemala). Staff collected demographic and health care characteristics with outcomes obtained at delivery. Cause of stillbirth was assigned by algorithm.Results: From 2010 through 2018, 573,148 women were enrolled with delivery data obtained. Of the 552,547 births that reached 500 g or 20 weeks gestation, 15,604 were stillbirths; a rate of 28.2 stillbirths per 1000 births. The stillbirth rates were 19.3 in the Guatemala site, 23.8 in the African sites, and 33.3 in the Asian sites. Specifically, stillbirth rates were highest in the Pakistan site, which also documented a substantial decrease in stillbirth rates over the study period, from 56.0 per 1000 (95% CI 51.0, 61.0) in 2010 to 44.4 per 1000 (95% CI 39.1, 49.7) in 2018. The Nagpur, India site also documented a substantial decrease in stillbirths from 32.5 (95% CI 29.0, 36.1) to 16.9 (95% CI 13.9, 19.9) per 1000 in 2018; however, other sites had only small declines in stillbirth over the same period. Women who were less educated and older as well as those with less access to antenatal care and with vaginal assisted delivery were at increased risk of stillbirth. The major fetal causes of stillbirth were birth asphyxia (44.0% of stillbirths) and infectious causes (22.2%). The maternal conditions that were observed among those with stillbirth were obstructed or prolonged labor, antepartum hemorrhage and maternal infections.Conclusions: Over the study period, stillbirth rates have remained relatively high across all sites. With the exceptions of the Pakistan and Nagpur sites, Global Network sites did not observe substantial changes in their stillbirth rates. Women who were less educated and had less access to antenatal and obstetric care remained at the highest burden of stillbirth.Study registration: Clinicaltrials.gov (ID# NCT01073475)

Treatment fidelity monitoring, reporting and findings in a complex aphasia intervention trial: a substudy of the Very Early Rehabilitation in SpEech (VERSE) trial

Background: Treatment fidelity is inconsistently reported in aphasia research, contributing to uncertainty about the effectiveness of types of aphasia therapy following stroke. We outline the processes and outcomes of treatment fidelity monitoring in a pre-specified secondary analysis of the VERSE trial. Methods: VERSE was a 3-arm, single-blinded RCT with a 12-week primary endpoint comparing Usual Care (UC) to two higher intensity treatments: Usual Care-Plus (UC-Plus) and VERSE, a prescribed intervention. Primary outcome results were previously reported. This secondary analysis focused on treatment fidelity. Video-recorded treatment sessions in the higher intensity study arms were evaluated for treatment adherence and treatment differentiation. Treatment components were evaluated using a pre-determined fidelity checklist. Primary outcome: prescribed amount of therapy time (minutes); secondary outcomes: (i) adherence to therapy protocol (%) and (ii) treatment differentiation between control and high intensity groups. Results: Two hundred forty-six participants were randomised to Usual Care (n=81), Usual Care-Plus (n=82), and VERSE (n=83). One hundred thirty-five (82%) participants in higher intensity intervention arms received the minimum prescribed therapy minutes. From 10,805 (UC 7787; UC-Plus 1450; VERSE 1568) service events, 431 treatment protocol deviations were noted in 114 participants. Four hundred thirty-seven videos were evaluated. The VERSE therapists achieved over 84% adherence to key protocol elements. Higher stroke and aphasia severity, older age, and being in the UC-Plus group predicted more treatment deviations. Conclusions: We found high levels of treatment adherence and differentiation between the intervention arms, providing greater confidence interpreting our results. The comprehensive systems for intervention fidelity monitoring and reporting in this trial make an important contribution to aphasia research and, we argue, should set a new standard for future aphasia studies

Treatment fidelity monitoring, reporting and findings in a complex aphasia intervention trial: A substudy of the very early rehabilitation in SpEech (VERSE) trial

Background: Treatment fidelity is inconsistently reported in aphasia research, contributing to uncertainty about the effectiveness of types of aphasia therapy following stroke. We outline the processes and outcomes of treatment fidelity monitoring in a pre-specified secondary analysis of the VERSE trial. Methods: VERSE was a 3-arm, single-blinded RCT with a 12-week primary endpoint comparing Usual Care (UC) to two higher intensity treatments: Usual Care-Plus (UC-Plus) and VERSE, a prescribed intervention. Primary outcome results were previously reported. This secondary analysis focused on treatment fidelity. Video-recorded treatment sessions in the higher intensity study arms were evaluated for treatment adherence and treatment differentiation. Treatment components were evaluated using a pre-determined fidelity checklist. Primary outcome: prescribed amount of therapy time (minutes); secondary outcomes: (i) adherence to therapy protocol (%) and (ii) treatment differentiation between control and high intensity groups. Results: Two hundred forty-six participants were randomised to Usual Care (n = 81), Usual Care-Plus (n=82), and VERSE (n = 83). One hundred thirty-five (82%) participants in higher intensity intervention arms received the minimum prescribed therapy minutes. From 10,805 (UC 7787; UC-Plus 1450; VERSE 1568) service events, 431 treatment protocol deviations were noted in 114 participants. Four hundred thirty-seven videos were evaluated. The VERSE therapists achieved over 84% adherence to key protocol elements. Higher stroke and aphasia severity, older age, and being in the UC-Plus group predicted more treatment deviations. Conclusions: We found high levels of treatment adherence and differentiation between the intervention arms, providing greater confidence interpreting our results. The comprehensive systems for intervention fidelity monitoring and reporting in this trial make an important contribution to aphasia research and, we argue, should set a new standard for future aphasia studies. Trial registration: ACTRN 1261300077670

The general population cohort in rural south-western Uganda: a platform for communicable and non-communicable disease studies.

The General Population Cohort (GPC) was set up in 1989 to examine trends in HIV prevalence and incidence, and their determinants in rural south-western Uganda. Recently, the research questions have included the epidemiology and genetics of communicable and non-communicable diseases (NCDs) to address the limited data on the burden and risk factors for NCDs in sub-Saharan Africa. The cohort comprises all residents (52% aged ≥13years, men and women in equal proportions) within one-half of a rural sub-county, residing in scattered houses, and largely farmers of three major ethnic groups. Data collected through annual surveys include; mapping for spatial analysis and participant location; census for individual socio-demographic and household socioeconomic status assessment; and a medical survey for health, lifestyle and biophysical and blood measurements to ascertain disease outcomes and risk factors for selected participants. This cohort offers a rich platform to investigate the interplay between communicable diseases and NCDs. There is robust infrastructure for data management, sample processing and storage, and diverse expertise in epidemiology, social and basic sciences. For any data access enquiries you may contact the director, MRC/UVRI, Uganda Research Unit on AIDS by email to [email protected] or the corresponding author

The Ministry of Health and Sanitation, Sierra Leone - Public Health England (MOHS-PHE) Ebola Biobank.

During the Ebola outbreak in 2014-2015 in Sierra Leone, residual clinical specimens and accompanying data were collected from routine diagnostic testing in Public Health England (PHE) led laboratories. Most of the samples with all the accompanying data were transferred to PHE laboratories in the UK for curation by PHE.  The remainder have been kept securely in Sierra Leone. The biobank holds approximately 9955 samples of which 1108 tested positive for Ebola virus. Researchers from the UK and overseas, from academia, government other research organisations and commercial companies can submit proposals to the biobank to access and use the samples. The Ministry of Health and Sanitation in Sierra Leone (MOHS) retains ownership of the data and materials and is working with PHE and other researchers to develop and conduct a series of research projects that will inform future healthcare and public health strategies relating to Ebola.  The Ebola Biobank Governance Group (EBGG) was established to guarantee equality of access to the biobank for the most scientifically valuable research including by researchers from low and middle-income countries. Ensuring benefit to the people of Sierra Leone is an over-arching principle for decisions of the EBGG.  Four ongoing research collaborations are based on the first wave of biobank proposals approved by EBGG.  Whilst the biobank is a valuable resource its completeness and sample quality are consistent with the outbreak conditions under which they were collected

A Chandra Study of the Rosette Star-Forming Complex. III. The NGC 2237 Cluster and the Region's Star Formation History

We present Chandra X-ray images of the NGC 2237 young star cluster on the periphery of the Rosette Nebula. We detect 168 X-ray sources, 80% of which have counterparts in USNO, 2MASS, and deep FLAMINGOS images. These constitute the first census of the cluster members with 0.2<~M<~2 Msun. Star locations in near-infrared color-magnitude diagrams indicate a cluster age around 2 Myr with a visual extinction of 1<Av<3 at 1.4 kpc, the distance of the Rosette Nebula's main cluster NGC 2244. We derive the K-band luminosity function and the X-ray luminosity function of the cluster, which indicate a population ~400-600 stars. The X-ray-selected sample shows a K-excess disk frequency of 13%. The young Class II counterparts are aligned in an arc ~3 pc long suggestive of a triggered formation process induced by the O stars in NGC 2244. The diskless Class III sources are more dispersed. Several X-ray emitting stars are located inside the molecular cloud and around gaseous pillars projecting from the cloud. These stars, together with a previously unreported optical outflow originating inside the cloud, indicate that star formation is continuing at a low level and the cluster is still growing. This X-ray view of young stars on the western side of the Rosette Nebula complements our earlier studies of the central cluster NGC 2244 and the embedded clusters on the eastern side of the Nebula. The large scale distribution of the clusters and molecular material is consistent with a scenario in which the rich central NGC 2244 cluster formed first, and its expanding HII region triggered the formation of the now-unobscured clusters RMC XA and NGC 2237. A large swept-up shell material around the HII region is now in a second phase of collect-and-collapse fragmentation, leading to the recent formation of subclusters. Other clusters deeper in the molecular cloud appear unaffected by the Nebula expansion.Comment: Accepted to ApJ. 49 pages, 16 figures, and 4 tables