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

Aphasia therapy: Measuring the relevance

Within aphasia therapy, there is constant discussion regarding how we measure the relevance of therapy for the individual with aphasia. Aphasia therapists grapple with the difficult issue of how to demonstrate that the effects of therapy seen, for example, in improved performance on specific linguistic measures, have relevance to the person’s everyday life. In contrast, there are occasions where positive life changes are seen for the individual, sometimes without corresponding change on linguistic measures (Morris, Howard et al. 2004). When changes in everyday communication and activity are seen or reported, we are usually restricted to offering anecdotal evidence of these

Liberal warriors and the violent colonial logics of “partnering and advising"

Building on the feminist literature that traces the (re)production of militarized masculinities in and through military interventions, this article details some of the ways British soldiering subjects are being shaped in today's counterinsurgency context. Required now to be both nation builders and war fighters, contemporary soldiers are a “softer,” less masculinized subjectivity, and what Alison Howell has termed “liberal warriors.” British troops with their long history of colonialism and frequent overseas military campaigns are understood to be particularly suited to this role. Taking the British military's involvement in the “partnering and advising” of the Afghan National Army (ANA), this article pays attention to the interlocking gendered, raced, and sexualized discourses through which the British/Afghan encounter is experienced. Exploring first British troops' preoccupation with the perceived femininity and homosexuality of their Afghan counterparts, and second, Afghan hypermasculinity as demonstrated by the characterizations of their violent and chaotic fighting tactics, colonial logics are revealed. While British liberal warriors come to know “who they are” through these logics, (mis)represented Afghan soldiers are rendered increasingly vulnerable to the very “real,” very material violences of war

Emergent canine visceral leishmaniasis in Argentina: Comparative diagnostics and relevance to proliferation of human disease.

BACKGROUND: Visceral leishmaniasis (VL) is a zoonotic protozoal vector-borne disease that is a major public health challenge. In Argentina, canine (CVL) and human visceral leishmaniasis (HVL) have recently emerged. There is a lack of standardised diagnostic tests for CVL, which hinders control of CVL and HVL. METHODOLOGY/PRINCIPAL FINDINGS: Sampling was carried out in Puerto Iguazú, Argentina, comprising 190 asymptomatic, oligosymptomatic and polysymptomatic dogs. The following diagnostics were applied: microscopy of lymph node aspirate (LNA); three immunochromatographic rapid diagnostic tests (RDTs), prototype rK28-ICT, rK39-ICT (both Coris BioConcept), commercial rK39 (InBios); ELISA for IgG, IgG1 and IgG2, against rK28, rK39 or crude lysate antigen. DNA detection and analysis, with 30 dogs, was of the ITS1 region using skin samples, and loop-mediated isothermal amplification (LAMP; Eiken Loopamp) of buffy coat, skin scrape or LNA. 15.4% of dogs were positive by LNA microscopy. The rK28 RDT had higher seropositivity rate (61%) than either a prototype rK39 RDT (31.4%) or commercial rK39 RDT (18.8%), without cross-reactivity with six other pathogens. IgG anti-rK39 ELISA antibody titres, but not IgG2, were positively correlated with number of clinical signs. LAMP with LNA had a higher positivity rate than PCR; buffy coat sampling was more sensitive than skin scrape. ITS1 confirmed Leishmania (Leishmania) infantum as the agent of CVL. Leishmania (Viannia) spp. was detected in skin samples from two dogs, compatible with Leishmania (Viannia) braziliensis. CONCLUSIONS/SIGNIFICANCE: Seroprevalence confirmed rapid increase in CVL in Puerto Iguazú. The rK28 RDT test potentially has great value for improved point-of-care diagnosis. Given cost reduction and accessibility, commercial LAMP may be applicable to buffy coat. RDT biomarkers of CVL clinical status are required to combat spread of CVL and HVL. The presence of Viannia, perhaps as an agent of human mucocutaneous leishmaniasis (MCL), highlights the need for vigilance and surveillance

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

A genetic model of malignant phase hypertension in rats

A genetic model of malignant phase hypertension in rats. A genetic model of malignant phase hypertension in rats is described which closely parallels the natural history of untreated human malignant phase hypertension. Although the factors initiating transition from essential hypertension to the accelerated phase in humans remain unknown, we report the characteristics of a genetically determined and reproducible phenotype which was found to result from a cross between hypertensive transgenic Ren-2 rats and normotensive Sprague-Dawley (Edinburgh) rats. Male F1 hybrids developed malignant phase hypertension with a penetrance of 73.5% (95% confidence limits 65.7 to 81.3%) by 100 days of age. Phenotypic features included an accelerated rise in blood pressure, fibrinoid necrosis, activation of the renal renin-angiotensin system and microangiopathic hemolytic anemia. In an analytical cross no significant difference in blood pressure was observed between malignant phase and non-malignant phase animals prior to transition, implying that a factor in addition to hypertension appears necessary for inducing transition to the malignant phase phenotype. Segregation of the malignant phenotype suggested that susceptibility is determined by at most two genetic loci