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Background and Purpose Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. Experimental Approach To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT(1) antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry. Key Results MAP before treatment was 153 +/- 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver-specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. Conclusion and Implications Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.

Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) lowers blood pressure, but its effectiveness in hypertensive chronic kidney disease is unknown. Considering that the kidney may generate its own AGT, we assessed the effectiveness of liver-targeted AGT siRNA in the 5/6th Nx (5/6th nephrectomy) rat—a hypertensive chronic kidney disease model. Five weeks after 5/6th Nx (baseline), rats were subjected to vehicle, AGT siRNA, AGT siRNA+losartan, losartan, or losartan+captopril. Baseline mean arterial pressure was 160±6 mm Hg. Over the course of 4 weeks, mean arterial pressure increased further by ≈15 mm Hg during vehicle treatment. This rise was prevented by AGT siRNA. Losartan reduced mean arterial pressure by 37±6 mm Hg and increased plasma Ang (angiotensin) II. Both AGT siRNA and captopril suppressed these effects of losartan, suggesting that its blood pressure–lowering effect relied on stimulation of vasodilator Ang II type 2 receptors by high Ang II levels. Proteinuria and cardiac hypertrophy increased with vehicle, and these increases were comparably abrogated by all treatments. No intervention improved glomerular filtration rate, while siRNA and losartan equally diminished glomerulosclerosis. AGT siRNA±losartan reduced plasma AGT by >95%, and this was accompanied by almost complete elimination of Ang II in kidney and heart, without decreasing renal AGT mRNA. Multiple linear regression confirmed both mean arterial pressure and renal Ang II as independent determinants of proteinuria. In conclusion, AGT siRNA exerts renoprotection in the 5/6th Nx model in a blood pressure–independent manner. This relies on the suppression of renal Ang II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human chronic kidney disease.

OBJECTIVE: Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) exerts beneficial effects on blood pressure and kidney function, but its effects in diabetes are still unknown. DESIGN AND METHOD: To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic with streptozotocin for 18 weeks and treated with vehicle, AGT siRNA, the angiotensin receptor blocker valsartan, the ACE inhibitor captopril, valsartan + siRNA, or valsartan + captopril for the final 3 weeks. Arterial pressure was measured via radiotelemetry. RESULTS: Baseline mean arterial pressure (MAP) was 164 ± 1 mm Hg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a further rise in MAP or a change in glomerular filtration rate. All treatments lowered MAP (by ~50 mm Hg) and cardiac hypertrophy identically. Treatment with siRNA resulted in the largest reduction in AGT, while in combination with valsartan AGT virtually disappeared. Only the dual treatment groups and captopril lowered circulating angiotensin II and aldosterone. No treatment affected renal AGT mRNA expression, confirming the liver-specificity of the siRNA. Yet, siRNA with or without valsartan, and valsartan + captopril, but not valsartan alone, or captopril alone, reduced renal angiotensin I and II. All treatments lowered albuminuria and proteinuria, while only siRNA with or without valsartan improved glomerulosclerosis and podocyte dysfunction. Multiple linear regression confirmed both mean arterial pressure and renal angiotensin II as independent determinants of albuminuria. CONCLUSIONS: In conclusion, AGT siRNA exerts renoprotection in diabetic TGR(mREN2)27 rats, and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human diabetic kidney disease.

Brain renin–angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6–8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions >90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

Background: RNAi therapeutics targeting angiotensinogen (AGT) lower blood pressure in animal models of essential hypertension, but whether this treatment is beneficial in hypertensive chronic kidney disease (CKD) is yet unknown. Our aim was to assess the effectiveness of a small interfering RNA (siRNA) targeting hepatic AGT in a rat model of hypertensive CKD. Methods: Sprague Dawley rats (n=7-12 per group) were subjected to 5/6th nephrectomy, allowed to recover for four weeks, and subsequently subjected to one of five treatments: (1) vehicle, (2) AGT siRNA (10-30 mg/kg, s.c. every 2 weeks), (3) AGT siRNA + losartan (30 mg/kg/d), (4) losartan (30 mg/kg/d), or (5) losartan + captopril (30 and 6 mg/kg/d). Mean arterial pressure (MAP) was measured by radiotelemetry for 4 weeks, glomerular filtration rate (GFR) was measured by transcutaneous FITC-sinistrin clearance. Results: AGT siRNA and AGT siRNA + losartan reduced plasma AGT by 96.5 ± 1.4% and 97.0 ± 2.3%, respectively. Over the course of 4 weeks, proteinuria increased with vehicle and this increase was abrogated by all treatments (Δ proteinuria at 4 weeks versus baseline: +0.17 [0.12, 0.23], +0.02 [-0.04, 0.05], -0.01 [-0.07, 0.06], -0.05 [-0.12, 0.00], -0.01 [-0.06, 0.11] for vehicle, AGT siRNA, AGT siRNA + losartan, losartan, losartan + captopril, P < 0.05 for all groups compared with vehicle). Similarly, heart weight was equally reduced by all treatments except vehicle. No intervention affected GFR. Over the course of 4 weeks, MAP increased (from a baseline of 154 ± 18 mmHg) during vehicle treatment and this rise was prevented by AGT siRNA (+13 ± 15 mmHg vs. -2 ± 14 mmHg, P > 0.05 for difference between groups). Combination treatment with AGT siRNA + losartan, losartan + captopril, and losartan alone caused a similar and marked reduction in MAP (-17 ± 14 mmHg, -21 ± 17 mmHg, and -33 ± 20 mmHg, P < 0.05 versus vehicle for all; differences between groups not significant). Conclusion: In experimental CKD, AGT siRNA monotherapy appears to reduce proteinuria and heart weight in a blood pressure-independent fashion, to a similar degree as losartan or combination treatment. Thus, an siRNA targeting hepatic AGT may be a potential therapeutic approach for providing renal and cardioprotection in CKD.

A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and sustained antihypertensive effect, lasting weeks to months in preclinical models. It is not known whether conventional vasopressors are effective to reverse RNAi-mediated blood pressure lowering. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion. Spontaneously hypertensive rats on a low-salt diet (

Deoxycorticosterone acetate (DOCA)-salt is suggested to increase blood pressure via selective upregulation of the brain renin-angiotensin system (RAS), while suppressing the circulating RAS. Yet, we have observed parallel downregulation of plasma and brain renin in mice. Here, we quantified brainstem angiotensinogen (AGT) and angiotensin (Ang) levels in rats exposed to DOCA (200mg; 60-day release) and 0.9% NaCl as drinking water for 7 weeks. To determine the contribution of AGT (liver vs. kidney/brain), Ang II type 1 receptors (AT1R) and blood pressure to tissue Ang II content, rats received vehicle, liver-targeted AGT siRNA (10 mg/kg fortnightly; s.c.), valsartan (31 mg/kg/day; s.c.) or spironolactone (80 mg/kg/day; s.c.) during the final 3 weeks, the latter fully normalizing blood pressure (n=3-9 per group). Plasma renin and AGT were determined by enzyme-kinetic assay, tissue AGT by western blotting, and Ang I and II by LC-MS/MS. Plasma renin, AGT, Ang I and II in rats not exposed to DOCA-salt were 24±8ng Ang I/mL per h, 731±51nM, 123±38pM and 109±43pM. AGT was present in liver, kidney and brainstem. Kidney Ang I and II were 540±135and 510±97fmol/g, while brainstem Ang I and II were undetectable in all and 50% of the rats, respectively (

Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt ) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (−68±4 mm Hg), followed by captopril+valsartan (−54±4 mm Hg), captopril (−23±2 mm Hg), siRNA (−14±2 mm Hg), and valsartan (−10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K + increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.

Angiotensinogen (AGT) synthesis is proposed to occur not only in the liver, but also in kidney, brain and adipocytes. Selectively deleting hepatic AGT might therefore not affect renal angiotensin (Ang) levels. Here we investigated whether arterial pressure lowering with liver-targeted AGT siRNA versus renin-Ang system (RAS) blockers affects renal function and Ang levels. Arterial pressure was measured via radiotelemetry in spontaneously hypertensive rats during vehicle, valsartan, captopril (both p.o.), siRNA (s.c. fortnightly injection), siRNA+valsartan or captopril+valsartan treatment for 4 weeks. Transcutaneous measurement of glomerular filtration rate (GFR) and 24h urinary excretory function was assessed at 2 and 4 weeks. Renal Ang levels were measured by mass spectrometry. Dual RAS blockade synergistically lowered arterial pressure compared to monotherapy. Valsartan and captopril increased AngI (1096±205 and 939±128 fmol/g, respectively versus 413±46 fmol/g in vehicle-treated; both P70% after valsartan, captopril and captopril+valsartan (all P1 R may allow renal AngII to remain intact after AGT siRNA, and only dual RAS blockade significantly reduces renal AngII. AGT siRNA synergistically lowers arterial pressure when combined with existing RAS blockers and may be a novel treatment for hypertension without apparent negative effects on renal function.

All angiotensin stems from angiotensinogen (AGT). A single dose of small interfering ribonucleic acids (siRNA) targeting AGT may provide long-lasting blood pressure reductions, as it would abolish angiotensin generation. Here we assessed efficacy of AGT siRNA in spontaneously hypertensive rats (SHRs). SHRs were treated for 4 weeks with vehicle, siRNA (10 mg/kg; s.c. every 2 weeks), valsartan (31 mg/kg/day; oral), captopril (100 mg/kg/day; oral), valsartan+siRNA, or captopril+valsartan (all groups n=8). Mean arterial pressure (MAP) was measured via radiotelemetry. Baseline MAP was 137±2 mmHg. ΔMAP was largest after valsartan+siRNA (-67±3 mmHg; P+ tended to increase in all groups, significance being reached only in the valsartan+siRNA group. Both types of dual blockade attenuated normal growth from the second week of treatment onwards. In conclusion, due to renin upregulation, circulating angiotensin II remained intact even with only 1.4% of AGT left, relative to pretreatment. Consequently, AGT siRNA caused a similar antihypertensive effect as valsartan and captopril. Importantly, when combining siRNA+valsartan, angiotensin II collapsed, and blood pressure decreased synergistically. Given the potential for low dosing frequency suggested by this study, this novel treatment may address medication adherence problems in patients with resistant hypertension and further development is warranted.

Policy makers, practitioners and researchers have identified risk as a key concept in relation to maternity care and childbirth. There is however a lack of research exploring women’s discursive constructions of risk and childbirth in relation to sociological risk theories. In this article we explore pregnant women’s everyday negotiations of risk in relation to the self-chosen plan to birth either at home or via an elective Caesarean section. We use sociocultural risk theories to contextualise our findings. This article draws on data from a study conducted in 2005–2006 in which we interviewed 24 pregnant middle-class South African women who were planning a home birth or elective Caesarean section and used social constructionist discourse analysis to analyse the data. We found that women’s risk constructions were related to three different conceptions of birthing embodiment: technocratic bodies, vulnerable bodies and knowing bodies. Women who planned Caesarean sections were committed to biomedical construct...

Women with Preeclampsia (PE), a form of new onset hypertension during pregnancy, exhibit alterations in the renin angiotension system (RAS). These differences include angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA), ANG II sensitivity, and increased oxidation and levels of angiotensinogen (AGT). While antihypertensive drugs are used in pregnancy, their use is associated with reduced fetal growth, and RAS blockade is specifically contraindicated due to fetotoxicity. AGT is the precursor to ANG II and the initial substrate of the RAS pathway. Genetic mutations that result in an over-expression of AGT are strongly associated with hypertension. We have previously shown that siRNA targeting maternal hepatic AGT in a transgenic model of preeclampsia (hAGT x hREN) resulted in lower blood pressure, a 90% reduction in AT1-AA activity, and normalized IUGR. The purpose of the present study is to examine the effect of silencing maternal hepatic AGT on maternal blood pressure and fetal growth in the reduced uterine placental perfusion pressure (RUPP) model of PE. Methods: Pregnant Sprague Dawley rats were divided into 4 groups: normal pregnant (NP, n=7); RUPP (n= 6); RUPP + siRNA (n =7); NP + siRNA (n=7). On day 12 of gestation (GD), siRNA was subcutaneously injected into rats (10mg/kg), GD14 the RUPP surgery was performed, GD18 carotid catheters inserted, and GD19 conscious blood pressure (MAP) and fetal weight was recorded. Results: MAP was elevated in RUPP vs. NP (134±6 vs. 101±4 mmHg, p< 0.05), but was lower in RUPP + siRNA (117±4 mmHg) and unchanged in the NP+siRNA (92±3 mmHg) group compared to NP. Average fetal weights by group were 2.30±0.09 g (NP), 1.89±0.10 g (RUPP), 2.38±0.09 g (NP+siRNA), and 2.12±0.06 (RUPP+siRNA). A one-way ANOVA indicates a significant reduction in pup weights between NP and RUPP, but not NP+siRNA and RUPP+siRNA, indicating administration of siRNA to RUPP rats prevented the decrease in fetal weight. Conclusion: Administration of AGT siRNA to RUPP rats blunts the increase in blood pressure and prevents a decrease in fetal weights in response to placental ischemia and thus could be a potential therapy for management of preeclampsia and other hypertensive disorders of pregnancy. Research Supported by Alnylam & T32HL105324

Since the 1970s, feminist research has provided a powerful critique of biomedical models of childbirth. While this critique has been extremely important, it has to some extent led to the neglect of other forms of power. For example, there has been little research which has explored childbirth as a way of ‘doing gender’ in which normative or resistant forms of gender and femininity are (re)performed. Drawing on the Foucauldian notion of ‘technologies of power’, we argue that gender is a form of disciplinary power which shapes the choices that women make in relation to childbirth. Drawing on pre-birth interviews with 21 white, middle-class pregnant South African women who were planning on either a home birth (n = 12) or an elective caesarean section (n = 9), we show how three central technologies of white femininity shaped and regulated women’s childbirth choices. These included: a patriarchal optics of childbirth, the ‘natural childbirth’ ideal and the ‘good mother’ imperative. The article concludes that women’s childbirth choices are heavily shaped by gendered technologies of power and that the decision to have a home birth or an elective caesarean section intersects with scripts of ‘doing white femininity’ in South Africa.

This article presents an historical survey of intergroup attitudes in South Africa, tracing social distance scores back to 1934 and semantic differential scores back to 1975. We compare the attitudes of different race groups towards each other over time by standardizing the scores from different historical periods on a common metric. This enables us to pursue two lines of investigation: (1) to chart the effect that racial classification has had on ingroup bias patterns, and (2) to assess the impact of changing historical contexts on intergroup attitudes — especially the threatening and competitive context of the post-1976 struggle for liberation and the post-1994 context of democracy and reconciliation. The data indicate that dramatic changes may be taking place, with white respondents showing declining levels of prejudice, the inversion of the historically asymmetric attitude ‘colour bar’, and a slight, perhaps negative, change in attitudes of black African respondents toward other groups.

Introduction Preeclampsia is a common and devastating pregnancy disorder, featuring hypertension and proteinuria. Studies have demonstrated that dysregulation of Renin-Angiotensin-System (RAS) is involved in the pathogenesis of the disease; however, treatment with a RAS-blocker is contraindicated due to fetal toxicity. Objective RNA interference (RNAi) is a potent means of gene-specific silencing. We sought to demonstrate maternal-specific RAS blockade by targeting maternal hepatic angiotensinogen (AGT) using small interfering RNA (siRNA). In this study we tested the ability of AGT-targeting siRNA to ameliorate symptoms of preeclampsia in two rat models, without inducing a placental pathology or affecting fetal health. Methods Two animal models of preeclampsia were used. The first model (transgenic) acts by upregulation of the circulating and uteroplacental Renin-Angiotensin-System (RAS). The second model is a surgical model that induces ischemia/reperfusion injury and subsequent local and systemic inflammation restriction (RUPP). Beginning on day 3 of gestation, transgenic rats were dosed subcutaneously with 10 mg/kg siRNA every third day through gestation day 15. In RUPP rats, siRNA was subcutaneously injected once (10 mg/kg) on day 12 of gestation. Results The major finding is that RNAi therapeutics targeting maternal hepatic AGT ameliorated the preeclamptic phenotype in both models. We were able to selectively reduce maternal RAS signaling while preserving the fetal RAS. In the transgenic model, silencing of hAGT leads to a reduction of blood pressure and urinary albumin excretion. Moreover, we improved intrauterine growth retardation, indicating an improved fetal development. The RUPP model confirmed the principal findings in a model that is not explicitly driven by the RAS. Discussion Investigational RNAi therapeutics targeting AGT ameliorated the clinical sequelae of preeclampsia in a transgenic rat model and improved the outcome of the fetus. We conclude that maternal specific RAS blockade improves maternal symptoms without deteriorating fetal health in rodent models.

The arts are valued for themselves in a civilized society. The arts are confidence building, self-affirming and identity forming. They help to create a sense of community and contribute to good hea...

Eleven well-educated students from a university in South Africa, all actively involved in the field of HIV/AIDS, were interviewed through a free-associative-narrative method. This study sought to explore students' perceptions of HIV/AIDS in an attempt to assess whether stigma may occur. To the authors' knowledge, no similar studies exploring HIV/AIDS-related stigma have been done on young adults in South Africa who are actively involved with, and highly educated on, issues around HIV/AIDS. Through their representations, the participants tend to “other” the epidemic and thus distance themselves from a sense of threat. Many of the discourses in which the participants invest also fit into existing power relations, reinforcing some of the most prevalent forms of oppression in South Africa. In line with psychosocial understandings of HIV/AIDS stigma, the results indicate that this “atypical” group of students possess stigmatizing tendencies toward the epidemic and those infected. The findings have both theoretical and practical implications for conceptualizing and challenging HIV/AIDS stigma.

The central question for whiteness in post-apartheid South Africa can be put simply: how to maintain privilege in a situation in which black people have achieved political power. Many stances to the new dispensation are available to white South Africans, but this article concerns only resistant white discourses, referred to as White Talk. Two weekly columns published through 2000 in the most widely read Sunday newspaper in the country were downloaded and analysed. The article demonstrates how two discursive repertoires, New South Africa Speak and White Ululation are played off against each other to enable positive self-presentation while resisting transformation. In some ways South African White Talk has come to resemble the more ‘respectable’ international whitenesses, but the postcolonial, post-apartheid context gives it a different edge, particularly in relation to constructions of Africa.

In this chapter, we argue that the construction of oppressed identities gives rise to a set of cognitive alternatives which enable social change. We use this argument to explain how South Africa’s liberation movement became possible. We also outline how the identity category and the social change belief system that were forged in the struggle against apartheid have been reformulated and reinvigorated in the post-apartheid context by marginalised groups and South Africa’s political leadership. Using three recent examples of social mobilisations we illustrate that the discourse of oppressed identities can be flexibly tailored to diverse race, class and political interests, and can even be used by the relatively privileged to mobilise others towards social change. The chapter illustrates that in order to understand how oppressed identities develop and are used it is important to analyse the rhetoric through which they are constructed.

Recently the South African Minister of Safety and Security, Charles Nqakula, argued that local and municipal police should be thought of as 'co-owned' by communities. To enable the realisation of this vision Nqakula was reported to be considering 'changes to the Police Services Act and the laws governing municipal policing'. In this report the Minister is quoted as saying that 'no police force, no matter how big it is, can ever effectively deal with crime' alone. In the Sunday Times, also of 6 May 2007, the Minister is reported as arguing for the importance of forging a closer relationship between the police and the private security industry.

Twelve years after the transition from apartheid to democracy. South Africa remains a severely unequal society. On the one side of the divide are relatively prosperous white South Africans and an increasing black middle and upper class; and on the other side are harshly poor black South Africans. Despite decreasing interracial inequality, many white South Africans remain in a highly privileged position at the intersection of continued race and class systems of privilege. Research on whiteness in South Africa indicates that inequality is actively maintained by the discourses mobilised by white South Africans. This study was interested in furthering such research. A discourse analysis was applied to ten in-depth, semi-structured interviews with white, wealthy South Africans, to identify the ways in which meaning was being constructed around issues of poverty and development. J.B. Thompson's (1984) framework was applied to these discourses, to identify whether they were operating ideologically (to m...

Provides a review of Gibson’s (2004) evaluation of the Truth and Reconciliation Commission (TRC) of South Africa. Offers a background to the TRC process then reckons with Gibson’s study in terms of his procedures, the context, the issue of “race”, the truth claims of the TRC, a digression on amnesty, and finally the link between truth and reconciliation. Concludes that this study offers substantial support for the TRC process.

This article reviews and comments on the six articles presented in the special focus section of this issue of the journal on ‘Racial isolation and interaction in everyday life’. Taken together, the articles call for a reinterpretation of the spaces of contact in everyday life, with a new focus on the ‘micro-ecology’ of racialised divisions. Contributions are made in three areas: (a) meta-theory, with a turn to materiality, (b) new methodologies, and (c) understandings of racial segregation and contact. The contact hypothesis is reconsidered with new emphases on relations between bodies–space–time. A ‘relational model’ is given in efforts at explanation.

T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.

IL-21 is a cytokine that regulates the activation of T and NK cells and promotes the proliferation of B cells activated via CD40. In this study, we show that rIL-21 strongly induces the production of all IgG isotypes by purified CD19+ human spleen or peripheral blood B cells stimulated with anti-CD40 mAb. Moreover, it was found to specifically induce the production of IgG1 and IgG3 by CD40-activated CD19+CD27− naive human B cells. Although stimulation of CD19+ B cells via CD40 alone induced γ1 and γ3 germline transcripts, as well as the expression of activation-induced cytidine deaminase, only stimulation with both anti-CD40 mAb and rIL-21 resulted in the production of Sγ/Sμ switch circular DNA. These results show that IL-21, in addition to promoting growth and differentiation of committed B cells, is a specific switch factor for the production of IgG1 and IgG3.

Over the past decade, advances in both gene discovery and ligand-receptor pairing techniques have led to the recognition that systematic pairing of 'orphan' database-derived cytokines and/or cytokine receptors with their cognate partners can lead to a marked acceleration in the elucidation of biological function. The sometimes-restricted tissue distribution of the receptor, coupled with the highly specific bioactivity of the corresponding ligand, can direct investigators rapidly towards regulatory function and site-of-action studies. The power of cytokine-receptor pairing to accelerate the understanding of function will be illustrated, citing several examples of candidate drug discoveries. Several of these discoveries, resulting from cytokine-receptor pairings, are at present advancing towards human clinical evaluation.

NK and T cell-derived IFN-γ is a key cytokine that stimulates innate immune responses and directs adaptive T cell response toward Th1 type. IL-15, IL-18, and IL-21 have significant roles as activators of NK and T cell functions. We have previously shown that IL-15 and IL-21 induce the expression of IFN-γ, T-bet, IL-12Rβ2, and IL-18R genes both in NK and T cells. Now we have studied the effect of IL-15, IL-18, and IL-21 on IFN-γ gene expression in more detail in human NK and T cells. IL-15 clearly activated IFN-γ mRNA expression and protein production in both cell types. IL-18 and IL-21 enhanced IL-15-induced IFN-γ gene expression. IL-18 or IL-21 alone induced a modest expression of the IFN-γ gene but a combination of IL-21 and IL-18 efficiently up-regulated IFN-γ production. We also show that IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFN-γ gene. Similarly, IL-21 induced the binding of STAT1, STAT3, and STAT4 to these elements. IL-15- and IL-21-induced STAT1 and STAT4 activation was verified by immunoprecipitation with anti-phosphotyrosine Abs followed by Western blotting with anti-STAT1 and anti-STAT4 Abs. IL-18 was not able to induce the binding of STATs to IFN-γ gene regulatory sites. IL-18, however, activated the binding of NF-κB to the IFN-γ promoter NF-κB site. Our results suggest that both IL-15 and IL-21 have an important role in activating the NK cell-associated innate immune response.

Interleukin 21 (IL-21) is a recently identified novel cytokine that plays an important role in the regulation of B, T, and NK cell functions. Its effects depend on binding to and signaling through an IL-21 receptor complex consisting of the IL-21 receptor (IL-21R) and the common gamma-chain (gamma(c)). In this study using biosensor technique, the ligand-binding properties of IL-21R and gamma(c), which are presently poorly understood on a molecular level, were analyzed employing recombinant ectodomains of IL-21R and gamma(c). The formation of a binary complex between IL-21 and immobilized IL-21R (K(D) 70pM), gamma(c) and immobilized IL-21 (K(D) 160 microM) and a ternary complex between gamma(c) and IL-21 saturated immobilized IL-21R (K(D) 160nM) could be analyzed. The gamma(c) residues involved in IL-21 binding were defined by alanine-scanning mutational analysis. The epitope comprises gamma(c) residues N44, Y103, N128, L161, E162, and L208. It is not identical but partially overlapping with the previously established gamma(c) epitope for IL-4 binding. These results open the way to understand the molecular recognition mechanism in the IL-21 receptor system and also the promiscuous binding properties of gamma(c).

IL-21 is a recently characterized T cell-derived cytokine that regulates NK and T cell function. IL-21R shares the common γ-chain (γc) with the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Despite the same γc, these cytokines have different effects on diverse cells. In this study, we have studied IL-15- and IL-21-induced gene expression in human primary NK and T cells and the NK-92 cell line. Both IL-15 and IL-21 rapidly induced mRNA synthesis for IFN-γ, T-bet, IL-2Rα, IL-12Rβ2, IL-18R, and myeloid differentiation factor 88 (MyD88), the genes that are important in activating innate immunity and Th1 response. IL-15 induced STAT5 DNA binding to the IL-2Rα IFN-γ-activated sequence (GAS), MyD88 GAS, and c-sis-inducible elements, whereas IL-21 induced STAT3 DNA binding to MyD88 GAS and c-sis-inducible elements. IL-21-induced STAT3 activation was verified by immunoprecipitation and Western blotting with anti-phosphotyrosine Ab. In addition, pretreatment of NK-92 cells with IL-15 or IL-21 strongly enhanced IL-12-induced STAT4 DNA binding to IL-2Rα GAS. The induction of IFN-γ, T-bet, IL-12Rβ2, and IL-18R gene expression in NK cells, along with STAT3 activation, suggests that IL-21 is involved in the activation of innate immune responses. Moreover, the enhanced transcription of these genes in T cells establishes a significant role for IL-21 also in the Th1 response.

Hemophilia A and B are inherited bleeding disorders characterized by deficiencies in procoagulant factor VIII (FVIII) or factor IX (FIX), respectively. There remains a substantial unmet medical need in hemophilia, especially in patients with inhibitory antibodies against replacement factor therapy, for novel and improved therapeutic agents that can be used prophylactically to provide effective hemostasis. Guided by reports suggesting that co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, we developed an RNA interference (RNAi) therapeutic (ALN-AT3) targeting antithrombin (AT) as a means to promote hemostasis in hemophilia. When administered subcutaneously, ALN-AT3 showed potent, dose-dependent, and durable reduction of AT levels in wild-type mice, mice with hemophilia A, and nonhuman primates (NHPs). In NHPs, a 50% reduction in AT levels was achieved with weekly dosing at approximately 0.125 mg/kg, and a near-complete reduction in AT levels was achieved with weekly dosing at 1.5 mg/kg. Treatment with ALN-AT3 promoted hemostasis in mouse models of hemophilia and led to improved thrombin generation in an NHP model of hemophilia A with anti-factor VIII inhibitors. This investigational compound is currently in phase 1 clinical testing in subjects with hemophilia A or B.

Preeclampsia, a disorder with the hallmark features of new-onset hypertension and proteinuria beginning after 20 weeks of gestation, affects 5% of pregnancies in industrialized nations. It is a major cause of fetal and maternal morbidity/mortality. Several studies have demonstrated that angiotensinogen is involved in the pathogenesis of the disease; however, treatment with ACE Inhibitor or AT1 Receptor blocker is contraindicated due to fetal toxicity. RNAi therapeutics are highly potent mediators of gene-specific silencing. We tested a human angiotensinogen (hAGT)-specifc siRNA, conjugated to triantennary GalNAc, for the ability to ameliorate symptoms of preeclampsia in an established rat model, without affecting the fetus. Transgenic rats expressing hAGT and human renin (hREN) were crossed to produce a model of preeclampsia (PE rat) in the dams. Beginning on day 3 of gestation, transgenic hAGT dams were dosed subcutaneously with 10 mg/kg siRNA every third day through gestation day 15. Mean blood pressure was continuously recorded by radiotelemetry and 24 hour urine samples were collected in metabolic cages at day 18 of gestation. Rats were euthanized at day 21 of gestation. Treatment with the GalNAc-conjugated siRNA reduced the spike in blood pressure seen on gestation day 13 and lasted through study termination (MAP on day 16 of gestation: 155.1 ± 1.4 mmHg untreated vs. 138.4 ± 1.8 mmHg treated). Proteinuria was ameliorated (21.7 ± 3.1 mg/d untreated vs. 2.7 ± 0.6 mg/d treated) and levels of agonistic autoantibodies against the angiotensin receptor AT1 were reduced below the limit of detection. Fetal and uteroplacental unit weights increased with RNAi therapy, demonstrating a reduction in intra-uterine growth restriction (brain to liver ratio (0.95 ± 0.04 untreated vs. 0.73 ± 0.02 treated). mRNA levels of hAGT were reduced to background levels in the liver, but were not affected in the placenta, which is of fetal origin. Our data show that an RNAi therapeutic targeting hAGT ameliorates the clinical sequelae of preeclampsia in a transgenic rat model and improves the outcome of the fetus.

This research sought to investigate the relationship between gang processes and differing forms of masculine expression. Three hundred and sixteen male participants, drawn from secondary schools within Cape Town, were included in the study. These schools were in areas differentially characterised by gang activity. The questionnaire included the newly devised Male Attitude Norm Inventory designed to explore hegemonic conceptualisations of masculinity. Factor analytic procedures rendered a three-factor model stressing the importance of male toughness, success and control. Through a series of t-tests for independent samples, as well as supporting qualitative data, participants from areas characterised by high gang activity were found to support these hegemonic elements to a significantly greater extent.

A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.

Feminist analyses of gender power inequalities in the negotiation of heterosexual sexuality (heterosex) have exposed heterosexuality as a key site for the reproduction of patriarchy. Empirical studies have highlighted women's lack of negotiation and men's dominance in heterosex. This paper reports on a qualitative study exploring the negotiation of heterosex among young men and women students at the University of the Western Cape, South Africa. A discourse analysis was carried out on the transcripts of focus group discussions held with over 100 male and female students speaking about their sexual experiences with the opposite sex. The study highlights the lack of a positive discourse on women's sexual desires, and continued double standards in the construction of masculine and feminine sexualities, with men viewed as positively sexual while women are representative of love and relationships. Nonetheless, there are some marginal voices contradicting these discourses and challenging the hegemonic constructi...

Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.