Prem Gathiram

Pre-eclampsia : its pathogenesis and pathophysiolgy : review articles

Abstract Pre-eclampsia is a pregnancy-specific disorder that has a worldwide prevalence of 5–8%. It is one of the main causes of maternal and perinatal morbidity and mortality globally and accounts for 50 000–60 00 deaths annually, with a predominance in the low- and middle-income countries. It is a multisystemic disorder however its aetiology, pathogenesis and pathophysiology are poorly understood. Recently it has been postulated that it is a two-stage disease with an imbalance between angiogenic and anti-antigenic factors. This review covers the latest thoughts on the pathogenesis and pathology of pre-eclampsia. The central hypothesis is that pre-eclampsia results from defective spiral artery remodelling, leading to cellular ischaemia in the placenta, which in turn results in an imbalance between anti-angiogenic and pro-angiogenic factors. This imbalance in favour of anti-angiogenic factors leads to widespread endothelial dysfunction, affecting all the maternal organ systems. In addition, there is foetal growth restriction (FGR). The exact aetiology remains elusive.

The optimization of a chronic nitric oxide synthase (NOS) inhibition model of pre-eclampsia by evaluating physiological changes.

OBJECTIVES In order to address the gap in our understanding of the pathogenesis and pathophysiology of PE, we optimized the NOS inhibition animal model by comparing changes in different parameters at various time frames during pregnancy, in both early and late-onset PE. STUDY DESIGN 120 nulliparous Sprague-Dawley rats were divided into 5 groups (n=24). A pregnant control, two groups that represented early and late-onset PE and two groups that were treated with sildenafil citrate (SC) to show reversal of the pre-eclamptic-like symptoms. RESULTS Our results showed that treatment with L-NAME caused significant changes in physiological parameters for both early and late-onset PE groups. There was a significant increase in systolic blood pressure (SBP) levels in the early-onset PE group (128.5±5.71 mmHg) and late-onset PE group (128.3±6.15 mmHg) on day 19 compared to the SBPs on day 0, (p<0.01). Urine excretion volumes in the early-onset PE group (13.62±3.18 mL) and in the late-onset PE (13.28±2.60 mL), compared to the pregnant control group (11.96±1.9 mL) were also increased (p<0.05). There was also an increase in total urinary protein in the early-onset PE group (0.62±0.08 g/L and the late-onset PE group (0.45±0.05 g/L), when compared to the pregnant control group (0.38±0.07) (p<0.05). We also found a decrease in fetal numbers in the PE group in comparison to the pregnant control and SC treated groups. The remission of these signs was seen after delivery of the fetuses. We also demonstrated that treatment of this syndrome with SC prevented the development of these signs. CONCLUSIONS The NOS inhibition model can be used for the study of the pathogenesis and pathophysiology of PE, since the pathogenic changes mimic those of early and late-PE.

The role of angiogenic, anti-angiogenic and vasoactive factors in pre-eclamptic African women: early- versus late-onset pre-eclampsia

Abstract The pathogenesis and aetiology of pre-eclampsia (PE) is still unclear. We investigated the role of angiogenic, anti-angiogenic and vasoactive factors in black South African women with early- and late-onset PE. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), soluble vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were determined using the ELISA technique, and placental mRNA expression levels of sFlt-1, VEGF, PlGF and AT1 receptors were determined using real-time PCR. Serum sFlt-1 levels were significantly elevated and PlGF significantly reduced in early-onset PE compared to the normotensive group. Placental VEGF mRNA expression levels were significantly reduced in the late-onset preeclamptic group compared with the normotensives. The placental mRNA expression of AT1 receptor in the late-onset pre-eclamptic group was relatively raised compared to the normotensives, suggesting hypersensitivity to pressor agents. We believe that the excess of serum sFlt-1 and reduced VEGF and PlGF levels favour an anti-angiogenic state and endothelial dysfunction leading to PE, and that the aetiology and pathogenesis of early- and late-onset PE differ.

Sanguinarine downregulates AT1a gene expression in a hypertensive rat model.

We studied the in vivo effects of sanguinarine in a hypertensive rat model and its effects on AT1a mRNA expression in kidney tissues. Rats received daily for 14 d sanguinarine 0.1 mg/kg (SangL) and 0.3 mg/kg (SangH), losartan 1 mg/kg by weight (Los), or DMSO (Con). Blood pressures were monitored regularly and urine volume and sodium concentration was measured on days 0, 7, and 14. On day 15, animals were anesthetized (sodium thiopentane, 50 mg/kg), blood samples for aldosterone levels were taken, and kidneys were removed for AT1a mRNA expression. Los and SangH groups showed reduced AT1a mRNA expressions by 4.22- and 5.9-fold, respectively. In the SangL group it was reduced by 2.7-fold. Decreases in systolic blood pressures mirrored decreases in AT1a mRNA expressions in all groups. Los and SangH groups showed reductions in systolic blood pressure of 12.3% and 19.3%, respectively, whereas in the SangL group, it was reduced by 8.07%. Urine output in the Los group increased (228% mean increase from days 0-14), whereas sodium excretion decreased by 69.6% (mean decrease from days 0-14). In the SangL and SangH groups, urine volumes increased significantly by 108.3% and 115% (mean increase from days 0-14), respectively. Urinary sodium excretion increased significantly by 60.9% in the SangH group. We concluded that sanguinarine reduces blood pressure in the Dahl rat because of decreased AT1 receptor expression and reduced aldosterone levels. The action of losartan on increased urinary volume and decreased sodium excretion may be attributed to reduced vasopressin secretion.

The effects of sildenafil citrate on uterine angiogenic status and serum inflammatory markers in an L-NAME rat model of pre-eclampsia

ABSTRACT Pre‐eclampsia (PE), a hypertensive disorder of pregnancy, is detrimental to both mother and foetus. There is currently no effective treatment, but we have shown that Sildenafil Citrate (SC) improve various foetal outcomes in Nω‐nitro‐L arginine methyl ester (L‐NAME) rat model of PE. Therefore, we aimed to investigate the effects of SC on a uterine angiogenic status and serum inflammatory markers in an L‐NAME rat model of PE. One hundred and twenty adult nulliparous pregnant female Sprague‐Dawley rats were used for the study. These were divided into five equal groups; the pregnant control, early and late onset PE and respective SC treated animals. Hypertension was manifested by considerably increased systolic blood pressure and placental lipid peroxidative marker (thiobarbituric acid reactive substances) and also we assessed the activities of plasma nitric oxide level, serum inflammatory marker (TGF‐&bgr; and IFN‐&ggr;) and uterine angiogenic status (VEGF and sFlt‐1) at two stages of PE. The administration of SC decreased systolic blood pressure, placental lipid peroxidation product and altered uterine angiogenic status; increased plasma nitric oxide levels in an early and late onset L‐NAME model of PE. In addition, histological findings of SC treated preeclamptic rat placenta support the biochemical findings of this study. Our findings revealed that SC enhanced plasma NO levels and uterine angiogenic status in an L‐NAME model of PE at two gestational stages.

Treatment of Pre-eclampsia: Implementing Research Findings

Pre-eclampsia is a complex disease that affects both mother and their developing fetus. Due to the multifactorial nature of the disease and its undeciphered etiology, we explore the possibility of improving intrinsic vasodilatory mechanisms as a method of treatment. Reduced utero-placental blood flow seems to be central in the manifestation of this disease leading to the secretions of various factors that maintain and/or worsen the condition. We and various other researchers have showed that improved placental perfusion shows promise in alleviating many symptoms of the disease. This serves as an excellent option at reducing both perinatal and maternal morbidity and mortality irrespective of the predisposing factors for the disease.

Association of gene polymorphisms of aldosterone synthase and angiotensin converting enzyme in pre-eclamptic South African Black women

INTRODUCTION The exact cause of preeclampsia (PE) remains elusive. Recently, many researchers have focused on the role of genetic variations in pathogenesis of PE. The renin-angiotensin-aldosterone system is affected in the pathogenesis of PE. OBJECTIVES To determine association of gene polymorphisms of aldosterone synthase (CYP11B2) and angiotensin converting enzyme (ACE) in PE and normotensive South African Black women. METHODS A group of 603 South African Black pregnant women, 246 normotensive and 357 with PE, was recruited. Purified DNA was extracted from venous blood. The distribution and frequencies of gene polymorphisms of CYP11B2 (C-344T) and ACE deletion/insertion (D/I) were determined by real time polymerase chain reaction. RESULTS As the main outcome measure, the risk of C allele for PE was 1.28 (95%CI: 0.94-1.74; p = .1) for all allele comparisons. Thus no significant association with development of PE was observed for the CYP11B2 variants. However, post analysis of the distribution of TT genotypes of CYP11B2 were higher in the HIV uninfected normotensive than in the HIV uninfected PE group (OR: 0.47, 95%CI: 0.27-0.79, p = .0027). The C alleles of late-onset PE and HIV uninfected PE were higher than all normotensive and HIV uninfected normotensive (OR: 1.47, 95%CI: 1.02-2.10, p = .03 and OR: 1.77, 95%CI: 1.13-2.81, p = .0094 respectively). The CT genotype of CYP11B2 was statistically significant between normotensive and PE in HIV uninfected groups (OR: 2.24, 95%CI: 1.28-3.98, p = .0026). There was no significant difference in frequencies of D/I for ACE gene in PE.

Medicine and medical sciences in Africa

The year 2014 is an important year because it will mark the 25th Anniversary of the founding of the African Association of Physiological Sciences (AAPS) and initial talks to launch the International Society for Pathophysiology (ISP). Both these organizations had a foothold in Finland and both occurred during the IUPS Centennial Celebration Congress in 1989. The congress was hosted by the Finnish Physiological Society in Helsinki, Finland in July 1989. For both organizations, Prof OsmoHänninen was instrumental in the launching and inauguration of AAPS and also to initiate the creation of ISP. In order to celebrate the 25th Anniversaries of both organizations it was decided to hold the ISP2014 congress on the African soil. Hence in 2004, at the 4th international congress of AAPS held in Morocco, Wail Benjeloun.the then secretary general of AAPS, submitted successfully a bid to host ISP2014 in Morocco. Following the inauguration of AAPS in Helsinki, the 1st Congress of AAPS was held in Nairobi, Kenya in 1992 where the Constitution of AAPS was drawn up. The Constitution was adopted at the 2nd congress of AAPS in Durban, South Africa in 1997. Following this congress, the next congress, as scheduled, was held in Pretoria, South Africa in 2000. The last congress (6th) of AAPS was held on 1-5 September 2012 in Ismailia, Egypt. This was an historical congress because of many reasons and amongst these was the appointment of Anthony B. Ebeigbe, Department of Physiology, University of Benin, Nigeria as its first Editor-in-Chief of its official journal, the Journal of the African association of Physiological Sciences (JAAPS). He successfully published the first issue in June 2013, as mandated in Ismailia. The Worlds medicine has its initial root in Africa and in fact it was in Memphis, Egypt as early as 2700 BC. During the Ptulomaic period the seat of medicine was in Alexandria, Egypt and Medical knowledge then spread to the Greeks 330 BC. Many western medical scientists acknowledge learning medicine and anatomy form the Egyptian experts. The University of Al Karaouine, in Fez, Morocco, Africa is considered the oldest continuously operating university in the world and has been a center of learning for more than 1,000 years. Medicine in Africa has been acknowledged by many authoritarians to be well developed, long before its development in Greece and other European Countries. Almost every African country has medical and medical sciences societies and associations. According the WHO, African journals online (AJOL) as the worlds largest collection of peer-reviewed journals. It is also believed that Africa will play a major role in Sciences in the future, and in fact one of the Worlds leading palaeo-anthropologist was a South African.

Poor control and management of type 2 diabetes mellitus at an under-resourced South African Hospital: is it a case of clinical inertia?

Evidence shows that even with the implementation of evidence-based medicine, the attainment of optimal glycaemic control is difficult and challenging for both patients and healthcare providers. This study was a one-year retrospective chart review with data collected during the period October 2010 to December 2010 of patients with Type 2 diabetes mellitus (T2DM) who attended the outpatients’ department at the Port Shepstone Regional Hospital (PSRH), South Africa (SA). The total study population was 360 patients with 51% Black African, 32% Indian, 16% White and 1% Coloured. Of the 111 patients’ charts only 78 had two consecutive HbA1c levels recorded. Of the 78/111 patients, only 10 patients had the target HbA1c level of < 7% at visit 1. By visit two, 15.4% (n = 12) had achieved the target HbA1c level. Over the one-year chart review only 3/111 (2.7%) maintained their HbA1c level of < 7% and 5/111 patients whose treatment was revised according to the 2009 SEMDSA guidelines reached HbA1c < 7% by visit 2 whilst 4/111 patients, whose treatment schedule was not modified according to the 2009 SEMDSA guidelines, also reached HbA1c < 7% at visit 2. However, this one-year chart review showed that glycaemia was poorly managed at this hospital, which may be explained by clinical inertia.

The Effect of Angiogenic and Anti-Angiogenic Factors on Urinary Podocyte mRNA Excretion in an Animal Model of Pre-Eclampsia

Objectives: We sought to optimise and validate an L-nitroarginine methyl ester (L NAME) pre-eclamptic model with a focus on the role of serum and renal angiogenic and antiangiogenic factors on urinary podocyte mRNA excretion.