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Morphometric comparisons of term placentae from normotensive and pre-eclamptic pregnancies suggest maladaptations of the fetal component of the placenta in pre-eclampsia.Ducray, Jennifer Frances. January 2012 (has links)
Adequate maternal, intervillous and fetal blood flow are all necessary for fetal wellbeing.
Compromise to any part of this exchange would be detrimental to pregnancy outcome. Preeclampsia
is associated with reduced maternal spiral artery flow, resulting in reduced placental
perfusion. This in turn creates an ischemic environment which may pre-dispose morphological
changes in placental villi. This pilot study utilized morphometric image analysis to examine
some features of the fetal component of the placenta in normotensive (NT) and pre-eclamptic
(PE) groups. The features examined included: density of placental villi (expressed as
percentage of field area occupied by placental tissue); stem vessel carrying capacity
(expressed as percentage of stem villus area occupied by vessel lumina); the thickness of the
stem arterial walls relative to artery size (expressed as percentage of artery area occupied by
arterial wall) and the extent of fibrosis associated with villi (expressed as percentage of field
area occupied by fibrosis). The results were as follows: density of placental villus arrangement
NT:51.89±6.19, PE:64.78±6.93 (P<0.001); carrying capacity of stem villi NT:17.20±11.78,
PE:8.67±8.51 (P<0.001); relative thickness of stem villi arterial walls NT:74.08±12.92, PE:
86.85±10.55 (P<0.001); and extent of fibrosis NT:0.727±0.310, PE:1.582±0.707 (P<0.001).
These significant differences between normotensive and pre-eclamptic placentae suggest
possible fetal maladaptations in response to the intervillous ischemia, compounding the
existing maternal compromise to materno-fetal exchange. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2012.
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The role of leptin in HIV associated pre-eclampsia.Haffejee, Firoza. January 2013 (has links)
HIV and hypertensive disorders in pregnancy, in particular pre-eclampsia, are the main causes of maternal mortality in South Africa. In HIV associated pre-eclampsia, it is biologically plausible that the immune activation associated with pre-eclampsia may be neutralised by the immune suppression of HIV infection. The precise aetiology of pre-eclampsia is unknown, however leptin has been implicated in its development. Leptin is an adipocyte hormone, also produced by the placenta. It has a role in the development of inflammation. Adipose tissue is reduced in HIV infected individuals, resulting in lower leptin levels with consequent impaired immune function. This study aimed to compare serum and placental leptin levels in HIV infected and uninfected normotensive and pre-eclamptic pregnancies. Since insulin levels may affect the secretion of leptin, the study also compared insulin levels in these pregnancies.
Following ethical clearance and hospital permission, 180 participants were recruited during their antenatal period. The groups were HIV- normotensive (n = 30), HIV+ normotensive (n = 60), HIV– pre-eclamptic (n = 30) and HIV+ pre-eclamptic (n = 60). Blood samples were collected ante-natally and placental samples post delivery. Serum leptin and insulin levels were determined by ELISA. Placental leptin levels were determined by ELISA and immunohistochemistry with morphometric image analysis. The placental production of leptin was determined by RT PCR. There was a non-significant increase in serum leptin levels in HIV- pre-eclampsia compared to HIV- normotensive pregnancies (p = 0.42). However leptin was decreased significantly in HIV+ pre-eclampsia compared to HIV- normotensive (p = 0.03). Based on HIV status leptin levels were decreased in HIV+ groups compared to HIV- groups in both pre-eclamptic (p < 0.01) and normotensive pregnancies (p < 0.01). Insulin levels of the HIV positive groups were lower than those of the HIV negative groups (p < 0.001). Insulin levels were also decreased in pre-eclampsia compared to normotensive pregnancies, irrespective of HIV status (p = 0.02).
Immunohistochemistry demonstrated an increase in immuno-reactivity of leptin in the exchange villi of pre-eclamptic compared to normotensive placentae, irrespective of HIV status (p < 0.001). Supporting this finding, ELISA also demonstrated elevated leptin levels in the placenta of pre-eclamptic compared to normotensive pregnancies (p < 0.001). Placental leptin levels were similar in both HIV positive and negative pregnancies (p = 0.36). However, the placental leptin mRNA expression was up-regulated in HIV negative pre-eclampsia (p = 0.04) but not in HIV positive pre-eclampsia (p = 1.00).
In conclusion, the elevated placental leptin in pre-eclampsia, irrespective of HIV status, is consistent with hypoxia. These elevated levels are not reflected in the maternal serum which raises the possibility of decreased leptin expression by adipose tissue especially in HIV infection where serum leptin levels are decreased. This would negate the increased placental leptin expression in pre-eclampsia. Furthermore, the elevated placental leptin levels are suggestive of an autocrine role of leptin in the placenta. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2013.
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The spectrum of HIV related nephropathy in KwaZulu-Natal : a pathogenetic appraisal and impact of HAART.Ramsuran, Duran. January 2012 (has links)
Sub-Saharan Africa bears 70% of the global HIV burden with KwaZulu-Natal (KZN) identified as
the epicenter of this pandemic. HIV related nephropathy (HIVRN) exceeds any other causes of
kidney diseases responsible for end stage renal disease, and has been increasingly recognized as a
significant cause of morbidity and mortality. There is nonetheless a general lack of surveillance
and reporting for HIVRN exists in this geographical region. Consequentially, the aim of this study
was to outline the histopathogical spectrum of HIVRN within KZN. Moreover, from a pathology
standpoint, it is important to address whether HIVRN was a direct consequence of viral infection
of the renal parenchyma or is it a secondary consequence of systemic infection. Additionally, an
evaluation of the efficacy of Highly Active Anti-Retroviral Therapy (HAART) in combination
with angiotensin converting enzyme inhibitors (ACE-I) was performed via a genetic appraisal of
localized replication of HIV-1 in the kidney, ultrastructural review and immunocytochemical
expression of a podocyte maturity and proliferation marker pre and post-HAART.
Blood and renal biopsies were obtained from 30 children with HIV related nephropathy pre-
HAART, followed-up clinically for a period of 1 year. This cohort formed the post-HAART
group. Clinical and demographic data were collated and histopathology, RT-PCR, sequencing,
immunocytochemistry and transmission electron microscopy was performed.
The commonest histopathological form of HIVRN in children (n = 30) in KZN was classical focal
segmental glomerular sclerosis (FSGS) presented in 13(43.33%); mesangial hypercellularity
10(30%); mesangial, HIV associated nephropathy 3(11%) and minimal change disease 2(6.67%).
Post-HAART (n = 9) the predominant pathology was mesangial hypercellularity 5(55.56%); FSGS
3(33.33%) and sclerosing glomerulopathy 1(11.11%). This study also provides data on the
efficacy of HAART combined with ACE-I. The immunostaining pattern of synaptopodin, Ki67
and p24 within the glomerulus expressed as a mean field area percentage was significantly downregulated
in the pre-HAART compared to the post-HAART group respectively (1.14 vs. 4.47%, p
= 0.0068; 1.01 vs.4.68, p < 0.001; 4.5% vs 1.4%, p = 0.0035). The ultrastructural assessment of all
biopsies conformed to their pathological appraisal however, features consistent with viral insult
were observed. Latent HIV reservoirs were observed within the podocyte cytoplasm but was
absent in mesangial or endothelial cells. Real-Time polymerase chain reaction assays provided
evidence of HIV-1 within the kidney. Sequence analysis of the C2-C5 region of HIV-1 env
revealed viral diversity between renal tissue to blood.
In contrast to a collapsing type of FSGS that occurs in adults, the spectrum of paediatric
nephropathy in treatment-naive children within KwaZulu-Natal was FSGS with mesangial
hypercellularity. Additionally, our study demonstrates podocyte phenotype dysregulation pre-
HAART and reconstitution post therapy. Evidence of ultrastructural viral reservoirs within
epithelial cells is supported by a genetic appraisal confirming the ubiquitous presence of HIV DNA
in renal tissue. Moreover, sequence analysis showed viral evolution and compartmentalization
between renal viral reservoirs to blood. Finally, the interplay of viral genes and host response,
influenced by genetic background, may contribute to the variable manifestations of HIV-1
infection in the kidney in our paediatric population. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2012.
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The role of soluble FMS-like tyrosine-kinase-1, vascular endothelial growth factor and placental growth factor in HIV associated pre-eclamptic pregnancies : a South African perspective.Govender, Nalini. January 2013 (has links)
Introduction and aims.
South Africa is the epicenter of the HIV/AIDS pandemic. Hypertensive disorders of pregnancy
(15.7%) are the second cause of maternal deaths of which pre-eclampsia represents 83%. Normal
pregnancy requires a balance between pro- and anti-angiogenic factors to necessitate effective
vasculogenesis, angiogenesis and placental development, however, pre-eclampsia is characterised
by an excess anti-angiogenic state. The hypoxic placenta releases excess anti-angiogenic factors
into the maternal circulation causing endothelial dysfunction. However, there is no data to verify
if HIV infection affects pre-eclampsia, or if the angiogenic imbalance is affected. Contradictory
data exists on the association between HIV infection and pre-eclampsia. In an attempt to assess
the role of HIV infection in pre-eclampsia, this study examined the immunolocalisation of sFlt-1,
sEng, PlGF and VEGF in placentae of HIV negative and positive normotensive and pre-eclamptic
pregnancies at term using immunohistochemistry (IHC) and immunoelectron microscopy (IEM).
Additionally, we estimated the placental expression of sFlt-1, sEng, PlGF and VEGF to verify if
the HIV negative differed from the HIV positive cohorts. We further evaluated the maternal
serum to determine if variations existed in the circulating levels of these factors in HIV negative
and positive normotensive and pre-eclamptic pregnancies.
Methods.
Following institutional ethical approval and informed consent, placental biopsies and maternal
serum were collected post-delivery. For IHC and IEM, 130 and 25 placentae were evaluated,
respectively. Following conventional immunohistochemical processing, 5μm sections were
immunostained & immunoexpression of the various antibodies were evaluated with the Zeiss
Axioscope A1 interfaced with an AxioVision Image analysis software package (version 4.8.3) in
combination with the auto-measurement module (Carl Zeiss, Germany). Post-conventional
immunoelectron processing, ultra-thin sections were immunolabelled. Sections were post-fixed,
contrast enhanced with uranyl acetate and Reynolds lead citrate and viewed on a Jeol 1011
Transmission Electron Microscope. Additionally, the placental expressions of these factors were
assessed using RT-PCR. In an attempt to confirm if maternal circulating levels of these factors
differed, we quantitatively evaluated these factors in serum from HIV negative normotensives,
HIV negative pre-eclamptics, HIV positive normotensives, and HIV positive pre-eclamptics using
ELISA techniques.
Results and Discussion.
The expression of sFlt-1, sEng, PlGF and VEGF was confirmed using immunohistochemistry,
RT-PCR and ELISAs. Irrespective of the HIV status, sFlt-1 and sEng was elevated with the
concomitant reduction in PlGF in pre-eclamptic compared to normotensive pregnancies. The
levels of VEGF were however undetectable across all study groups. It is plausible that this lack of
effect of HIV status on the factors under study may be attributed to the treatment regimen as
HAART is known to restore the immune response of HIV positive preeclamptic women.
However, a concise anti-retroviral treatment history in our study was unavailable.
Additionally, this study is novel in that it ultrastructurally immunolocalises sFlt-1, sEng, PlGF and
VEGF within the placenta. This immunoelectron localisation data corresponds to our
immunohistochemical data. Our study further demonstrates strong immunoreactivity of both
placental sFlt-1 and sEng in pre-eclampsia with concurrent elevations in the maternal circulation.
A qualitative increase in the occurrence of syncytial knots in the pre-eclamptics compared to the
normotensive pregnancies was noted. These observations support the detachment of antixxx
angiogenic rich microparticles from syncytial knots in the pre-eclamptics compared to the
normotensive pregnancies was noted. These observations support the detachment of antiangiogenic rich microparticles from syncytial knots and their subsequent deportation and elevation
in the maternal circulation. Moreover, their consequent antagonistic effects on VEGF, PlGF and
TGF-β, disrupts the vascular endothelial maintenance.
The strong immunoreactivity of sFlt-1, sEng, PlGF and VEGF was observed in villous endothelial
cells. Moreover, a strong sFlt-1 and sEng but a weak PlGF and VEGF immunoreactivity was
noted in syncytio- and cytotrophoblasts. This immunoexpression within trophoblasts is suggestive
of their autocrine mode of action on normal trophoblast functions including invasion,
differentiation and production. It is plausible that the angiogenic imbalance observed in our study,
will impact on placental function, by modifying trophoblast activity thereby contributing to
abnormal placentation.
Conclusion.
Our study supports the hypothesis that pre-eclampsia is characterized by an imbalance between
pro- and anti-angiogenic factors. Whether the pregnancy is complicated by immune
insufficiencies or not, does not affect the role of the anti-angiogenic factors in pre-eclampsia
development. Nevertheless, the neutralising effect of HIV infection on the immune system may
be insufficient in the development of pre-eclampsia. To our knowledge, the quantification of
serum pro-/anti-angiogenic factors in HIV-associated pre-eclampsia is novel. In conclusion, our
data reinforces the hypothesis that increased concentrations of sFlt-1 and sEng are involved in the
pathogenesis of pre-eclampsia and indicates their possible use as discriminatory factors between
diseases. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2013.
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