Bone Absorptiometry in Metabolic Bone Disease: Baseline Values and Long-Term Treatment with Calcitriol (Post-Menopausal Osteoporosis Versus Osteomalacia)

Total body bone absorptiometry reveals low mineral density in both postmenopausal osteoporosis and osteomalacia patients. The method was used to investigate the effect of calcitriol administration on patients suffering from one of these conditions. In osteomalacia, the administration of calcitriol resulted in a dramatic improvement in bone mineral density (sometimes up to 50% in 12 months), indicating the rapid mineralization of previously uncalcified bone tissue as a result of the normalization of the Ca x P product. In osteoporosis a similar treatment was seen to halt the progressive decrease in bone mineral levels and sometimes resulted in minor increases in density (up to 5%). This is likely to be due to a normalization of intestinal calcium malabsorption which halts secondary homeostatic bone resorption

The double life of MULE in preeclamptic and IUGR placentae

The E3 ubiquitin ligase MULE (Mcl-1 Ubiquitin Ligases E3) targets myeloid cell leukemia factor 1 (Mcl-1) and tumor suppressor p53 for proteasomal degradation. Although Mcl-1 and p53 have been implicated in trophoblast cell death in preeclampsia (PE) and intrauterine growth restriction (IUGR), the mechanisms regulating their expression in the human placenta remains elusive. Herein, we investigated MULE's involvement in regulating Mcl-1 and p53 degradation during normal and abnormal (PE, IUGR) placental development. MULE expression peaked at 5–7 weeks of gestation, when oxygen tension is low and inversely correlated with that of Mcl-1 and p53. MULE efficiently bound to Mcl-1 and p53 and regulated their ubiquitination during placental development. Exposure of first trimester villous explants to 3% O2 resulted in elevated MULE expression compared with 20% O2. Low-oxygen-induced MULE expression in JEG3 choriocarcinoma cells was abolished by hypoxia-inducible factor (HIF)-1α siRNA. MULE was overexpressed in both PE and IUGR placentae. In PE, MULE preferentially targeted p53 for degradation, allowing accumulation of pro-apoptotic Mcl-1 isoforms. In IUGR, however, MULE targeted pro-survival Mcl-1, allowing p53 to accumulate and exert its apoptotic function. These data demonstrate that oxygen regulates Mcl-1 and p53 stability during placentation via HIF-1-controlled MULE expression. The different preferential targets of MULE in PE and IUGR placentae classify early-onset PE and IUGR as distinct molecular pathologies

Ceramide-induced BOK promotes mitochondrial fission in preeclampsia

Mitochondria are in a constant balance of fusing and dividing in response to cellular cues. Fusion creates healthy mitochondria, whereas fission results in removal of non-functional organelles. Changes in mitochondrial dynamics typify several human diseases. However, the contribution of mitochondrial dynamics to preeclampsia, a hypertensive disorder of pregnancy characterized by placental cell autophagy and death, remains unknown. Herein, we show that the mitochondrial dynamic balance in preeclamptic placentae is tilted toward fission (increased DRP1 expression/activation and decreased OPA1 expression). Increased phosphorylation of DRP1 (p-DRP1) in mitochondrial isolates from preeclamptic placentae and transmission electron microscopy corroborated augmented mitochondrial fragmentation in cytotrophoblast cells of PE placentae. Increased fission was accompanied by build-up of ceramides (CERs) in mitochondria from preeclamptic placentae relative to controls. Treatment of human choriocarcinoma JEG3 cells and primary isolated cytrophoblast cells with CER 16:0 enhanced mitochondrial fission. Loss- and gain-of-function experiments showed that Bcl-2 member BOK, whose expression is increased by CER, positively regulated p-DRP1/DRP1 and MFN2 expression, and localized mitochondrial fission events to the ER/MAM compartments. We also identified that the BH3 and transmembrane domains of BOK were vital for BOK regulation of fission. Moreover, we found that full-length PTEN-induced putative kinase 1 (PINK1) and Parkin, were elevated in mitochondria from PE placentae, implicating mitophagy as the process that degrades excess mitochondria fragments produced from CER/BOK-induced fission in preeclampsia. In summary, our study uncovered a novel CER/BOK-induced regulation of mitochondrial fission and its functional consequence for heightened trophoblast cell autophagy in preeclampsia

A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia

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Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies

BACKGROUND: The pathogenesis of preeclampsia, a serious pregnancy disorder, is still elusive and its treatment empirical. Hypoxia Inducible Factor-1 (HIF-1) is crucial for placental development and early detection of aberrant regulatory mechanisms of HIF-1 could impact on the diagnosis and management of preeclampsia. HIF-1α stability is controlled by O(2)-sensing enzymes including prolyl hydroxylases (PHDs), Factor Inhibiting HIF (FIH), and E3 ligases Seven In Absentia Homologues (SIAHs). Here we investigated early- (E-PE) and late-onset (L-PE) human preeclamptic placentae and their ability to sense changes in oxygen tension occurring during normal placental development. METHODS AND FINDINGS: Expression of PHD2, FIH and SIAHs were significantly down-regulated in E-PE compared to control and L-PE placentae, while HIF-1α levels were increased. PHD3 expression was increased due to decreased FIH levels as demonstrated by siRNA FIH knockdown experiments in trophoblastic JEG-3 cells. E-PE tissues had markedly diminished HIF-1α hydroxylation at proline residues 402 and 564 as assessed with monoclonal antibodies raised against hydroxylated HIF-1α P402 or P564, suggesting regulation by PHD2 and not PHD3. Culturing villous explants under varying oxygen tensions revealed that E-PE, but not L-PE, placentae were unable to regulate HIF-1α levels because PHD2, FIH and SIAHs did not sense a hypoxic environment. CONCLUSION: Disruption of oxygen sensing in E-PE vs. L-PE and control placentae is the first molecular evidence of the existence of two distinct preeclamptic diseases and the unique molecular O(2)-sensing signature of E-PE placentae may be of diagnostic value when assessing high risk pregnancies and their severity

Polymorphisms in the hypoxia-inducible factor 1 alpha gene in Mexican patients with preeclampsia: A case-control study

<p>Abstract</p> <p>Background</p> <p>Although the etiology of preeclampsia is still unclear, recent work suggests that changes in circulating angiogenic factors play a key role in its pathogenesis. In the trophoblast of women with preeclampsia, hypoxia-inducible factor 1 alpha (HIF-1α) is over-expressed, and induces the expression of non-angiogenic factors and inhibitors of trophoblast differentiation. This observation prompted the study of HIF-1α and its relation to preeclampsia. It has been described that the C1772T (P582S) and G1790A (A588T) polymorphisms of the <it>HIF1A </it>gene have significantly greater transcriptional activity, correlated with an increased expression of their proteins, than the wild-type sequence. In this work, we studied whether either or both <it>HIF1A </it>variants contribute to preeclampsia susceptibility.</p> <p>Results</p> <p>Genomic DNA was isolated from 150 preeclamptic and 105 healthy pregnant women. Exon 12 of the <it>HIF1A </it>gene was amplified by PCR, and the genotypes of <it>HIF1A </it>were determined by DNA sequencing.</p> <p>In preeclamptic women and controls, the frequencies of the T allele for C1772T were 4.3 vs. 4.8%, and the frequencies of the A allele for G1790A were 0.0 vs. 0.5%, respectively. No significant differences were found between groups.</p> <p>Conclusion</p> <p>The frequency of the C1772T and G1790A polymorphisms of the <it>HIF1A </it>gene is very low, and neither polymorphism is associated with the development of preeclampsia in the Mexican population.</p

Sense of place in the changing process of house form: Case studies from Ankara, Turkey

This paper aims to investigate the impact of typomorphological changes of residential environments on residents’ sense of place’. Seven housing developments representing different types introduced in Ankara, Turkey since the late 19th-century are selected as case studies. Their morphological characters at the building, street and neighbourhood scales are examined, and typological transformations among the cases in terms of the degrees of continuity are identified. The paper proposes a conceptual model consisting of ten indicators to assess sense of place at the building, street and neighbourhood scales of the residents of the seven cases. The scores of sense of place are generated through structured interviews with the residents and analysed in SPSS. The results show that sense of place is negatively affected by typomorphological changes over time, particularly when mutational changes occur. Continuity in typomorphological transformation helps to maintain sense of place at a desirable level. Furthermore, physical changes at the street and neighbourhood scales have larger impact on sense of place than that at the building scale. The research thus suggests that planning and design should be responsive to traditional types in residential development, particularly at the street and neighbourhood scales to maintain residents’ sense of place

Towards analytical typologies of plot systems: quantitative profile of five European cities

The importance of the plot (also referred to as ‘property’) as one of the fundamental elements of urban form is well recognized within the field of urban morphology. Despite the fact that it is often described as the basic element in the pattern of land divisions, which are essential as organizational frameworks for urban form, studies offering comprehensive descriptions and classifications of plot systems are quite scant. The aim of the paper is to introduce a classification of plot systems into typologies based on five European cities, in order to distinguish particular spatial differences and similarities in terms of their plot structure. The proposed typologies are developed using unsupervised k-means cluster analysis based on numeric attributes derived from central theories in urban morphology. The introduced typologies are essentially configurational, allowing collective systematic properties of plot systems to be captured. Numeric attributes include plot differentiation (or plot size), plot frontage and compactness ratio, corresponding to essential qualities of plot systems such as the capacity to carry differences in space, the ability to operate as interface between street and building and providing a framework for evolution of built form over time. All three attributes are translated into configurational measures in order to capture the context of the plot system, rather than the parameters of individual plots. The combination of these deductively defined variables with algorithmically defined classification methods results in seven plot types that can be used to scale up traditional urban morphological analysis to whole city regions and conduct substantial comparison of patterns within, but also between these regions. Further, it also makes it possible to describe commonly recognized plot patterns and discover new ones

Cell Free Expression of hif1α and p21 in Maternal Peripheral Blood as a Marker for Preeclampsia and Fetal Growth Restriction

Preeclampsia, a severe unpredictable complication of pregnancy, occurs in 6% of pregnancies, usually in the second or third trimester. The specific etiology of preeclampsia remains unclear, although the pathophysiological hallmark of this condition appears to be an inadequate blood supply to the placenta. As a result of the impaired placental blood flow, intrauterine growth restriction (IUGR) and consequential fetal oxidative stress may occur. Consistent with this view, pregnancies complicated by preeclampsia and IUGR are characterized by up-regulation of key transcriptional regulators of the hypoxic response including, hif1α and as well as p53 and its target genes. Recently, the presence of circulating cell-free fetal RNA has been documented in maternal plasma. We speculated that pregnancies complicated by preeclampsia and IUGR, will be associated with an abnormal expression of p53 and/or hif1α related genes in the maternal plasma. Maternal plasma from 113 singleton pregnancies (72 normal and 41 complicated pregnancies) and 19 twins (9 normal and 10 complicated pregnancies) were collected and cell free RNA was extracted. The expression of 18 genes was measured by one step real-time RT-PCR and was analyzed for prevalence of positive/negative expression levels. Results indicate that, among the genes examined, cell free plasma expressions of p21 and hif1α were more prevalent in pregnancies complicated by hypoxia and/or IUGR (p<0.001). To conclude, we present in this manuscript data to support the association between two possible surrogate markers of hypoxia and common complications of pregnancy. More work is needed in order to implement these findings in clinical practice

Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy

In the first trimester the extravillous cytotrophoblast cells occlude the uterine spiral arterioles creating a low oxygen environment early in pregnancy, which is essential for pregnancy success. Paradoxically, shallow trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester may result in impaired placental perfusion and chronic placental ischemia and hypoxia later in gestation leading to adverse pregnancy outcomes. The hypoxia inducible factors (HIFs) are key mediators of the response to low oxygen. We aimed to elucidate mechanisms of regulation of HIFs and the role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. The Pubmed database was consulted for identification of the most relevant published articles. Search terms used were oxygen, placenta, trophoblast, pregnancy, HIF and hypoxia. The HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate supply of blood and oxygen to the placenta) and in pathological pregnancies complicated by placental hypoxia/ischemia. During normal pregnancy HIFs may respond to complex alterations in oxygen, hormones, cytokines and growth factors to regulate placental invasion, differentiation, transport and vascularization. In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes