Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: molecular evidence for "placental hyperoxia" in intrauterine growth restriction

Early placental development occurs in an environment of relative hypoxia. Hypoxia promotes angiogenesis and up-regulates vascular endothelial growth factor (VEGF) expression while it down-regulates placenta growth factor (PIGF) that possess 53% homology with VEGF. Morphological studies show poor placental vascular development and an increase in the mitotic index of cytotrophoblasts in intrauterine growth restriction (IUGR). We hypothesized that the reported relatively high oxygen level in the intervillous space in contact with IUGR placental villi will limit angiogenesis by changes in VEGF and PIGF expression and function. Western immunoblot analysis demonstrates a diametric expression of PIGF and VEGF proteins throughout pregnancy with PIGF levels increasing and VEGF levels decreasing, consistent with placental oxygenation. In IUGR placentae, the ratio of PIGF/GAPDH mRNA was increased by 2.3-fold (p < 0.03) and PIGF protein levels were also increased, (p < 0.05) as compared with gestationally-matched normal placentae. PIGF mRNA and protein were localized to the trophoblast bilayer and villous mesenchyme of the human placenta throughout gestation. In vitro studies demonstrated that increasing oxygen tension (hyperoxia) up-regulated PIGF protein in term placental villous explants, whereas hypoxic culture of a term trophoblast choriocarcinoma cell line (BeWo) down-regulated PIGF mRNA and protein and VEGFR-1 (Flt-1) autophosphorylation. The addition of PIGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line stimulated DNA synthesis while PIGF-2 had little effect. VEGF and PIGF exert their biological actions by means of a common receptor VEGFR-1. In the first trimester trophoblast cells, PIGF-1 increased the association of phosphorylated extracellular signal-related kinase (ERK) with VEGFR-1 immunoprecipitates while both PIGF-1 and PIGF-2 also potentiated endogenous VEGF mediated association of phosphorylated extracellular related kinase (ERK) with VEGFR-2 (KDR). More importantly, the addition of PIGF-1 had little effect while PIGF-2 inhibited cell growth in cultured endothelial cells derived from human umbilical vein. Nitric oxide (NO) is reported to promote angiogenesis and PIGF-2 inhibited the basal release of NO from the first trimester trophoblast. The tissue expression and functional studies support the hypothesis of "placental hyperoxia" in early-onset IUGR because hypoxia down-regulates trophoblast PIGF levels, PIGF expression is increased in IUGR, and PIGF-2 inhibits endothelial cell growth. Taken together, these changes provide a cellular explanation for the observed poor angiogenesis in the pathogenesis of IUGR and show that the two PIGF isoforms may modulate trophoblast and endothelial cell function differently, possibly through potentiation of VEGF mediated activation of VEGF-2.     

The Role of Uric Acid in Preeclampsia: Is Uric Acid a Causative Factor or a Sign of Preeclampsia?

Purpose of Review

Because of the significant discrepancies on this topic, this review will focus on the role of uric acid in PE, uric acid as a predictor of preeclampsia and fetal growth retardation. We considered eligible review and original articles relevant to the research question.

Recent Findings

Hypertensive disorders of pregnancy such as preeclampsia (PE) are a major cause of both maternal and fetal morbidity and mortality worldwide. Uric acid has been reported as a key factor contributing to the pathogenesis of PE. Some studies have indicated that serum uric acid levels increase with the severity of PE, while several studies have shown contradictory results. Some studies suggested high uric acid levels lead to PE, while others state that PE causes an increase in uric acid levels.

Summary

Despite the strong association of uric acid in the pathogenesis of preeclampsia, current data is still contradictory hence genetic and high-end laboratory investigations may clarify this enigma.

     

An occult finding in heparin drip order set

Background: In 1998, the Institute of Medicine (IOM) noted that the American healthcare system had many problems. A major concern was the pervasiveness of medical errors. Electronic medical records (EMR) were introduced for myriad of reasons, one being to reduce these errors. Within the EMR, order sets have been shown to reduce variation in clinical practice and improve the quality of care. However, the lack of standardization in these sets enables peculiar orders, such as fecal occult blood test (FOBT) in the heparin drip order set at our hospital, to be surprisingly included. Our study was conducted to evaluate the consequences associated with having FOBT in this order set. Methods: A retrospective study of 898 adult hospitalized patients over a 6-month period, who had a heparin drip ordered at a single academic center, was conducted. The main focus of our study was the 130 patients for whom the FOBT was sent. Results: Fifteen percent (n = 130) of patients started on IV heparin had FOBT sent, of which 33 (25%) came back positive. Approximately one-third (36%) of the positive results were documented by a provider, either in a progress note or discharge summary. In eight instances of a positive FOBT (24%), the heparin drip was stopped. For 10 patients with a positive test (30%), gastroenterology was consulted, and 4 (12%) patients had inpatient endoscopy. Five patients with positive FOBT died while in the hospital (15%) as compared to seven patients (7%) in the negative FOBT group, p < 0.05. Conclusions: Most patients started on heparin did not have FOBT tested, and the results changed management infrequently, even when positive. The regular review of all order sets is imperative to ensure that they remain evidenced-based and sensible.     

Correlation of Ki-67, p53, and Adnab-9 immunohistochemical staining and ploidy with clinical and histopathologic features of severely dysplastic colorectal adenomas

Variations of Ki-67, p53, and Adnab-9 monoclonal antibody reactions in colonic adenomas may be associated with colonic cancer risk. We studied the predictive value of these markers for adverse behavior in severely dysplastic colorectal adenomas, such as an associated carcinoma, multiplicity of adenomas, and subsequent development of adenomas. For this purpose we compared the clinical, gross, and histologic characteristics of highly dysplastic index polyps in 42 patients with Ki 67, p53, and Adnab-9 immunostaining and other molecular markers. Polyps were removed endoscopically, and severely dysplastic polyps were stained immunohistochemically with Ki-67, Adnab-9, and p53 protein by the avidin biotin conjugate (ABC) technique. Quantitative DNA (QDNA) was analyzed by computer-assisted image analysis. Ki-67 immunohistochemistry showed reversal of normal distribution of nuclear staining from the normal basal position to the upper third of the colonic crypts. This abnormality of immunostaining in dysplastic adenomas was the earliest detected by the panel we used. A statistically significant correlation was seen between invasiveness of carcinoma in the index polyp and polyp size (P = 0.003), sessile morphology (P = 0.037), and villous or tubulovillous histology (P = 0.019). In the index adenoma, p53 positivity was correlated with multiplicity at initial examination (P = 0.053), villous histology (P = 0.053), invasiveness of carcinoma (P < 0.003), and recurrence of colorectal adenomas (P = 0.025). Although p53 positivity and aneuploidy were correlated with invasiveness of carcinoma in the index polyp (P = 0.025), Adnab-9 positivity was not. However, Adnab-9 positivity in the index polyp was associated with multiplicity of adenomas (P = 0.04) as well as recurrence of adenomas (P < 0.024). In conclusion, in addition to the morphologic and histologic markers already known, Ki-67, Adnab-9 antibody, and p53 protein may be prognostic indicators useful in follow-up of patients with severely dysplastic colorectal adenomas. Adnab-9 antibody may identify a field defect in above-average-risk adenoma-bearing patients.     

Effects of chloroquine, amodiaquine and pyrimethamine-sulfadoxine on Plasmodium falciparum gametocytemia

The effects of chloroquine, amodiaquine and pyrimethamine-sulfadoxine (SP) (Fansidar) on the infection rate and density of Plasmodium falciparum gametocytes were studied in 198 patients with falciparum malaria from an area in the Punjab where malaria is endemic but seasonally transmitted. One month following treatment of 100 patients, SP had reduced the gametocyte carrier rate from 37% to 6% and the mean gametocyte density from 80 to 1.4 per mm3 of blood. Chloroquine and amodiaquine were much less effective. Since SP has no gametocytocidal properties and the reduction in gametocytes coincided with clearance of asexual parasitemias, gametocytes were probably reduced subsequent to the cure of the asexual malaria infections. If used during the nontransmission season, SP might be an effective component of an integrated program for reducing malaria transmission in the Punjab and other areas where 4-aminoquinoline-resistant and SP-sensitive falciparum malaria exists.     

Patients' perspectives on the management of emotional distress in primary care settings

Objective  To investigate how important treatment for emotional distress is to primary care patients in general and to primary care patients with depression, and to evaluate the types of mental health interventions they desire. Design  Patient surveys. Setting  Five private primary care practices. Measurements and main results  Patients' desire for treatment of emotional distress and for specific types of mental health interventions were measured, as well as patients' ratings of the impact of emotional distress, the frequency of depressive symptoms, and mental health functioning. Of the 403 patients, 33% felt that it was “somewhat important” and 30% thought it was “extremely important” that their physician tries to help them with their emotional distress. Patient desire for this help was significantly related to a diagnosis of depression (P<.001), perceptions about the impact of emotional distress (p<.001), and mental health functioning (p<.001). Among patients with presumptive diagnoses of major and minor depression, 84% and 79%, respectively, felt that it was at least somewhat important that they receive this help from their physician. Sixty-one percent of all primary care patients surveyed and 89% of depressed patients desired counseling; 23% of all patients and 33% of depressed patients wanted a medication; and 11% of all patients and 5% of depressed patients desired a referral to a mental health specialist. Conclusions  A majority of these primary care patients and almost all of the depressed patients felt that it was at least somewhat important to receive help from their physician for emotional distress. The desire for this help seems to be related to the severity of the mental health problem. Most of the patients wanted counseling, but relatively few desired a referral to a mental health specialist. Funded by grant R01 MH51067 from the National Institute of Mental Health.