The pleiotropic function of PPAR gamma in the placenta

At different stages of placental development the cytotrophoblasts differentiate into specialized cells that are vital for specific placental tasks. These types include the invasive trophoblasts, which are responsible for invasion of the placenta into the uterine wall, and syncytiotrophoblasts, which form a barrier between the maternal and fetal circulations, govern trans-placental transport of gas, nutrient and waste, and produce placental hormones. Recent research illuminated the role of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) in the areas of adipocyte and macrophage biology, insulin action, bioenergetics and inflammation. It was somewhat surprising that PPAR gamma was also found to play a pivotal role in placental biology. In this review we summarize recent data, which show that PPAR gamma is expressed in the placenta, particularly in trophoblasts, and is essential for placental development, trophoblast invasion, differentiation of cytotrophoblasts into syncytium, and regulation of fat accumulation in trophoblasts. PPAR gamma may also play a role in modulating fetal membrane signals toward parturition. The data presented here underscore the need for a focused investigation of the unique aspects of PPAR gamma function in trophoblasts, which may have direct implications for the use of PPAR gamma ligands during pregnancy.     

Diagnosis of normocalcemic hyperparathyroidism by oral calcium loading test

We evaluated the oral calcium-loading test (OCLT) in diagnosing normocalcemic primary hyperparathyroidism. Calcium and PTH levels were measured before, 60, 120 and 180 min after oral 1 g of calcium gluconolactate administration in 102 consecutive females with high circulating PTH levels, and 25 controls. Patients were classified as follows: Group A, patients with a parathyroid adenoma identified by two imaging modalities. Sub-Group AO, hyperparathyroid patients [no.=13, mean age 59 yr (SD=10)] evaluated prior to parathyroidectomy. Sub-Group AH, non-operated hypercalcemic patients [no.=29, age 63 yr (SD=11)]. Sub-Group AN, normocalcemic non-operated women [no.=14, age 59 yr (SD=8)]. Group B, normocalcemic individuals [no.=46, age 58 yr (SD=11)] with negative parathyroid imaging. Group C, control patients [no.= 25, age 56 yr (SD=12)]. The concentrations of calcium and PTH overlapped in the normocalcemic groups during the OCLT. Product P, defined as circulating PTH nadir (pg/ml) x peak calcium concentration (mg/dl), better discriminated Sub-Group AN from Group B, AUC=0.98 (95% CI 0.95, 1.00) than did Ratio R, defined as relative PTH decline/relative calcium increment, AUC= 0.86 (95%CI 0.73, 0.99). Assuming normal threshold of Product P and Ratio R at 260 and 17 respectively, the combined parameters diagnose normocalcemic hyperparathyroid patients with 100% sensitivity and 87% specificity.     

Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer

Targeting of the nuclear prostaglandin receptor peroxisome proliferator-activated receptor delta (PPARdelta) by homologous recombination results in placental defects and frequent (>90%) midgestation lethality. Surviving PPARdelta(-/-) mice exhibit a striking reduction in adiposity relative to wild-type levels. This effect is not reproduced in mice harboring an adipose tissue-specific deletion of PPARdelta, and thus likely reflects peripheral PPARdelta functions in systemic lipid metabolism. Finally, we observe that PPARdelta is dispensable for polyp formation in the intestine and colon of APC(min) mice, inconsistent with its recently proposed role in the establishment of colorectal tumors. Together, these observations reveal specific roles for PPARdelta in embryo development and adipocyte physiology, but not cancer.     

Clopidogrel resistance--the cardiologist's perspective

Platelet activation and aggregation play a major role in the pathogenesis of acute coronary syndromes. While clopidogrel has convincingly been shown to reduce atherothrombotic events in patients with acute coronary syndromes, and following percutaneous coronary interventions (PCI), a significant portion of patients continue to suffer cardiovascular events. A growing body of literature suggests that at least part of this treatment failure can be attributed to resistance to anti-thrombotic treatment in these patients. The purpose of this review is to clarify the current knowledge regarding clopidogrel resistance.     

Alloimmunization to transfused HOD red blood cells is not increased in mice with sickle cell disease

BACKGROUND: Increased rates of red blood cell (RBC) alloimmunization in patients with sickle cell disease may be due to transfusion frequency, genetic predisposition, or immune dysregulation. To test the hypothesis that sickle cell pathophysiology influences RBC alloimmunization, we utilized two transgenic mouse models of sickle cell disease. STUDY DESIGN AND METHODS: Transgenic sickle mice, which express human α and β^S globin, were transfused with fresh or 14‐day‐stored RBCs containing the HOD (hen egg lysozyme, ovalbumin, and human Duffy^b) antigen; some recipients were inflamed with poly(I : C) before transfusion. Anti‐HOD alloantibody responses were subsequently measured by enzyme‐linked immunosorbent assay and flow crossmatch; a cohort of recipients had posttransfusion serum cytokines measured by bead array. RESULTS: Both Berkeley and Townes homozygous (SS) and heterozygous (AS) mice had similar rates and magnitude of anti‐HOD RBC alloimmunization after fresh HOD RBC transfusion compared with control animals; under no tested condition did homozygous SS recipients make higher levels of alloantibodies than control animals. Unexpectedly, homozygous SS recipients had blunted cytokine responses and lower levels of anti‐HOD alloantibodies after transfusion of 14‐day stored RBCs, compared with control animals. CONCLUSIONS: In sum, homozygous β^S expression and the ensuing disease state are not alone sufficient to enhance RBC alloimmunization to transfused HOD RBCs in two distinct humanized murine models of sickle cell disease under the conditions examined. These data suggest that other factors may contribute to the high rates of RBC alloimmunization observed in humans with sickle cell disease.     

The significance of persistent ST elevation versus early resolution of ST segment elevation after primary PTCA

OBJECTIVES

To determine the prevalence and clinical significance of early ST segment elevation resolution after primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI).

BACKGROUND

Despite angiographically successful restoration of coronary flow early during AMI, adequate myocardial reperfusion might not occur in a substantial portion of the jeopardized myocardium due to microvascular damage. This phenomenon comprises the potentially beneficial effect of early recanalization of the infarct related artery (IRA).

METHODS

Included in the study were 117 consecutive patients who underwent angiographically successful [Thrombolysis in Myocardial Infarction (TIMI III)] primary PTCA. The patients were classified based on the presence or absence of reduction ≥50% in ST segment elevation in an ECG performed immediately upon return to the intensive cardiac care unit after the PTCA in comparison with ECG before the intervention.

RESULTS

Eighty-nine patients (76%) had early ST segment elevation resolution (Group A) and 28 patients (24%) did not (Group B). Group A and B had similar clinical and hemodynamic features before referring to primary PTCA, as well as similar angiographic results. Despite this, ST segment elevation resolution was associated with better predischarge left ventricular ejection fraction (LVEF) (44.7 ± 8.0 vs. 38.2 ± 8.5, p < 0.01). Group B patients, as compared with those of Group A, had a higher incidence of in-hospital mortality (11% vs. 2%, p = 0.088), congestive heart failure (CHF) [28% vs. 19%, odds ratio (OR) = 4, 95% confidence interval (CI) 1 to 15, p = 0.04], higher long-term mortality (OR = 7.3, 95% CI 1.9 to 28, p = 0.004 with Cox proportional hazard regression analysis) and long-term CHF rate (OR = 6.5, 95% CI 1.3 to 33, p = 0.016 with logistic regression).

CONCLUSIONS

Absence of early ST segment elevation resolution after angiographically successful primary PTCA identifies patients who are less likely to benefit from the early restoration of flow in the IRA, probably because of microvascular damage and subsequently less myocardial salvage.     

Efficacy of a two-hour infusion of 150-mg tissue plasminogen activator in acute myocardial infarction

Forty-two patients with acute myocardial infarction received 150-mg recombinant human tissue-type plasminogen activator (rt-PA) at 2.3 +/- 1.2 hours after the onset of chest pain. After a 40 U/kg bolus of heparin, rt-PA was given as a 10-mg bolus followed by a 2-hour continuous infusion of 90 mg in the first hour and 50 mg in the second hour. Nonangiographic signs of reperfusion occurred during treatment (41 +/- 21 minutes) in 35 patients and in 1 other patient about 30 minutes after rt-PA. Three patients had discordant nonangiographic signs of reperfusion, 2 patients had no evidence of reperfusion and 1 patient in cardiogenic shock died before completion of the rt-PA infusion and before reperfusion status could be ascertained. Clinical signs of early reocclusion occurred in 4 of the 36 patients with evidence of reperfusion, 3 of whom were retreated with rt-PA with clinical success in 2. Coronary angiography 10 +/- 8 hours later revealed a patent artery of infarction in 35 patients: 32 with nonangiographic signs of sustained reperfusion, both patients with successfully treated reocclusion and 1 of 3 patients with discordant signs of reperfusion. Angiography revealed evidence of partial reperfusion in the remaining 2 patients with discordant signs, and an occluded artery was found in both patients without any evidence of reperfusion and in both patients with clinical signs of persistent reocclusion. Hemorrhagic complications occurred in 9 patients, 7 were related to procedural trauma and 2 patients required a blood transfusion. Four patients died, each of a cardiac cause: 3 in hospital and 1 at home.(ABSTRACT TRUNCATED AT 250 WORDS)     

The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice

The miR-17-92 cluster and its 6 encoded miRNAs are frequently amplified and aberrantly expressed in various malignancies. This study demonstrates that retroviral-mediated miR-17-92 overexpression promotes expansion of multipotent hematopoietic progenitors in mice. Cell lines derived from these miR-17-92-overexpressing mice are capable of myeloid and lymphoid lineage differentiation, and recapitulate the normal lymphoid phenotype when transplanted to nonobese diabetic/severe combined immunodeficiency mice. However, overexpression of individual miRNAs from this locus, miR-19a or miR-92a, results in B-cell hyperplasia and erythroleukemia, respectively. Coexpression of another member of this cluster miR-17, with miR-92a, abrogates miR-92a-induced erythroleukemogenesis. Accordingly, we identified several novel miR-92a and miR-17 target genes regulating erythroid survival and proliferation, including p53. Expression of this critical target results in marked growth inhibition of miR-92a erythroleukemic cells. In both murine and human leukemias, p53 inactivation contributed to the selective overexpression of oncogenic miR-92a and miR-19a, and down-regulation of tumor-suppressive miR-17. This miR-17-92 expression signature was also detected in p53- B-cell chronic lymphocytic leukemia patients displaying an aggressive clinical phenotype. These results revealed that imbalanced miR-17-92 expression, also mediated by p53, directly transforms the hematopoietic compartment. Thus examination of such miRNA expression signatures should aid in the diagnosis and treatment of cancers displaying miR-17-92 gene amplification.     

The significance of sweat Cl/Na ratio in patients with borderline sweat test

Recently a few cystic fibrosis (CF) patients with borderline or normal sweat tests have been reported. These patients present a diagnostic challenge. We aimed to study the sweat CINa ratio in cystic fibrosis patients and to assess whether this ratio could be used as a diagnostic criteria. The mean sweat CINa ratio of 3 groups was compared: Group A: 71 CF patients carrying 2 mutations known to be associated with severe disease presentation (ΔF508, W1282X, G542X, N1303K, 1717-1G → A). Group B: 10 compound heterozygous patients who carry one mutation associated with mild clinical disease (3849 + 10 kb C → T). Group C: 142 normal subjects. Sweat chloride levels higher than those of sodium were found in 96% of patients in Group A as compared to 3% of patients in Group C. In Group B 40% of the patients had sweat chloride levels higher than or equal to sodium levels. The mean Cl/Na ratio of Group A (1.2 ± 0.1) differed significantly from that of Group B (0.94 ± 0.1) and both groups had significant higher mean CINa ratio compared to Group C (0.7 ± 0.4) (P < 0.001). Thus in individuals with a borderline sweat test and a Cl/Na ratio < 1 the diagnosis of CF should be considered. However, a Cl/Na ratio < 1 does not exclude CF, since patients carrying mild mutations may have sweat sodium levels higher than those of chloride. Our findings suggest that the sweat CINa ratio in CF is genetically determined and it may be of help in establishing the diagnosis of CF in patients with a borderline sweat test. Pediatr Pulmonol. 1995; 20:369–371 . © 1995 Wiley-Liss, Inc.