In-hospital monitoring of T-wave alternans in a case of amiodarone-induced torsade de pointes: clinical and methodologic insights

We report a case of macroscopic T-wave alternans occurring 30 min before the onset of amiodarone-induced torsade de pointes, illustrating a means to monitor for proarrhythmia.     

No association found between the Ala54Thr polymorphism of FABP2 gene and obesity and obesity with dyslipidemia in Japanese schoolchildren

To investigate whether the Ala54Thr polymorphism of the fatty acid binding protein 2 gene is associated with obesity and obesity with dyslipidemia in Japanese schoolchildren, we analyzed 370 children with morbid obesity and 463 control children of normal weight. The allele frequencies did not differ significantly between the control group and the morbidly obese group. The odds ratio (95% confidence interval CI) in obesity of the The54 allele was 1.0 (0.9-1.3). There were no significant differences in obesity index and metabolic characteristics between the two groups. The odds ratio (95% CI) in dyslipidemia of the Thr54 allele was 1.1 (0.8-1.4) in the morbidly obese group. Our data suggested that Ala54Thr polymorphism of the FABP2 gene is not a major contributing factor for obesity and obesity with dyslipidemia in Japanese children.     

Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes

Myeloid cells such as monocytes and monocyte-derived macrophages promote tumor progression. Recent reports suggest that extramedullary hematopoiesis sustains a sizable reservoir of tumor-infiltrating monocytes in the spleen. However, the influence of the spleen on tumor development and the extent to which spleen monocytes populate the tumor relative to bone marrow (BM) monocytes remain controversial. Here, we used mice expressing the photoconvertible protein Kikume Green-Red to track the redistribution of monocytes from the BM and spleen, and mice expressing fluorescent ubiquitination-based cell-cycle indicator proteins to monitor active hematopoiesis in these tissues. In mice bearing late-stage tumors, the BM, besides being the major site of monocyte production, supplied the expansion of the spleen reservoir, replacing 9% of spleen monocytes every hour. Deployment of monocytes was equally rapid from the BM and the spleen. However, BM monocytes were younger than those in the spleen and were 2.7 times more likely to migrate into the tumor from the circulation. Partly as a result of this intrinsic difference in migration potential, spleen monocytes made only a minor contribution to the tumor-infiltrating monocyte population. At least 27% of tumor monocytes had traveled from the BM in the last 24 h, compared with only 2% from the spleen. These observations highlight the importance of the BM as the primary hematopoietic tissue and monocyte reservoir in tumor-bearing mice, despite the changes that occur in the spleen monocyte reservoir during tumor development.Myeloid cells such as monocytes infiltrate almost all solid tumors (1). The presence of tumor-associated macrophages, which are derived directly from monocytes, correlates with poor prognosis (2, 3). These cells influence tumor progression through direct interactions with tumor cells, by modulating adaptive immune responses to the tumor, and by creating conditions that support angiogenesis, invasion, and metastasis (4–6). Understanding the origins and characteristics of tumor-infiltrating myeloid cells may lead to novel approaches to cancer therapy.In healthy adult humans and mice, all myeloid cell formation occurs in the bone marrow (BM) (7). However, in certain disease states, organs such as the liver and spleen become sites of extramedullary hematopoiesis (8, 9). In tumor-bearing mice myeloid cells accumulate in the spleen (10–12), making this organ a candidate source of tumor-infiltrating cells. Recent reports propose that a rapidly mobilized reservoir of monocytes in the spleen contributes significant numbers of infiltrating cells in acute and chronic inflammatory conditions including myocardial infarction (13–15), stroke (14), atherosclerosis (15), and cancer (16, 17). In cancer, extramedullary hematopoiesis in the spleen is suggested to sustain a continuous supply of monocytes to the tumor (16, 17). These reports challenge the classical view of the BM as the primary site of monocyte production and supply (18). Current approaches to measuring tissue origin and migration include BrdU labeling, adoptive transfer, tissue transplantation, and parabiosis experiments. However, it has remained difficult to assess accurately the relative contributions of different pools of myeloid cells to the tumor-infiltrating monocyte population (16).In the present study, we developed methods using mice expressing the photoconvertible protein Kikume Green-Red (KikGR) (19, 20) or fluorescent ubiquitination-based cell cycle indicator (Fucci) proteins (21, 22), which enabled us to compare the BM and spleen monocyte pools directly in terms of supply and production. We demonstrate that spleen-pool monocytes make only a minor contribution to the tumor-infiltrating monocyte population, partly because BM-pool monocytes have an intrinsic migration advantage over their spleen-pool counterparts.     

Impact of fetal sex in pregnancy-induced hypertension and preeclampsia in Japan

The male antigen (HY), the elevated level of fetal antigen in twin pregnancies, and the increased number of MHC mismatches in dizygotic twin pregnancies might affect immunological tolerance during pregnancy. Using the Perinatal Database of the Japanese Society for Obstetrics and Gynecology, we studied the occurrence of pregnancy-induced hypertension (PIH) and preeclampsia in mothers delivering singleton babies and in those delivering monochorionic diamniotic (MD) twin pregnancies and dichorionic diamniotic (DD) twin pregnancies at 125 centers of the perinatal network in Japan from 2001 through 2005. In singleton pregnancies, pregnant women carrying female fetuses had a significantly higher incidence of PIH and preeclampsia compared with those carrying male fetuses. In MD twin pregnancies, compared with mothers carrying male-male fetuses, those carrying female-female fetuses had significantly higher incidences of PIH and preeclampsia and a marked difference was observed in primiparous cases. In DD twin pregnancies, the incidences of PIH and preeclampsia were significantly higher in mothers with female-female fetuses than those with male-male fetuses, while those with male-female fetuses had intermediate values. The incidence of PIH and preeclampsia in MD twin pregnancies was similar to that in DD twin pregnancies with male-male fetuses or female-female fetuses. The male antigen and the increased number of MHC mismatches in DD twin pregnancies were not a risk factor for PIH and preeclampsia. Female fetal sex was a risk factor for PIH and preeclampsia.     

LRH1 as a driving factor in pancreatic cancer growth

Liver receptor homolog 1 (LRH1), directs the development and differentiation of embryonic pancreas, and is overexpressed in pancreatic cancer (PC). We hypothesized that LRH1 promotes PC growth. Cell proliferation and tumorigenicity in nude mice were compared between empty vector-transfected (control) and stable LRH1-overexpressed PC cell lines. The subsequent tumor burden, vasculature development, and histologic features were evaluated. LRH1 overexpression enhanced the expression of downstream target genes (cyclin D1/E1) and stimulated cell proliferation in PC cell lines. LRH1 upregulated cyclin E1 truncated T1/T2 isoforms expression which may occur through ERα–calpain1 signaling. Compared with the control, LRH1 overexpressing stable cells generated tumors with increased weight, proliferation index and enhanced angiogenesis. Cyclin D1/E1 and calpain1 were overexpressed in human PC tumors compared to adjacent normal pancreas. These observations demonstrate that LRH1 promotes PC growth and angiogenesis, suggesting that LRH1 is a driving factor in tumorigenesis and may serve as a potential therapeutic target.     

Downregulation of vasopressin V(1A) receptors and activation of mitogen-activated protein kinase in rat mesangial cells cultured under high-glucose conditions

SUMMARY: In the present study we examined the effects of high extracellular glucose concentrations on vasopressin (AVP) V(1A) receptor kinetics and signal transduction in cultured rat mesangial cells. Scatchard analysis of [(3) H]-AVP binding to mesangial cell plasma membranes showed that although high glucose (30?mmol/L) decreased V(1A) receptor numbers relative to cells cultured in normal glucose (10?mmol/L), receptor affinity was not affected. This V(1A) receptor downregulation was associated with an attenuated increase in AVP-stimulated cytosolic free calcium concentrations ([Ca(2+) ](i) ). In addition, high glucose increased both the basal and AVP-stimulated activity of the classic mitogen-activated protein kinase, namely extracellular signal-regulated kinase (ERK). Furthermore, high glucose induced activation of protein kinase C (PKC) in mesangial cells that could be inhibited by coincubation with the PKC inhibitor staurosporine (10?nmol/L). Staurosporine also markedly attenuated the high glucose-induced downregulation of V(1A) receptors on mesangial cells and blocked the depressed [Ca(2+) ](i) response and increased ERK activity induced by AVP. The results indicate that high extracellular glucose downregulates V(1A) receptors on rat mesangial cells and modulates their signal transduction properties via PKC activation.