Thoracoscopic esophagectomy with extended lymph node dissection in the left lateral position: technical feasibility and oncologic outcomes.

The aim of this study was to estimate the technical and oncologic feasibility of video-assisted thoracoscopic radical esophagectomy (VATS) in the left lateral position. From January 2003 to December 2011, 132 patients with esophageal cancer underwent VATS. The mean duration of the thoracic procedure and the entire procedure was 294 ± 88 and 623 ± 123 minutes, respectively. Mean blood loss during the thoracic procedure and the entire procedure was 313 ± 577 and 657 ± 719 g, respectively. The mean number of dissected thoracic lymph nodes was 32.6 ± 12.9. There were four in-hospital deaths (3.0%); two patients (1.5%) died of acute respiratory distress syndrome and two patients (1.5%) died of tumor progression. Postoperative unilateral or bilateral recurrent laryngeal nerve (RLN) palsy, or pneumonia was found in 33 (25.0%), 21 (15.9%), and 27(20.5%) patients, respectively. The patients were divided into the first 66 patients who underwent VATS (Group 1) and the subsequent 66 patients (Group 2). The numbers of cases who underwent neoadjuvant or induction chemotherapy for T4 tumor and intrathoracic anastomosis were higher in Group 2 than in Group 1. The duration of the procedure, amount of blood loss, and the number of dissected thoracic lymph nodes were not different between the two groups. The total number of dissected lymph nodes was higher in Group 2 than in Group 1 (72.6 ± 27.8 vs. 62.6 ± 21.6, P = 0.023). The rate of bilateral RLN palsy was less in Group 2 than in Group 1 (7.6% vs. 24.2%, P = 0.042). The mean follow-up period was 38.7 months. Primary recurrence consisted of hematogenous, lymphatic, peritoneal dissemination, pleural dissemination, and locoregional in 15 (11.3%), 20 (15.1%), 3 (2.3%), 4 (3.0%), and 5 patients (3.8%), respectively. The rate of regional lymph node recurrence within the dissection field was only 4.5%. The prognosis of patients with lymph node metastasis was significantly poorer than that of patients without lymph node metastasis. However, the prognosis of the 11 cases that had metastasis only around RLNs was similar to that of node-negative cases. Thirteen patients with pathological remnant tumor (R1 or R2) did not survive longer than 5 years at present. The overall 5-year survival rate of stage I, II, and III disease after curative VATS was 82.2%, 77.0%, and 52.3%, respectively. Expansion of VATS criteria for patients after induction chemotherapy for T4 tumor or thoracoscopic anastomosis did not adversely affect the surgical results by experience. Although the VATS procedure is accompanied by a certain degree of morbidity including RLN palsy and pulmonary complications, VATS has an excellent locoregional control effect. In addition, the favorable survival after VATS shows that the procedure is oncologically feasible.

Learning of thoracoscopic radical esophagectomy: how can the learning curve be made short and flat?

Attainment of proficiency in video-assisted thoracoscopic radical esophagectomy (VATS) for thoracic esophageal cancer requires much experience. We have mastered this procedure safely under the direction of an experienced surgeon. After adoption of the procedure, the educated surgeon directed induction of this surgical procedure at another institution. We evaluated the efficacy of instruction during the induction period by comparing the results at the two institutions in which VATS had been newly induced. We defined the induction period as the time from the beginning of VATS to the time when the last instruction was carried out. From January 2003 to December 2007, 53 patients were candidates for VATS at Kanazawa University (institution 1). Of these, 46 patients underwent curative VATS by a single operator. We divided this period into three parts: the induction period of VATS, post-induction period, and proficient period when the educated surgeon of institution 1 directed the procedure at Maebashi Red Cross Hospital (institution 2). At institution 1, 12 VATS were scheduled, and nine procedures (75%) (group A) including eight instructions were completed during the induction period (from January 2003 to August 2004). Thereafter, VATS was performed without instruction. In the post-induction period, nine VATS were scheduled, and eight procedures (88.8%) (group B) were completed from September 2004 to August 2005. Subsequently, 32 VATS were scheduled, and 29 procedures (90.6%) (group C) were completed during the proficient period (from September 2005 to December 2007). The surgeon at Maebashi Red Cross Hospital (institution 2) started to perform VATS under the direction of the surgeon who had been educated at institution 1 from September 2005. VATS was completed in 13 (76.4%) (group D) of 17 cases by a single surgeon including seven instructions during the induction period at institution 2 from September 2005 to December 2007. No lethal complication occurred during the induction period at both institutions. We compared the results of VATS among four groups from the two institutions. There were no differences in the background and clinicopathological features among the four groups. The number of dissected lymph nodes and amount of thoracic blood loss were similar in the four groups (35 [22-52] vs 41 [26-53] vs 32 [17-69] vs 29 [17-42] nodes, P = 0.139, and 170 [90-380] vs 275 [130-550] vs 220 [10-660] vs 210 [75-543] g, P = 0.373, respectively). There was no difference in the duration of the thoracic procedure during the induction period at the two institutions. However, the duration of the procedure was significantly shorter in the proficient period of institution 1 (group C: 266 [195-555] minutes) than in the induction period of both institutions (group A: 350 [280-448] minutes [P = 0.005] and group D: 345 [270-420] mL [P = 0.002]). There were no surgery-related deaths in any of the groups. The incidence of postoperative complications did not differ among the four groups. Thoracoscopic radical esophagectomy can be mastered quickly and safely with a flat learning curve under the direction of an experienced surgeon. The educated surgeon can instruct surgeons at another institution on how to perform thoracoscopic esophagectomy. The operation time of thoracoscopic surgery is shortened by experience.

Effect of maternal stress on fetal heart rate assessed by vibroacoustic stimulation.

This study was designed to determine whether maternal stress levels, state and trait anxiety levels, and stress hormones affect fetal heart rate (FHR) patterns after vibroacoustic stimulation (VAS) at 30 weeks of gestation. A total of 24 healthy pregnant women with a single fetus pregnancy were enrolled. Corticotropin releasing hormone (CRH) and adrenocorticotropic hormone in maternal plasma and cortisol, and chromogranin A in saliva were measured. The FHR patterns after VAS were divided into three types: type I, a long period of acceleration or one acceleration lasting > 1 min or at least two accelerations lasting > 15 s; type II, a biphasic response with acceleration followed by deceleration; and type III, no response or prolonged deceleration. In the high trait anxiety group, CRH levels were significantly higher than in the low trait anxiety group, and FHR patterns after VAS showed mostly a type II response pattern. These findings suggest that stress in pregnant women with high trait anxiety may influence FHR patterns after VAS.

Thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. Cross talk between endocrine control of stress response and cellular antioxidant defense system.

Adaptation to stress evokes a variety of biological responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and synthesis of a panel of stress-response proteins at cellular levels: for example, expression of thioredoxin (TRX) is significantly induced under oxidative conditions. Glucocorticoids, as a peripheral effector of the HPA axis, exert their actions via interaction with a ligand-inducible transcription factor glucocorticoid receptor (GR). However, how these stress responses coordinately regulate cellular metabolism is still unknown. In this study, we demonstrated that either antisense TRX expression or cellular treatment with H2O2 negatively modulates GR function and decreases glucocorticoid-inducible gene expression. Impaired cellular response to glucocorticoids is rescued by overexpression of TRX, most possibly through the functional replenishment of the GR. Moreover, not only the ligand binding domain but the DNA binding domain of the GR is also suggested to be a direct target of TRX. Together, we here present evidence showing that cellular glucocorticoid responsiveness is coordinately modulated by redox state and TRX level and propose that cross talk between neuroendocrine control of stress responses and cellular antioxidant systems may be essential for mammalian adaptation processes.

Functional interference of Sp1 and NF-kappaB through the same DNA binding site.

Gene activation by NF-kappaB/Rel transcription factors is modulated by synergistic or antagonistic interactions with other promoter-bound transcription factors. For example, Sp1 sites are often found in NF-kappaB-regulated genes, and Sp1 can activate certain promoters in synergism with NF-kappaB through nonoverlapping binding sites. Here we report that Sp1 acts directly through a subset of NF-kappaB binding sites. The DNA binding affinity of Sp1 to these NF-kappaB sites, as determined by their relative dissociation constants and their relative efficiencies as competitor DNAs or as binding site probes, is in the order of that for a consensus GC box Sp1 site. In contrast, NF-kappaB does not bind to a GC box Sp1 site. Sp1 can activate transcription through immunoglobulin kappa-chain enhancer or P-selectin promoter NF-kappaB sites. p50 homodimers replace Sp1 from the P-selectin promoter by binding site competition and thereby either inhibit basal Sp1-driven expression or, in concert with Bcl-3, stimulate expression. The interaction of Sp1 with NF-kappaB sites thus provides a means to keep an elevated basal expression of NF-kappaB-dependent genes in the absence of activated nuclear NF-kappaB/Rel.

Alternative splicing variants of IkappaB beta establish differential NF-kappaB signal responsiveness in human cells.

To release transcription factor NF-kappaB into the nucleus, the mammalian IkappaB molecules IkappaB alpha and IkappaB beta are inactivated by phosphorylation and proteolytic degradation. Both proteins contain conserved signal-responsive phosphorylation sites and have conserved ankyrin repeats. To confer specific physiological functions to members of the NF-kappaB/Rel family, the different IkappaB molecules could vary in their specific NF-kappaB/Rel factor binding activities and could respond differently to activation signals. We have demonstrated that both mechanisms apply to differential regulation of NF-kappaB function by IkappaB beta relative to IkappaB alpha. Via alternative RNA processing, human IkappaB beta gives rise to different protein isoforms. IkappaB beta1 and IkappaB beta2, the major forms in human cells, differ in their carboxy-terminal PEST sequences. IkappaB beta2 is the most abundant species in a number of human cell lines tested, whereas IkappaB beta1 is the only form detected in murine cells. These isoforms are indistinguishable in their binding preferences to cellular NF-kappaB/Rel homo- and heterodimers, which are distinct from those of IkappaB alpha, and both are constitutively phosphorylated. In unstimulated B cells, however, IkappaB beta1, but not IkappaB beta2, is found in the nucleus. Furthermore, the two forms differ markedly in their efficiency of proteolytic degradation after stimulation with several inducing agents tested. While IkappaB beta1 is nearly as responsive as IkappaB alpha, indicative of a shared activation mechanism, IkappaB beta2 is only weakly degraded and often not responsive at all. Alternative splicing of the IkappaB beta pre-mRNA may thus provide a means to selectively control the amount of IkappaB beta-bound NF-kappaB heteromers to be released under NF-kappaB stimulating conditions.

Von Willebrand Factor Deposition and ADAMTS-13 Consumption in Allograft Tissue of Thrombotic Microangiopathy-like Disorder After Living Donor Liver Transplantation: A Case Report.

BACKGROUND: Thrombotic microangiopathy (TMA) pathogenesis after living donor liver transplantation (LDLT) is thought to be caused by release of unusually large von Willebrand factor multimers (UL-vWFMs) resulting from sinusoidal endothelial cell damage and induction of platelet adhesion and aggregation. A decrease in a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13 (ADAMTS-13) that cleave UL-vWFMs might cause excessive UL-vWFMs activity and result in platelet thrombus formation. However, this phenomenon has not undergone a full pathologic assessment. PROCEDURES: A 60-year-old man was diagnosed with hepatitis C-related end-stage cirrhosis. His son was the donor, and he underwent LDLT. On postoperative day 44, his laboratory findings met most TMA diagnostic criteria, and he was diagnosed with TMA-like disorder (TMALD). Localization of CD42b as a platelet marker, vWF, and ADAMTS-13 in allograft tissue of this patient were evaluated using immunohistochemistry. RESULTS: CD42b expression was observed as platelet aggregates attached to hepatocytes or within the hepatocyte cytoplasm, a morphology called extravasated platelet aggregation (EPA). vWF expression was observed mainly as deposited compact clusters, and ADAMTS-13 expression resembled distinct dots throughout the liver tissue. CONCLUSION: These findings suggest that EPA indicated sinusoidal endothelial cell damage followed by detachment, and vWF deposition resulted from UL-vWFM oversynthesis. ADAMTS-13 might be consumed in the allograft tissue to cleave UL-vWFMs, but ADAMTS-13 levels might be insufficient to cleave all the deposited UL-vWFMs. We present the case of an LDLT recipient diagnosed with TMALD using blood tests, which showed the presence of TMA pathogenesis in the allograft.

Ischemia reperfusion-facilitated sinusoidal endothelial cell injury in liver transplantation and the resulting impact of extravasated platelet aggregation.

BACKGROUND: The exact sequence of events leading to ultimate hepatocellular damage following ischemia/reperfusion (I/R) is incompletely understood. In this article, we review a mechanism of organ dysfunction after hepatic I/R or immunosuppressive treatment, in addition to the potential of liver sinusoidal endothelial cell (LSEC) protection and antiplatelet treatment for the suppression of hepatocellular damage. METHODS: A review of the literature, utilizing PubMed-NCBI, was used to provide information on the components necessary for the development of hepatocellular damage following I/R. RESULTS: It is well-established that LSECs damage following hepatic I/R or immunosuppressive treatment followed by extravasated platelet aggregation (EPA) is the root cause of organ dysfunction in liver transplantation. We have classified three phases, from LSECs damage to organ dysfunction, utilizing the predicted pathogenic mechanism of sinusoidal obstruction syndrome. The first phase is detachment of LSECs and sinusoidal wall destruction after LSECs injury by hepatic I/R or immunosuppressive treatment. The second phase is EPA, accomplished by sinusoidal wall destruction. The various growth factors, including thromboxane A2, serotonin, transforming growth factor-beta and plasminogen activator inhibitor-1, released by EPA in the Disse's space of zone three, induce portal hypertension and the progression of hepatic fibrosis. The third phase is organ dysfunction following portal hypertension, hepatic fibrosis, and suppressed liver regeneration through various growth factors secreted by EPA. CONCLUSION: We suggest that EPA in the space of Disse, initiated by LSECs damage due to hepatic I/R or immunosuppressive treatment, and activated platelets may primarily contribute to liver damage in liver transplantation. Endothelial protective therapy or antiplatelet treatment may be useful in the treatment of hepatic I/R following EPA.

Elevation of plasma thrombomodulin level in diabetic patients with early diabetic nephropathy.

Thrombomodulin (TM) is a membrane protein in the vascular endothelium, and it plays an important role as a cofactor in the thrombin-catalyzed activation of protein C. It has also been found in human plasma; however, its clinical significance is not known. In this study, fasting plasma TM concentrations in 67 diabetic patients with different degrees of albuminuria (39 men aged 57 +/- 8 yr, 28 women aged 57 +/- 11 yr; means +/- SD) and 34 age- and sex-matched healthy subjects were investigated by use of a one-step sandwich enzyme immunoassay, a new method developed by H.I. and others. As a screening, the patients were divided into three groups according to the first morning urinary concentrations of albumin: group 1, less than 30 micrograms/ml (normoalbuminuria); group 2, 30-140 micrograms/ml (microalbuminuria); group 3, greater than 140 micrograms/ml (clinical nephropathy). There was no significant difference in plasma TM level between the control group (17.7 +/- 3.7 ng/ml, n = 34) and group 1 (16.9 +/- 3.4 ng/ml, n = 30); however, plasma TM concentrations in group 2 (22.8 +/- 3.4 ng/ml, n = 22) and group 3 (29.6 +/- 6.1 ng/ml, n = 15) increased significantly compared with those in the control group and group 1, respectively. As a further investigation, three timed overnight urine collections were made. The patients were allocated to three groups according to their rates of albumin excretion: group I, less than 20 micrograms/min (normoalbuminuria); group II, 20-200 micrograms/min (microalbuminuria); group III greater than 200 micrograms/min (clinical nephropathy).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of metabolic control and body weight to hypercholesterolemia in NIDDM patients with apolipoprotein E4.

OBJECTIVE: We previously reported that non-insulin-dependent diabetes mellitus (NIDDM) patients with apolipoprotein E4 (apoE4) are more susceptible to hypercholesterolemia. The purpose of this study was to clarify whether metabolic control or body weight is related to hypercholesterolemia in NIDDM patients with apoE4. RESEARCH DESIGN AND METHODS: Two hundred forty NIDDM patients with apoE4 or apoE3/3 who had either hypercholesterolemia or normolipidemia were studied. ApoE phenotypes were determined by isoelectric focusing method. RESULTS: The apoE4-carrying NIDDM patients with hypercholesterolemia (n = 39) showed significantly higher fasting plasma glucose (8.4 vs. 7.2 mM, P less than 0.05), HbA1 (9.3 vs. 8.1%, P less than 0.05), and percentage of ideal body weight values (116 vs. 102%, P less than 0.01) than the apoE4-carrying NIDDM patients with normolipidemia (n = 26), whereas there was no significant difference in their levels between the apoE3/3-carrying NIDDM patients with hypercholesterolemia (n = 47) and normolipidemia (n = 128). CONCLUSIONS: In addition to our previous finding, this study indicates that hypercholesterolemia in apoE4-carrying NIDDM patients may be more closely related to poor metabolic control and increased percentage of ideal body weight.

Efficacy of conversion gastrectomy following docetaxel, cisplatin, and S-1 therapy in potentially resectable stage IV gastric cancer.

BACKGROUND: Recent advances in gastric cancer chemotherapy have made macroscopic complete resection possible in some patients with stage IV disease. METHODS: We retrospectively investigated the efficacy of multimodal therapy with combined docetaxel, cisplatin, and S-1 (DCS) and conversion gastrectomy in 57 patients with stage IV gastric cancer. RESULTS: Of the 57 patients, 15 patients were categorized into potentially resectable case, which is defined as patients with single incurable factor including the upper abdominal para-aortic lymph node metastasis (16a2b1 PAN metastasis) or fewer than three peripheral liver metastases. The other 42 were categorized as initially unresectable. All of patients underwent DCS therapy, and then 34 patients underwent conversion gastrectomy. The 3-year overall survival (OS) rate among the patients who underwent conversion gastrectomy was 50.1% with MST of 29.9 months. They had significantly longer OS than patients who underwent DCS therapy alone (p < 0.01). Univariate analysis among the patents with conversion gastrectomy identified 16a2b1PAN metastasis, peritoneal metastasis, potential resectable case, R0 resection as significant prognostic factors. A 3-year OS in potential resectable cases was 92.9%. Multivariate analysis identified potential resectability as the only independent prognostic factor contributing to OS (HR 0.133, 95%CI 0.024-0. 744, p = 0.021). In contrast, clinical response was selected as the only independent prognostic factor in the subgroup of initially unresectable cases (HR 0.354, 95%CI 0.151-0.783, p = 0.021). CONCLUSION: Patients with potentially resectable disease had a remarkably good prognosis among stage IV gastric cancer patients, and might be ideal candidates for conversion gastrectomy following DCS therapy.

The effects of hydrocortisone and RU486 (mifepristone) on iodide uptake in porcine thyroid cells in primary culture.

The effects of hydrocortisone on iodide uptake and DNA synthesis were studied in porcine thyroid cells cultured in phenol red-free medium supplemented with low concentrations (0-1%) of charcoal-stripped fetal calf serum. Hydrocortisone dose-dependently stimulated TSH-induced iodide uptake at physiological concentrations (1-1000 nM), and the minimum detectable dose was 33 nM hydrocortisone. Treatment of thyroid cells with hydrocortisone for 72 h increased cAMP production stimulated by TSH. In addition, this stimulatory effect of hydrocortisone was observed when iodide uptake was induced with 0.25 mM 8-bromo-cAMP. These results suggest that hydrocortisone stimulates iodide uptake, influencing cAMP production and post-cAMP pathways. The synthetic glucocorticoid antagonist RU486 alone had no effect on iodide uptake in porcine thyroid cells; however, along with TSH, RU486 a weak agonist activity. As a glucocorticoid antagonist, RU486 inhibited the stimulatory actions of hydrocortisone on iodide uptake in combination with TSH and also with 8-bromo-cAMP, suggesting a specific effect of hydrocortisone mediated by a glucocorticoid receptor. The effect of hydrocortisone on thyroid cell multiplication was also studied. Hydrocortisone decreased [3H]thymidine incorporation into DNA slightly but not significantly when the cells were treated with 100 ng/ml insulin-like growth factor-I and hydrocortisone. In summary, it has been demonstrated that hydrocortisone directly stimulated the function of porcine thyroid cells at physiological concentrations, by using a glucocorticoid receptor and by affecting cAMP pathways. The data that RU486 inhibited iodide uptake induced by hydrocortisone and TSH propose that monitoring of thyroid function may be necessary if RU486 is been used for a long time.

Reduced levels of messenger ribonucleic acid for calcium channel, glucose transporter-2, and glucokinase are associated with alterations in insulin secretion in fasted rats.

Expression of the genes for voltage-dependent calcium channels (VDCCs), glucose transporter-2 (GLUT2), and glucokinase was studied in pancreatic islets obtained from normal rats after periods of fasting and refeeding using a competitive polymerase chain reaction procedure. A 72-h fast induced about a 3-fold decrease in the beta-cell/neuroendocrine type VDCC alpha 1-subunit and GLUT2 messenger RNA (mRNA) levels and about a 2-fold decrease in insulin and glucokinase mRNA levels compared to those in fed and refed rats. No significant differences were found in beta-actin and the cardiac-type VDCC alpha 1-subunit mRNA levels among fed, fasted, anf refed rats. We also studied insulin secretion from the isolated perfused pancreata obtained from these animals. We found an elevated threshold and decreased insulin release in response to a stepwise increase in glucose concentrations in the isolated perfused pancreata obtained from fasted rats. Fasting also resulted in a dramatic decrease in insulin secretory responses during the application of an L-type VDCC agonist, Bay K8644 (1 microM). Furthermore, fasting resulted in a significant decrease in both 45Ca2+ uptake by the isolated islets and insulin release from the islets. A strong positive correlation was observed between glucose-induced 45Ca2+ uptake and insulin output among the animals studied. On the other hand, after a 24-h refeeding, significant increases in the insulin secretory response to glucose and Bay K8644 were found, with a normalization in mRNA levels for these components. It, thus, appears that the alterations in beta-cell sensitivity to glucose that occur with fasting and refeeding are the result of complex metabolic alterations in the islet associated with reductions in expression of at least in part the beta-cell/neuroendocrine type VDCC in addition to two components of the glucose-sensing apparatus, including glucokinase and GLUT2, and the reduction in mRNA for insulin.

Expression of adrenomedullin in feto-placental circulation of human normotensive pregnant women and pregnancy-induced hypertensive women.

The adrenomedullin (AM) peptide and the expression of AM messenger RNA (mRNA) from feto-maternal tissues of 22 normotensive pregnant women and from 7 women with pregnancy-induced hypertension (PIH) during third-trimester were examined to clarify the pathophysiological features of PIH. Samples of the placenta, uterine muscle, umbilical artery, and fetal membranes were obtained from each patients under informed consent. The AM peptide was measured by a radioimmunoassay and the AM mRNA level was analyzed by Northern hybridization. The total immunoreactive AM (fmol/mg wet tissue) was significantly increased in the fetal membranes (1.95+/-0.20 vs. 3.03+/-0.44) and the umbilical artery (0.11+/-0.01 vs. 0.15+/-0.02) of the patients with PIH. On the other hand, the AM mRNA level was higher in the umbilical artery, and lower in the fetal membranes in the patients with PIH. The present results thus suggest that the changes in the expression of AM in fetal membrane and umbilical artery in PIH may play an important role in the fetal and maternal circulation.

Relationship of thyroid states and serum thrombomodulin (TM) levels in patients with Graves' disease: TM, a possible new marker of the peripheral activity of thyroid hormones.

Thrombomodulin (TM) is a thrombin receptor glycoprotein that functions as an anticoagulant on the surface of endothelial cells. Serum TM is regarded as a new marker of generalized endothelial cell damage. Serum TM concentrations were measured in 75 patients with Graves' disease and 75 age- and sex-matched healthy subjects. Serum TM levels in patients in the hyperthyroid state were significantly increased, while those in patients in the hypothyroid state due to treatment were significantly decreased compared with levels in control subjects. All patients with untreated Graves' disease had markedly elevated TM levels. Serum TM levels correlated closely with thyroid hormone concentration (TM vs. free T4, r = 0.858; P = 0.001). Serial measurement of individual patients revealed that serum TM levels paralleled thyroid hormone concentration, reaching normal control values upon attainment of euthyroidism. On the other hand, there was no significant correlation between serum TM concentration and titer of antithyroglobulin antibodies, titer of antimicrosomal antibodies, serum thyroglobulin level, or goiter size, and serum TM was not directly influenced by TSH receptor antibodies or resting pulse rates. The close correlation between serum TM and thyroid hormone concentration suggests that thyroid hormones might influence the synthesis or metabolism of TM on the surface of endothelial cells in patients with Graves' disease.

Apolipoprotein-E2 and hyperlipoproteinemia in noninsulin-dependent diabetes mellitus.

The association of apolipoprotein-E2 (apoE2) with hyperlipoproteinemia (HLP) was investigated in 23 noninsulin-dependent diabetes mellitus patients with apoE2 and 24 nondiabetic controls with apoE2. The frequency of HLP was significantly higher in diabetic subjects with apoE2 (73.9%) than in nondiabetic controls (37.5%). HLP in nondiabetic subjects with apoE2 included only type IV (n = 9), whereas HLP in diabetic subjects with apoE2 included type IIb (n = 1), type III (n = 7), and type IV (n = 9). Diabetic patients with apoE2 were characterized by increased levels of plasma triglyceride, total cholesterol (chol), very low density lipoprotein (VLDL)-chol, and apoE and an increased VLDL-chol/VLDL-triglyceride ratio, i.e. the accumulation of remnants. In addition, fasting plasma glucose and hemoglobin-A1 levels were significantly higher in hyperlipoproteinemic diabetic patients with apoE2 than in normolipidemic diabetic patients with apoE2. It is concluded that diabetes (poor metabolic control) predisposes apoE2 (epsilon 2)-carrying subjects to HLP (particularly type III) and that apoE2 may be one factor linking diabetes with HLP and cardiovascular disease.

Alteration of the adrenomedullin receptor components gene expression associated with the blood pressure in pregnancy-induced hypertension.

Adrenomedullin (AM) is a potent vasodilator. Pregnancy-induced hypertension (PIH) is a common cause of maternal or fetal mortality. We measured the changes of adrenomedullin receptor components gene expression, receptor activity-modifying protein 2 (RAMP2) and calcitonin receptor-like receptor (CRLR), at feto-maternal tissues in human normotensive pregnant women and pregnancy-induced hypertensive women by Northern blot analysis. Samples of the placenta, uterine muscle, umbilical artery, and fetal membranes were obtained from each patient under informed consent. RAMP2 mRNA significantly decreased in the umbilical artery (54%, P < 0.01) and uterus (53%, P < 0.01) of the patients with PIH. CRLR mRNA also significantly decreased in both tissues of the patients with PIH. On the other hand, the RAMP2 mRNA was significantly increased in the fetal membrane of the patients with PIH. In addition, there was a significant negative correlation between the RAMP2 mRNA levels in the umbilical artery (systolic; r = -0.623, P < 0.01, diastolic; r = -0.552, P < 0.01) and uterine muscle (systolic; r = -0.563, P < 0.01, diastolic; r = -0.553, P< 0.01) and blood pressure. However, there was no correlation between the mRNA level and blood pressure in fetal membrane and placenta, suggesting that there is no close relationship to the pathogenesis in PIH. These findings suggested that the reduced expression of adrenomedullin receptor component in umbilical artery and uterus may have some role in PIH.

Apolipoprotein E2, renal failure and lipid abnormalities in non-insulin-dependent diabetes mellitus.

The association of apolipoprotein E (apo E) genetic polymorphism, particularly apo E2, with renal failure (plasma creatinine > or = 1.4 mg/dl, and urinary albumin excretion index > or = 300 mg/g.creatinine and/or persistent proteinuria) was investigated in 57 non-insulin-dependent diabetic (NIDDM) patients. Apo E2 allele frequency was significantly higher in diabetic patients with renal failure (9.6%) than in diabetic patients without renal failure (3.2%) and in the general Japanese population (3.7%). This finding suggests that apo E2 is associated with renal failure in NIDDM. In addition, to elucidate the association of apo E2 with lipid abnormalities, plasma lipid and lipoprotein levels were compared among the apo E2 (E2/2 and E3/2) and E3/3 groups of NIDDM with renal failure (n = 27) and the apo E2 (E3/2) and E3/3 groups of NIDDM with normoalbuminuria (n = 34). In diabetic patients, the apo E2 group with renal failure had significantly higher levels of plasma total cholesterol (T-chol), very-low-density lipoprotein (VLDL)-chol, triglyceride (TG), VLDL-TG and apo E than the apo E3/3 group with renal failure, and had significantly higher levels of plasma T-chol, VLDL-chol, TG and VLDL-TG than the apo E2 and E3/3 groups with normoalbuminuria. Furthermore, the apo E2 group with renal failure had significantly higher ratios of VLDL-(chol/TG) and VLDL-chol/TG (an index of remnants in plasma) than the apo E3/3 group with renal failure and the apo E2 and E3/3 groups with normoalbuminuria. These results suggest that apo E2 leads to the accumulation of TG-rich lipoprotein and remnants in plasma. It is concluded that apo E2 is associated with renal insufficiency in NIDDM and that apo E2 may be a factor that aggravates lipid abnormalities in NIDDM with renal failure.

Triglyceride-rich lipoproteins from apolipoprotein E3/2 subjects with hypertriglyceridemia enhance cholesteryl ester synthesis in human macrophages.

The ability of triglyceride (TG)-rich lipoproteins from apolipoprotein (apo) E2 heterozygote, apo E3/2 which is relatively common, to stimulate cholesteryl ester synthesis in human monocyte-derived macrophages was studied to clarify the atherogenicity of apo E3/2. Twenty-three subjects were randomly sampled from our hospitals, and divided into the following 4 groups: 7 apo E3/3 subjects with normolipidemia, 6 apo E3/3 subjects with hypertriglyceridemia (HTG), 5 apo E3/2 subjects with normolipidemia and 5 apo E3/2 subjects with HTG. Plasma levels of TG and total cholesterol (chol) were significantly (P < 0.001) higher in apo E3/3 and apo E3/2 subjects with HTG than in apo E3/3 and apo E3/2 subjects with normolipidemia, but plasma levels of TG and total chol were not significantly different between apo E3/3 and apo E3/2 subjects with HTG. [14C]oleate incorporation into cholesteryl esters in macrophages was significantly (P < 0.001) higher in apo E3/2 subjects with HTG (0.661 nmol/mg cell protein) than in apo E3/3 subjects with normolipidemia (0.228) and with HTG (0.325) and in apo E3/2 subjects with normolipidemia (0.257). It is concluded that TG-rich lipoproteins from apolipoprotein E3/2 subjects with HTG enhance cholesteryl ester synthesis in human macrophages.