Reduced incidence of hepatic metastases by perioperative treatment with recombinant human interleukin-2

Abdominal operations induce immunosuppression during the time when tumors are manipulated and tumor cells are released into the circulation. The authors tested the hypothesis that the combined effect of these factors may promote the development of metastatic tumor implants and that perioperative treatment with Human Recombinant Interleukin-2 (RIL-2), a known immunostimulant of t, natural killer (NK), and lymphokine activated killer (LAK) cells may reduce the incidence of liver metastases from transplantable rat colon cancers. Hepatic metastases were induced in male Fischer 344 (F344) rats by injecting 10(7) rat colon tumor cells into the portal venous system during laparotomy. Control rats developed tumors by four weeks and were dead by ten weeks. Eleven groups of rats underwent celiotomy with portal vein injection of tumor on day three. Rats received either no RIL-2, RIL-2, or excipient buffer at varying doses on days 1 through 5 or 3 through 7 of these experiments. Animals were assessed for the presence of tumor and the incidence of liver metastases at autopsy (sacrifice and autopsy performed at seven weeks). Eighty-five percent of the rats in the untreated group developed tumor. This compared with only 50 percent of animals receiving 10(3) u/dose (P less than .025) and 42 percent of animals receiving 10(4) u/dose (P less than .01) of Interleukin-2 on days 1 through 5. Animals receiving very high doses of RIL-2 (10(5) or 4 X 10(5) units per dose) had a greater chance of developing tumors than did control rats, or rats receiving lower doses of RIL-2 (P less than .05). It is concluded that the perioperative period may be critical for the implantation and growth of metastatic disease and that perioperative immunostimulation with RIL-2 can decrease the incidence of tumors in these animals. This model may have relevance to the treatment of human colon cancer.     

Alterations of circadian expressions of clock genes in Dahl salt-sensitive rats fed a high-salt diet

In mammals, behavioral and physiologic processes display 24-hour rhythms that are regulated by a circadian system consisting of central and peripheral oscillators. Because various cardiovascular functions show diurnal variations and abnormal patterns of circadian blood pressure variation carry a high risk of cardiovascular complications, we investigated whether the expression of clock genes is altered in an animal model of hypertension. In Dahl salt-sensitive rats fed a high-salt (4% NaCl) diet for 6 weeks (DS-H), radiotelemetry monitoring showed increased amplitude of circadian variations in blood pressure. The ratio of heart weight to body weight and the ratio of kidney weight to body weight were higher in DS-H. Echocardiographic data showed that the wall thickness of the left ventricle was greater in DS-H. Northern blot analysis and single cosinor analysis revealed that the amplitudes of circadian expression changes of the clock genes (mPer2, Bmal1, and dbp) in the heart, liver, and kidney were significantly decreased in DS-H rats compared with a normal-salt-diet group, except for Bmal1 in the liver. The circadian expression changes of plasminogen activator inhibitor-1, a clock-regulated gene, were attenuated in the hearts of DS-H. The present results demonstrate that DS-H show altered circadian expression of peripheral clock genes. Detailed analyses of the relation between circadian expression of clock genes and blood pressure regulation might reveal a role for chronologic therapy of cardiovascular disease.     

Two cases of Chlamydia psittaci infection occurring in employees of the same pet shop]

We report here 2 cases of psittacosis in a pet shop. In the first case, a 44-year-old male was admitted with fever, and a chest radiograph showed an infiltration shadow in the right lower lung. One day later, a colleague of the first patient, a 42-year-old man, developed fever and was admitted. In this patient, chest radiography revealed an infiltration shadow in the left lower lung. Both patients had mild liver dysfunction. The serum titer of a complement fixation (CF) test against Chlamydia psittaci was elevated fourfold in the first case and sixteen-fold in the second on the analysis of paired acute- and convalescent-phase serum specimens. Clinical symptoms and abnormal laboratory data were attenuated by the administration of minocycline for 2 weeks. Since both patients worked in same pet shop and since some parakeets at the shop had died, we speculated that the psittacosis had originated from these birds.     

Adult Drosophila sensory neurons specify dendritic territories independently of dendritic contacts through the Wnt5–Drl signaling pathway

Sensory neurons with common functions are often nonrandomly arranged and form dendritic territories in stereotypic spatial patterns throughout the nervous system, yet molecular mechanisms of how neurons specify dendritic territories remain largely unknown. In Drosophila larvae, dendrites of class IV sensory (C4da) neurons completely but nonredundantly cover the whole epidermis, and the boundaries of these tiled dendritic fields are specified through repulsive interactions between homotypic dendrites. Here we report that, unlike the larval C4da neurons, adult C4da neurons rely on both dendritic repulsive interactions and external positional cues to delimit the boundaries of their dendritic fields. We identify Wnt5 derived from sternites, the ventral-most part of the adult abdominal epidermis, as the critical determinant for the ventral boundaries. Further genetic data indicate that Wnt5 promotes dendrite termination on the periphery of sternites through the Ryk receptor family kinase Derailed (Drl) and the Rho GTPase guanine nucleotide exchange factor Trio in C4da neurons. Our findings thus uncover the dendritic contact-independent mechanism that is required for dendritic boundary specification and suggest that combinatory actions of the dendritic contact-dependent and -independent mechanisms may ensure appropriate dendritic territories of a given neuron.     

Intrarenal hemodynamic changes after captopril test in patients with type 2 diabetes: a duplex Doppler sonography study

OBJECTIVE: ACE inhibitors are known to be effective in preventing the progression of diabetic nephropathy. Activation of the renin-angiotensin system (RAS) is reported to contribute to intrarenal hemodynamic abnormality in diabetic patients. We examined whether RAS blockade by captopril induces intrarenal hemodynamic changes in normotensive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The patients ranged in age from 40 to 65 years (20 men and 20 women). A total of 15 age- and sex-matched healthy individuals served as control subjects. Resistive index (RI) of interlobar arteries was examined by duplex Doppler sonography before and after the oral captopril (25 mg) test. RESULTS: At baseline, no significant differences in RI values or plasma renin activity (PRA) were seen between the patients and healthy subjects. In healthy subjects, the RI values after the captopril test were significantly higher than baseline values (P < 0.01). However, in patients with type 2 diabetes, both with normoalbuminuria and microalbuminuria, RI values after the test were significantly lower than baseline values (P < 0.001). There were significant negative correlations between DeltaRI value and HbA1c (r = -0.458, P < 0.005) and between DeltaRI value and baseline PRA in diabetic patients (r = -0.339, P < 0.05). Multiple regression analysis showed that HbA1c and baseline PRA significantly and independently affected the magnitude of decrease in RI values after captopril administration in diabetic patients (R2 = 0.391, P < 0.0001). CONCLUSIONS: These results indicate that the intrarenal RAS may be activated in diabetic patients, that such activation may be affected by poor glycemic control, and that blockade of RAS activation by ACE inhibitor reduces intrarenal vascular resistance in diabetic patients. The results emphasize the beneficial effects of ACE inhibition in improving intrarenal hemodynamics in diabetic patients.     

Increased Activity of Insulin-like Growth Factor-binding Protein in Human Thyroid Papillary Cancer Tissue

It has been shown that both insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs) are produced by thyroid cells in culture and that the cells respond to IGF-I with increased DNA synthesis, suggesting an autocrine/paracrine role of IGF-I in the regulation of thyroid cell growth. We investigated the tissue contents of immunoreactive IGF-I (irIGF-I) and IGFBPs in human papillary carcinoma and compared them with those of normal thyroid tissue. When irIGF-I was measured after separation of the IGFBPs by gel-filtration, its content in carcinoma tissue was not different from that in adjacent normal tissue (566±58 vs. 424±75 pg/mg protein, N = 10). Nor was there any difference in the abundance of IGF-I mRNA expression determined by slot blot analysis. On the other hand, IGFBP activity measured in terms of ¹²⁵I-IGF-I binding was significantly higher in cancer extracts. Western ligand blot analysis of IGFBPs revealed several species (24–42 kDa) of IGFBPs. The IGF-I-binding activity of 38–41 kDa species (corresponding to IGFBP-3) was not different between extracts of cancer tissue and those of normal tissue, whereas that of 28–32 kDa species was significantly higher in cancer tissue extracts. Since IGFBPs have been reported to modulate cellular responses to IGF-I, the present data suggest that higher IGFBP activity in cancer tissue is involved in regulating growth of thyroid papillary carcinoma cells.     

Effect of atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus

OBJECTIVE: A statin, a potent lipid-lowering drug, improves pain-free walking distance in patients with peripheral arterial disease (PAD) without increasing the ankle-brachial pressure index (ABI). Arterial stiffness affects the blood flow of peripheral arteries. The purpose of this study was to evaluate the effect of cholesterol-lowering with atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus. METHODS: The subjects were 22 type 2 diabetic patients with hypercholesterolemia, who received atorvastatin at a daily dose of 10 mg for 6 months. Before and after the treatment with atorvastatin, we measured pulse wave velocity (PWV) in the heart-brachial, heart-carotid, heart-femoral and femoral-ankle segments. RESULTS: Following treatment with atorvastatin, femoral-ankle PWV showed a significant reduction. The PWV of other arterial segments tended to decrease, although the changes were not statistically significant. We found no significant changes in blood pressure, heart rate, ABI, or plasma concentrations of glucose, L-arginine and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial function. CONCLUSIONS: Atorvastatin treatment was associated with an improvement in the stiffness of leg arteries in type 2 diabetes mellitus. This may partly explain the statin-mediated improvement of walking performance in those with PAD.     

Association of serum TRAIL levels with atherosclerosis in patients with type 2 diabetes mellitus

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was originally isolated as an inducer of apoptosis. Recent cross-sectional and prospective studies suggest an inverse association of serum TRAIL levels with the severity of coronary artery disease (CAD) and with an adverse outcome in patients with CAD or heart failure. However, it is unknown whether TRAIL can inversely reflect the progression of atherosclerosis from its early stage. We therefore examined the association between TRAIL measured by ELISA and intima-media thickness (IMT) in carotid and femoral arteries evaluated by ultrasonography as a surrogate marker of atherosclerosis in 416 type 2 diabetic patients without any symptoms of CAD and heart failure. Concurrently, the existence of calcified plaque (CP) was examined. There was no significant association between TRAIL and carotid IMT (ρ = −0.096, p = 0.052) or femoral IMT (ρ = −0.025, p = 0.610), although TRAIL was associated with carotid IMT in a subset of patients with macrovascular diseases (ρ = −0.174, p = 0.034). No difference in TRAIL levels was found between two groups with or without CP. TRAIL may not be a good candidate as a biomarker to evaluate early-stage atherosclerotic lesions.