umin.ac.jp/ctr Identifier: C000000412.

PURPOSEIt is not well known how the omission of whole-brain radiotherapy (WBRT) affects the neurocognitive function of patients with 1-4 brain metastases who are treated with stereotactic radiosurgery (SRS). MATERIALS AND METHODSIn a prospective randomized trial between WBRT+SRS and SRS-alone in patients with 1-4 brain metastases, neurocognitive function was assessed by the Mini-Mental Score Examination (MMSE). Among 132 enrolled patients, MMSE scores were available for 110 patients. RESULTSIn the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and KPS. Among 92 patients who received follow-up MMSE, 39 patients had a baseline MMSE of 27 or lower (17 in the WBRT+SRS group, 22 in the SRS-alone group).Improvements of >=3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (P=0.85) were observed. Among 82 patients who had baseline MMSEs >=27 or whose baseline MMSEs were <=26 but improved to >=27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free Aoyama H et al. 4 rates of the 3-point drop in MMSE were 76.1%, 68.5%, and 14.7% in the WBRT+SRS group, and were 59.3%, 51.9%, and 51.9% in the SRS-alone group.The average duration until deterioration was 16.5 months in WBRT+SRS and 7.6 months in SRS-alone patients (P=0.05). CONCLUSIONSThe current study revealed that, for the majority of brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effect of WBRT on neurocognitive function may not be negligible.

Given that angiotensin II (AII) type 1 and 2 receptors (Agtr1 and Agtr2) are expressed in adipose tissue, AII may act directly on adipose tissue. However, regardless of whether AII directly modulates adipose tissue growth and metabolism in vivo and, if so, whether it is mediated via Agtr1 are still matters of debate. To understand the functional role of Agtr1 in adipose tissue growth and metabolism in vivo, we examined the metabolic phenotypes of mice lacking Agtr1a (Agtr1a-/- mice) during a high-fat diet. The Agtr1a-/- mice exhibited the attenuation of diet-induced body weight gain and adiposity, and insulin resistance relative to wild-type littermates (Agtr1a+/+ mice). They also showed increased energy expenditure accompanied by sympathetic activation, as revealed by increased rectal temperature and oxygen consumption, increased expression of uncoupling protein-1 mRNA in brown adipose tissue, and increased urinary catecholamine excretion. The heterozygous Agtr1a-deficient mice (Agtr1a+/- mice) also exhibited metabolic phenotypes similar to those of Agtr1a-/- mice. Using mouse embryonic fibroblasts derived from Agtr1a+/+ and Agtr1a-/- mice, we found no significant difference between genotypes in the ability to differentiate into lipid-laden mature adipocytes. In primary cultures of mouse mature adipocytes, AII increased the expression of mRNAs for some adipocytokines, which was abolished by pharmacological blockade of Agtr1. This study demonstrates that Agtr1a-/- mice exhibit attenuation of diet-induced weight gain and adiposity through increased energy expenditure. The data also suggest that AII does not affect directly adipocyte differentiation, but can modulate adipocytokine production via Agtr1.

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objective: This study was designed to examine the effect of peroxisome proliferator-activated receptor-α (PPAR-α) ligands on the inflammatory changes induced by the interaction between adipocytes and macrophages in obese adipose tissue. Methods and Procedures: PPAR-α ligands (Wy-14,643 and fenofibrate) were added to 3T3-L1 adipocytes, RAW264 macrophages, or co-culture of 3T3-L1 adipocytes and RAW264 macrophages in vitro, and monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) mRNA expression and secretion were examined. PPAR-α ligands were administered to genetically obese ob/ob mice for 2 weeks. Moreover, the effect of PPAR-α ligands was also evaluated in the adipose tissue explants and peritoneal macrophages obtained from PPAR-α-deficient mice. Results: In the co-culture of 3T3-L1 adipocytes and RAW264 macrophages, PPAR-α ligands reduced MCP-1 and TNF-α mRNA expression and secretion in vitro relative to vehicle-treated group. The anti-inflammatory effect of Wy-14,643 was observed in adipocytes treated with macrophage-conditioned media or mouse recombinant TNF-α and in macrophages treated with adipocyte-conditioned media or palmitate. Systemic administration of PPAR-α ligands inhibited the inflammatory changes in adipose tissue from ob/ob mice. Wy-14,643 also exerted an anti-inflammatory effect in the adipose tissue explants but not in peritoneal macrophages obtained from PPAR-α-deficient mice. Discussion: This study provides evidence for the anti-inflammatory effect of PPAR-α ligands in the interaction between adipocytes and macrophages in obese adipose tissue, thereby improving the dysregulation of adipocytokine production and obesity-related metabolic syndrome.