Roles of the auditory cortex in discrimination learning by rats

We investigated the roles of the auditory cortex in sound discrimination learning in Wistar rats. Absolute pitch or relative pitch can be used as discrimination cues in sound frequency discrimination. To clarify this, rats were trained to discriminate between rewarded (S+) and unrewarded (S-) test stimuli (S+ frequency>S- frequency). After learning was acquired by rats, performance was tested in a new test in which S+ frequency was constant but S+ frequencyS- frequency but both frequencies were increased. If the discrimination cue of the first test was preserved in the new test, performance following change of testing procedures was expected to remain high. The measured performance suggested that rats used relative pitch in half octave discrimination (difference between S+ and S- frequencies, 0.5 octave), and absolute pitch in octave discrimination (difference between S+ and S- frequencies, 1.0 octave). Bilateral lesions in the auditory cortex had almost no effect on performance before procedure change. Furthermore, performance following procedure change was not affected by lesions in the auditory cortex when the discrimination cue was preserved. However, performance was impaired by lesions in the auditory cortex when a new discrimination cue was used following procedure change. Lesions in the auditory cortex also impaired multimodal discrimination between sound and sound plus light. The present findings suggest that the auditory cortex plays a role as a sensory interface of the higher cortices required for flexible learning and multimodal discrimination.     

Altered phospholipid transfer protein gene expression and serum lipid profile by topotecan

Camptothecin (CPT) and its structural analogues including topotecan and irinotecan, are inhibitors of topoisomerase I. These drugs are clinically active against a broad spectrum of cancers. To understand the genesis of chemotherapeutic resistance to the CPT family of anticancer drugs, we examined by gene expression profiling the pharmacological response to topotecan in the human hepatoma HepG2 cells and found a striking induction of the phospholipid transfer protein (PLTP) gene expression by topotecan. We showed that activation of PLTP gene expression is specific to CPT and its analogues including specific enantiomers that inhibit topoisomerase I. PLTP-mediated lipid transfer to high-density lipoprotein (HDL) is thought to be important for shuttling and redistribution of lipids between lipoproteins, which are normally returned to the liver for metabolism via the reverse cholesterol transport pathway. Hence, we asked whether elevated PLTP levels might increase the transfer of drugs into HDL. We observed that CPT was not accumulated in HDL and other lipoproteins. In addition, topotecan treatment in mice caused a marked reduction in serum HDL that was accompanied by an increase in triglyceride and cholesterol levels. These results showed that PLTP does not mediate the transfer of topoisomerase I inhibitors to serum lipoproteins. However, elevated serum PLTP levels following treatment with topoisomerase I inhibitors in cancer patients may serve as a biomarker for monitoring the development of hypertriglyceridemia and acute pancreatitis.     

Combination of 5‐aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft‐versus‐host disease

Scleroderma or systemic sclerosis (SSc) is a clinically heterogeneous rheumatological autoimmune disease affecting the skin, internal organs and blood vessels. There is at present no effective treatment for this condition. Our study investigated the effects of 5‐aminolevulinic acid (5‐ALA), which is a precursor of haem synthesis, on graft‐vs‐host disease (GvHD)‐induced SSc murine model. Lymphocytes were intravenously injected from donor mice (B10.D2) into recipient BALB/c mice (recombination‐activating gene 2 (Rag‐2)‐null mice) deficient in mature T and B cells to induce sclerodermatous GvHD (scl‐GvHD). To investigate the effect of 5‐ALA on scl‐GvHD, combination of 5‐ALA and sodium ferrous citrate (SFC) was orally administered to the recipient mice for 9 weeks. 5‐ALA/SFC treatment significantly reduced progressive inflammation and fibrosis in the skin and ears. Furthermore, 5‐ALA/SFC suppressed mRNA expression of transforming growth factor‐β, type I collagen and inflammatory cytokines. These results indicate that the 5‐ALA/SFC combination treatment has a protective effect against tissue fibrosis and inflammation in a murine scl‐GvHD‐induced skin and ear inflammation and fibrosis. Furthermore, the efficacy of 5‐ALA/SFC suggests important implications of HO‐1 protective activity in autoimmune diseases, and therefore, 5‐ALA/SFC may have promising clinical applications. These findings suggested that the 5‐ALA/SFC treatment may be the potential strategies for SSc.     

Embryonic development of the self‐fertilizing mangrove killifish Kryptolebias marmoratus

Developing embryos of the self‐fertilising mangrove killifish Kryptolebias marmoratus. PTU‐treated embryo (left) lacking melanin pigmentation and a normal embryo (right), 10 days post‐fertilisation. Due to its ability to self‐fertilise, this species proves to be a highly useful embryological model with unique genetics. From Mourabit et al., Developmental Dynamics 240:1694–1704, 2011.     

Comparison between unattended automated office blood pressure and conventional office blood pressure under the environment of health checkup among Japanese general population

Unattended automated office blood pressure (AOBP) measurement has been endorsed as the preferred in‐office measurement modality in recent Canadian and American clinical practice guidelines. However, the difference between AOBP and conventional office blood pressure (CBP) under the environment of a health checkup remains unclear. We aimed to identify the clinical significance of AOBP as compared to CBP under the environment of a health checkup. There were 491 participants (333 females, mean age of 62.5 years) who were at least 20 years old, including 179 participants who were previously diagnosed with hypertension. Mean AOBPs were 131.8 ± 20.9/76.6 ± 11.7 mm Hg, and CBPs were 135.6 ± 21.6/77.3 ± 11.5 mm Hg. There was a difference of 3.9 mm Hg in systolic blood pressure (SBP) and 0.8 mm Hg in diastolic BP between AOBP and CBP. In all participants, SBP and pulse pressure, as well as the white coat effect (WCE), increased with age. The cutoff value used was 140/90 mm Hg for CBP and 135/85 mm Hg for AOBP, and the prevalence of WCE and masked hypertension effect (MHE) was 12.4% and 14.1%, respectively. Even in a health checkup environment of the general population, there was a difference between the AOBP and CBP, and the WCE was observed more strongly in the elderly with a history of hypertension, suggesting that a combination of AOBP with CBP may be useful in detecting WCE and MHE in all clinical scenarios including health checkups, and help solve the “hypertension paradox” not only in Japan but in all over the world.     

Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer

AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability(MSI) status in Japanese colorectal cancer(CRC) population.METHODS: We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected, stage Ⅰ-Ⅲ CRC and examined associations of these mutations with disease-free survival(DFS) and overall survival(OS) using uni- and multivariate Cox proportional hazards models.RESULTS: KRAS and BRAF mutations were detected in 312(38%) of 812 and 40(5%) of 811 tumors, respectively. KRAS mutations occurred more frequently in females than in males(P = 0.02), while the presence of BRAF mutations was significantly associated with the female gender(P = 0.006), proximal tumor location(P 0.001), mucinous or poorly differentiated histology(P 0.001), and MSI-high tumors(P 0.001). After adjusting for relevant variables, including MSI status, KRAS mutations were associated with poorer DFS(HR = 1.35; 95%CI: 1.03-1.75) and OS(HR = 1.46; 95%CI: 1.09-1.97). BRAF mutations were poor prognostic factors for DFS(HR = 2.20; 95%CI: 1.19-4.06) and OS(HR = 2.30; 95%CI: 1.15-4.71). Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS.CONCLUSION: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, inJapanese patients with curatively resected CRC.     

Interstitial pneumonia complicated by Sjögren's syndrome, Hashimoto's disease, rheumatoid arthritis and primary biliary cirrhosis

A 66-year-old woman diagnosed as having Hashimoto's disease and rheumatoid arthritis manifested interstitial pneumonia. We diagnosed Sj?gren's syndrome and primary biliary cirrhosis as complications in this case. Steroid therapy was relatively effective for the interstitial pneumonia which was in an active state; however, during tapering of the steroid, there was a relapse and also severe dry throat. Cyclophosphamide was added and was effective in the prevention of recurrence. Even after discontinuation of steroid therapy, her general condition is stabilized. It is very important to carefully investigate other organ involvement as a prognostic factor in cases in which there are multiple autoimmune diseases.     

Slow continuous hemodialysis--new therapy for acute renal failure in critically ill patients--Part 1. Theoretical consideration and new technique

In order to treat acutely uremic patients in an unstable hemodynamic state, we developed a new system for slow continuous hemodialysis. It is well known that continuous hemofiltration or peritoneal dialysis are successful in terms of removing the excess body water without adverse effects on hemodynamics. On the other hand, hemodialysis is far more effective in eliminating solutes such as uremic toxins, especially under a catabolic state. In order to combine the merits of both interventions, volume control and solute removal were dealt with separately in our system. The main system is composed of a double-pump driven closed circuit for the re-circulated hemodialysis. Volume control was achieved accurately within +/- 5% error of the set rate. The dialysance was evaluated in vitro and the efficacy of solute elimination was simulated mathematically. It was speculated that slow continuous hemodialysis could be a new method of treating critically ill patients with acute renal failure.