Translational approach to apathy-like behavior in mice: From the practical point of view.

Apathy is a pervasive clinical phenomenon that deserves more attention at the translational and pre-clinical levels. To study apathy-like behavior in mice, we relied on an operational definition of apathy: the quantitative reduction of voluntary, goal-directed behaviors. We recently found that the chronic loss of function of a specific cell type (striatal dopamine receptor type 2-expressing medium spiny neurons, D2-MSN) in a restricted region (the ventrolateral striatum, VLS) was sufficient to induce apathy-like behavior in a food-seeking operant task. We further showed that VLS D2-MSN are activated at the preparatory period, and that optogenetic inhibition of VLS D2-MSN during that period resulted in transient decreases in instrumental motivation, strengthening the hypothesis that VLS D2-MSN mediate apathy-like behavior in mice. Mice bearing VLS D2-MSN dysfunction can thus be regarded as an apathy model for future translational studies.

AppNL-G-F/NL-G-F mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation.

Apathy is clinically defined as lack of motivation. Apathy is a frequent symptom in patients with Alzheimer's disease (AD). It is unclear whether amyloid ß (Aß) pathology is associated with apathy. To address this question, we employed the AppNL-G-F/NL-G-F mouse, an Aß deposition-bearing mouse without neurofibrillary tangles and neuronal cell death throughout the lifespan and used a progressive-ratio (PR) task to monitor instrumental motivation between the ages of 16 and 39 weeks. In the PR task, the number of lever presses to receive one reward increases and the number of active lever presses in the final trial a mouse completes represents a break point, which is an index of motivation. During the observation period, AppNL-G-F/NL-G-F mice overall did not show impaired motivation. However, AppNL-G-F/NL-G-F mice showed a dispersion of the break point at 39 weeks of age within the group. Therefore, we examined the association between the degree of the break point and Aß pathology; the number of cored amyloid plaques in the striatum was inversely correlated with the degree of motivation. Furthermore, we measured the dopamine transporter (DAT) levels in the subcortical tissues including the striatum using western blot analysis and showed that AppNL-G-F/NL-G-F mice have lower DAT levels than do C57BL/6J mice. Although we could not directly determine the effect of core amyloid plaques on the DAT, the results of this study suggest a pathway through which cored amyloid plaques damage the DAT and cause impaired motivation. These results will draw attention to cored amyloid plaques and will aid researchers searching for new strategies that are effective for the prevention and treatment of impaired motivation.

Yokukansankachimpihange increased body weight but not food-incentive motivation in wild-type mice.

Yokukansankachimpihange (YKSCH), a traditional Japanese medicine, is widely used for the amelioration of the behavioral and psychological symptoms of dementia with digestive dysfunction. Regardless of its successful use for digestive dysfunction, the effect of YKSCH on body weight was unknown. Furthermore, if YKSCH increased body weight, it might increase motivation according to Kampo medicine theory. Therefore, we investigated whether YKSCH had the potential to increase body weight and enhance motivation in mice. To address this, C57BL/6J mice were used to evaluate the long-term effect of YKSCH on body weight and food-incentive motivation. As part of the evaluation, we optimized an operant test for use over the long-term. We found that feeding mice YKSCH-containing chow increased body weight, but did not increase their motivation to food reward. We propose that YKSCH may be a good treatment option for preventing decrease in body weight in patients with dementia.

Goshajinkigan for Low Back Pain: An Observational Study.

OBJECTIVES: Low back pain (LBP) is a chronic condition. Although Western treatments are available, Kampo (traditional Japanese) medicine is widely prescribed and covered by health insurance in Japan. Goshajinkigan (GJG), a Kampo formula, is commonly used to treat LBP. However, cases we have occasionally been encountered in which GJG did not show the expected effects. Hence, the purpose of this retrospective study was to investigate patient factors important in developing the effects of GJG. METHODS: This was a retrospective observational study based at the Center for Kampo Medicine, Keio University Hospital. Data were retrieved from the medical records of 28 patients who visited our hospital between May 2008 and March 2013 and who received GJG for LBP. The patients were divided into responders and non-responders based on whether their LBP improved post treatment. The groups were compared with respect to daily GJG dose, incidence of spine disease, and side effects. RESULTS: Ten patients (responders) reported an improvement in LBP within 6 months. One patient experienced decreased appetite as a side effect. Nine patients reported no improvement (non-responders). The number of patients prescribed the usual daily dose of GJG (7.5 g) was significantly higher among responders than it was among non-responders (p = 0.023), and the number of patients with spine disease was significantly greater among non-responders than it was among responders (p = 0.020). The number of patients with spinal stenosis was significantly higher among non-responders than it was among responders (p = 0.011). Therefore, the usual daily dose of GJG provided significant relief of LBP, particularly in patients without any spine disease. CONCLUSIONS: Routine daily administration of GJG in patients without spine disease seems to lead to the effects of the product. However, further investigations using the above-mentioned parameters are needed to confirm these findings.

[Clinical experience with transurethral resection of bladder tumor (TUR-Bt) guided by photodynamic diagnosis (PDD)].

PURPOSE: To report our clinical experience regarding transurethral resection of bladder tumor (TUR-Bt) guided by photodynamic diagnosis (PDD) with intravesical instillations of 5-aminolevulinic acid (ALA) and to assess the usefulness of the therapeutic method. MATERIALS AND METHODS: TUR-Bt guided by PDD was performed in 57 patients of which 47 were men and 10 women with a median age of 74.3 years (range 45-90), 36 were primary cases and 21 were recurrent cases with non-muscle invasive bladder cancer. Two to two and half hours prior to endoscopy 1.5 g ALA dissolved in 50 ml of 8.4% sodium hydrogen carbonate (NaHCO3) solution was instilled intravesically. For fluorescence excitation a blue light source (D-LIGHT System, Karl Storz Endoscopy Japan K.K.) was used. The tumorous lesions under white light guidance and the lesion with fluorescent excitation under blue (fluorescence) light guidance were taken by cold cup as a biopsy and also resected sequentially. To evaluate the accuracy of PDD, the levels in images of the ALA-induced fluorescence were compared with the pathological results. To evaluate the availability of TUR-Bt guided by PDD, survival Analysis regarding vesical recurrence was retrospectively examined compared to the cases underwent conventional TUR-Bt under white light guidance. Moreover, in these cases, multivariate analysis using Cox proportional-hazards model was performed to detect the clinico-pathological factor independently contribute to improving prognosis. (Results) In the 301 specimens obtained from 57 patients, the sensitivity and specificity of PDD were 92.5% and 60.1%, whereas the sensitivity and specificity of conventional endoscopic examination under white light guidance were 81.6% and 79.5%, respectively. Median follow-up period was 19.1 (range 8.6-49.9) months in 57 patients underwent TUR-Bt guided by PDD. Eight of 57 patients recurred and recurrence-free survival rate was 88.2 +/- 0.1% (at 12 months) and 76.2 +/- 0.1% (24-48 months). Median follow-up period was 49.9 (5.0-145.0) months in 149 patients underwent conventional TUR-Bt. Ninety-nine of 149 patients recurred and recurrence-free survival rate was 60.3 +/- 0.0% (12 months) and 31.6 +/- 0.0% (24-48 months). There was statistical significance in recurrence-free survival rate between these 2 therapeutic groups (p < 0.001). Moreover, multivariate analysis revealed the independent factor contribute to improving prognosis was only TUR-Bt guided by PDD (hazard ratio 0.279, p = 0.001). CONCLUSION: It was suggested that TUR-Bt guided by PDD might reduce the risk of vesical recurrence in the early stage after operation of non-muscle invasive bladder cancer.

Synthesis of 2-methyl 16-membered macrolide derived from tylosin.

To improve the metabolic stability of a 16-membered macrolide, 2-methylated derivatives of desmycosin were synthesized. Among these derivatives, 2beta-methyldesmycosin retained antibacterial activity and showed improved stability in rat serum compared to desmycosin.

[Partial nephrectomy using microwave tissue coagulator--application for laparoscopic operation].

We report our clinical findings on 12 tumors (11 patients) successfully resected by partial nephrectomy with a microwave tissue coagulator (MTC) without renal pedicle clamping, including laparoscopic operation in 4 patients. All patients presented with a renal tumor detected incidentally by ultrasonography or computed tomography. The mean size of renal tumor was 1.9 (range 0.8-3.4) cm. Pathological diagnosis was renal cell carcinoma in 9 tumors and hemorrhagic cyst in 3 tumors. Mean operative time was 249 minutes. Mean blood loss was 183 ml in cases with a laparoscopic operation, that was statistically less than 486 ml in cases with an open operation (p<0.05), and 376 ml in all cases. There was no significant change in the creatinine clearance of cases with laparoscopic operation, compared with that of cases with an open operation. There were no other serious complications postoperatively. These findings suggested that partial nephrectomy with the MTC can be safely and successfully carried out while sparing renal function. Moreover, partial nephrectomy with the MTC for a laparoscopic operation may provide these patients with more benefits.