A mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) is approved as one of the immunosuppressive drugs for the prevention of graft organ rejection as well as the agent against various types of cancer and tuberous sclerosis complex. EVR in combination with cyclosporine was approved as an immunosuppressive regimen for the patients after heart transplantation in 2007 in Japan. After that, EVR was also approved for the prevention of graft kidney rejection in 20111. Tacrolimus has been used as a primary calcineurin inhibitor (CNI) in patients after kidney transplantation, and therefore, it is important to establish the methodology of EVR monitoring including the appropriate target range.

Minimizing the use of CNI after organ transplantations reduces long-term complications, including nephrotoxicity and myelosuppression2,3. It was reported that another mTOR inhibitor sirolimus reduced interstitial fibrosis and glomerular sclerosis after kidney transplantation in patients with chronic allograft nephropathy4. In the subtotal nephrectozised (5/6Nx) rats, which are well acknowledged as a good animal model of chronic renal failure in human, marked activation of the mTOR pathway was found at glomeruli and proximal tubules in remnant kidneys5. EVR treatment reduced the expression levels of the phosphorylated S6 which is a marker of activated mTOR. In addition, EVR-treatment restored the tubular reabsorption of albumin, suggesting the regeneration from the functional impairment of tubular epithelial cells5.

Taken together, both of the results of the clinical trials and animal experiments suggest that EVR in combination with the minimized CNI would be a strong strategy in patients after organ transplantation preventing long-term CNI-induced nephrotoxicity such as fibrotic renal disease.

References:

1 Highlights of prescribing information of ZORTRESS® (everolimus) (2016).

2 van Gelder, T., Fischer, L., Shihab, F. & Shipkova, M. Transplant Rev 31, 151-157 (2017).

3 Shipkova, M. et al. Ther Drug Monit 38, 143-169 (2016).

, L. et al. Transplantation 85, 821-826 (2008).

5 Nakagawa, S., Masuda, S., Nishihara, K. & Inui, K. Biochem Pharmacol 79, 67-76 (2010).

Grant information: KAKENHI from MEXT Japan (15H04666)

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We report a case of diffuse large B-cell lymphoma (DLBCL) of the retroperitoneum showing a cohesive cytological pattern. Imprint smears of the lesion were easily diagnosed as DLBCL by Diff-Quick staining, but tumor cells with large round nuclei and clear pale cytoplasm also showed a cohesive pattern in Papanicolau staining, meaning that clear-cell renal carcinoma could not be ruled out. DLBCL rarely affects retroperitoneal lymph nodes or soft tissue. Our case thus indicates that DLBCL may show a cohesive pattern both in cytological and histological specimens.

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Vasopressin (0.8-1.0 IU), diluted with saline (10 IU vasopressin per 100 ml saline), was selectively injected into the external carotid artery (ECA) to control massive hemorrhage caused by inaccessible serious craniofacial injuries in two patients. This method produced remarkable angiographic vasoconstriction at the involved ECA branches and resulted in immediate hemostasis. Intra-arterial vasopressin injection is a useful option for the treatment of intractable traumatic hemorrhage from inaccessible ECA branches.

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Fast-disintegrating (FD) tablets containing nicorandil-loaded dry emulsions were prepared and their controlled-release properties were examined and compared with the plain FD tablets (FD tablets without dry emulsions) and commercial tablets. The dry emulsions were prepared with myristyl alcohol and stearyl alcohol and their property was modified by mixing the ratio of the two alcohols. Disintegration time of the prepared FD tablets was sufficiently fast (i.e., 12 to 23s). In vitro release of nicorandil from the FD tablets containing the dry emulsions was sustained over 6h, while that from plain FD and commercial tablets was complate within 5min. In vivo absorption of nicorandil from the tablets was evaluated by oral administration in beagle dogs. FD tablets containing dry emulsions showed a similar AUC, lower C_max, and delayed T_max compared to the plain FD and commercial tablets. These results suggest that the dry emulsion-loaded FD tablets can be utilized to improve the sustained-release property of active drugs.

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A 63-year-old man presented with hypoglycemia-induced hemiparesis manifesting as diffusion-weighted magnetic resonance (MR) imaging changes in the splenium of the corpus callosum and internal capsule which disappeared after glucose administration. Clinicians should be aware that hypoglycemia can cause reversible splenium abnormalities on MR imaging, although the underlying mechanism still remains unclear, as this may be helpful in the differential diagnosis of hypoglycemia-induced hemiparesis and stroke.

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A 35-year-old man developed osteosarcoma of the left parietal and occipital bones 16 years after radiotherapy for glioma in the right occipital lobe. Radiotherapy of the primary neoplasm used 50 Gy administered to a localized field through two lateral ports. The secondary neoplasm arose contralateral to the primary lesion but within the irradiated field. The tumor had a multilocular cyst with considerable intracranial extension, and symptoms of elevated intracranial pressure were prominent early in the course. After a short-lived initial remission following surgical intervention and chemotherapy, the patient deteriorated because of tumor recurrence and died 18 months after the diagnosis. Radiation-induced osteosarcoma is a well-known but rare complication of radiotherapy for brain neoplasms with a poor prognosis.

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  Gambir (asen'yaku in Japanese), an aqueous extract of leaves and young twigs of Uncaria gambir Roxb., has traditionally been used as a treatment for diarrhea and dysentery as an internal medicine and for sore throat as a gargle. Although it is a pharmacopoeic medicine in Japan, the quantitative evaluation of its constituents has not yet been adopted in the Japanese pharmacopoeia. We analyzed polyphenolic constituents in 31 gambir and related products to establish evaluation methods, since gambir contains large amounts of polyphenolic constituents. The total flavan contents in the samples revealed using the vanillin-HCl estimation method ranged from 24-79%. Reversed-phase high performance liquid chromatography (RP-HPLC) analysis indicated that catechin was the most abundant constituent in each sample, with contents in the range of 7-76%. The catechin contents in the gambir products between the first and third quartiles were 28-54%. Thus, the lower limit of the catechin content in gambir products can be set at around 20% for quality management. Fifteen tested samples were subjected to HPLC analysis to show the presence of epicatechin (1.5% on average) and the dimeric compounds procyanidin B1, procyanidin B3, and gambiriin A1 (ca. 1% each). The molecular weight distributions of polymeric flavans in the gambir products were analyzed by gel permeation chromatography (GPC) and showed that the average degree of polymerization for each sample was 3 to 7. These results indicate that the combination of the vanillin-HCl method, RP-HPLC analysis, and GPC analysis gives valuable information for evaluating the polyphenolic profiles of gambir products.

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This paper describes phase noise floor level of digital phase noise measurement. It has estimated the noise floor level of phase noise from ENOB of the analog to digital converter and sampling frequency. We have discussed phase noise measurement using normal sampling based on sampling theorem and under sampling which samples longer sampling period than the signal under the test. We compared the phase noise spectral density of noise floor between normal sampling and under sampling. As a result, measurement results are in good agreement in both methods.

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Nutritional survey was conducted in a winter season of 1992-3 by collecting seventy-one 24-hour food duplicate samples from three groups of middle-aged women (22 to 25 subjects per group) in traditional residential areas in the cities of Tokyo (two groups) and Kyoto (one group), two cultural centers in Japan known to have different food customs. The analysis in terms of intake of nutrients such as energy, carbohydrate, protein, lipid, minerals, vitamins and fibers did not show significant difference among the three groups studied. Sodium chloride intake also did not differ. Daily consumption of food materials (evaluated as classified in terms of, e.g., cereals, meat, fish and vegetables) was similar. Relative weight of three meals and snacks in energy intake did not vary among the groups. Consumption of milk and bread as indicators of intake of non-traditional food was also comparable among the groups. The observation as a whole suggests that the different food custom once known to be present between the two local cultures is no longer detectable. Nationwide extensive transport of food materials is discussed as one of possible causes.

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  The local delivery of antibiotics in the treatment of infectious respiratory diseases is an attractive alternative to deliver high concentration of antimicrobials directly to the lungs and minimize systemic side effects. In this study, inhalable microparticles containing doxycycline hyclate, sodium carboxymethylcellulose, leucine and lactose were prepared by spray drying of aqueous ethanol formulations. Box-Behnken design was used to study the influence of various independent variables such as polymer concentration, leucine concentration, ethanol concentration and inlet temperature of the spray dryer on microparticle characteristics. The microparticles were characterized in terms of particle morphology, drug excipient interaction, yield, entrapment efficiency, Carr's index, moisture content, thermal properties, X-ray powder diffraction, aerosolization performance and in vitro drug release. The effect of independent variables on spray dryer outlet temperature was also studied. The overall shape of the particles was found to be spherical like doughnuts in the size range of 1.16-5.2 μm. The optimized formulation (sodium carboxymethylcellulose concentration 14% w/v, leucine concentration 33% w/v, ethanol concentration 36% v/v, inlet temperature of 140°C) exhibited the following properties: yield 56.69%, moisture content 3.86%, encapsulation efficiency 61.74%, theoretical aerodynamic diameter 3.11 μm and Carr's index 23.5% at an outlet temperature 77°C. The powders generated were of a suitable mass median aerodynamic diameter (4.89 μm) with 49.3% fine particle fraction and exhibited a sustained drug release profile in vitro.

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We report 2 cases with an isolated single coronary artery who underwent successful primary coronary intervention for acute coronary syndrome. Although coronary angioplasty with stenting may be a feasible therapeutic option for atherosclerotic stenosis in a single coronary artery, the operator should be aware of the potential risk of complications.

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A 60-year-old female presented with a carotid-cavernous fistula (CCF) manifesting as left abducens nerve palsy. Left internal carotid digital subtraction angiography showed a persistent primitive trigeminal artery (PPTA) near the CCF. Super-selective angiography showed direct shunt flow between the PPTA trunk aneurysm and the left cavernous sinus. The aneurysm was successfully occluded with detachable coils. The CCF disappeared and the PPTA was preserved. The abducens nerve paralysis had disappeared 6 months later. CCF caused by a PPTA trunk aneurysm is extremely rare. We speculate that the PPTA trunk aneurysm formed and then ruptured due to hemodynamic stress caused by hypoplasia of the basilar artery.

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The initial, linear elastic range of a soil stress-strain curve is often defined by the small-strain elastic modulus E₀ or shear modulus G₀. In the present study, simpler and effective methods are proposed for the estimation of the small-strain stiffness of clean and silty sands; these are based on triaxial compression test results and the CPT cone resistance q_c. In the method based on stress-strain curves obtained from triaxial compression tests, an extrapolation technique is adopted within the small-strain range of a transformed stress-strain curve to obtain estimates of the small-strain elastic modulus. Calculated small-strain elastic modulus values were compared with the values measured using bender element tests performed on clean sands and sands containing nonplastic fines. The results showed that the method proposed produces satisfactory estimates of the small-strain elastic modulus for practical purposes. In the CPT-based method, two G₀-q_c correlations available in the literature were evaluated. For isotropic conditions, both correlations produced reasonably good estimates of G₀ for clean sands but overestimated it for silty sands. A G₀-q_c correlation which is proposed takes into account the effect of silt content of the sand and stress anisotropy.

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The anti-edema effect of edaravone, a free radical scavenger, was evaluated by magnetic resonance imaging in six patients with extensive hemispheric ischemic stroke. T₂ relaxation time in the infarct core, the boundary zone of the infarct, and the noninfarcted hemisphere were calculated, and T₂ mapping was performed before and after edaravone administration. Edaravone administration significantly decreased the mean T₂ relaxation time in the boundary zone of the infarct from 121.5 ± 9.2 (mean ± standard deviation) to 114.5 ± 9.9 msec (p = 0.008), but not in the core from 142.3 ± 13.4 to 142.2 ± 18.5 msec (p = 0.97) or the noninfarcted hemisphere from 93.0 ± 3.7 to 93.1 ± 3.8 msec (p = 0.91). The T₂ subtraction map clearly demonstrated shortened T₂ relaxation time in the boundary zone of the infarct. The present results indicate that edaravone can salvage the boundary zone of the infarct and is a useful cytoprotective anti-edema agent.

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Postoperative nausea and vomiting (PONV) with morphine therapy develops in more than 60% of patients after surgery, markedly reducing patient QOL. The prophylactic effect of several antiemetics has already been studied, but evaluations, and even those using the same drug, are not uniform. The present research involved a meta-analysis of randomized controlled trials on prophylactic drug therapy for PONV in patients receiving morphine for the treatment of postoperative pain. The efficacy of the prophylactic administration of the drugs was examined. As a result, meta-analysis of five drugs was possible and the evidence of efficacy was shown for three drugs ranked in order of an increasing odds ratio (OR) and confidence interval (CI): dexamethasone (OR: 0.23, 95% CI: 0.15-0.35, p<0.00001), droperidol (OR: 0.27, 95% CI: 0.21-0.34, p<0.00001), and metoclopramide (OR: 0.48, 95% CI: 0.30-0.75, p<0.001). These results suggest that the three drugs are effective in prophylactic treatment for PONV. Of them, dexamethasone used as a prophylactic drug for PONV provided the best results. Dexamethasone was shown to reduce the incidence of PONV from 66-80% to 16-50% with a dose of 1.25 to 10 mg and to be suitable as a first drug of choice.

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　症例は53歳の男性で，右下腹部痛を主訴として来院した．腹部CT検査では小腸に連続した径４cm大の腫瘤が存在し，内部に低吸収構造を認めた．膿瘍を伴うMeckel憩室炎を強く疑い，腹腔鏡下に観察した．回腸末端から約60cm口側の回腸に，憩室が存在した．そこで自動縫合器を用いて，回腸の一部を含めて憩室を切除した．切除標本では憩室の粘膜は壊死し，内部に膿が存在した．術後経過は良好で，術後７日目に退院した．Meckel憩室炎に対する腹腔鏡下手術は大変有用で，確定診断から治療までを一貫して施行できた．

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  癌患者でも自己抗体の産生が報告されているが，全身性自己免疫性リウマチ性疾患（SARD）関連自己抗体の検討は少ない．本研究では乳癌患者における自己抗体特異性と癌の臨床的，病理学的，免疫組織化学的所見との関連を追求することを目的とした．【方法】メキシコ人乳癌患者152名の血清自己抗体は免疫沈降法，ELISAで検索した．自己抗体特異性と乳癌の組織型，免疫組織化学でのエストロゲン受容体（ER），プロゲステロン受容体（PGR），上皮成長因子受容体2（HER2）発現などとの関連を分析した．【結果】抗TIF1γ抗体（n＝2），Ro60（n＝6），Ro52（n＝9），Su/Ago2（n＝4），PM-Scl（n＝1），DFS70（n＝8）が検出された．DFS70を除いたSARD関連抗体（+）群（n＝19）ではER（+）が陰性例（n＝133）に比べ高かった（37％ vs 65％，P＜0.05）．抗体特異性別では抗Ro60（+）群で陰性群に比しER（+）（33％ vs 65％），PGR（+）（33％ vs 58％）が低くHER2（+）は高く（100％ vs 50％，p＝0.06），HER2，3+はRo60群で多かった（60％ vs 20％，p＝0.07）．DFS70（+）はPM-Scl（+）1例以外はSARD関連抗体と重複なく，ER（+）50％，PGR（+）75％，HER2（+）38％（3+染色13％）とSARD関連抗体やRo60（+）と逆の関連がみられた．【結語】自己抗体特異性と乳癌組織ホルモン受容体発現に関連がみられた．受容体の刺激は自己抗原の発現やリン酸化に影響を与えることが報告されており，これらの変化が自己抗体産生に関与する可能性が示唆された．

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A 23 year-old Taiwanese male presented with complete membranous obstruction of the inferior vena cava at its suprahepatic portion. After 3 angioplasty procedures using Inoue-balloon catheters, a Wall stent was deployed for restenosis 4 years after the first procedure. Venography at 6 months showed no significant restenosis. At 20 months transfemoral venography confirmed patency of the vena cava.

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症例は45歳の男性.検診で便潜血反応陽性であったため精査目的で外来を受診した.大腸内視鏡検査で横行結腸に粘膜下腫瘍を認め,腹腔鏡補助下結腸楔状切除術を施行した.病理組織検査では紡錘形細胞が線維束状に増殖しており,免疫染色でc-kit, vimentin, S-100, NSE (neuron specific enorase)が陽性, CD34, desmin, α-SMA (smooth muscle actin), NF (neurofilament)が陰性であった.横行結腸gastrointestinal stromal tumorのneural typeと診断した.術後10カ月経過した現在,無再発生存中である.

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