Nutcracker syndrome as the main cause of left renal vein thrombus and pulmonary thromboembolism.

INTRODUCTION: Left renal vein thrombus complicating nutcracker syndrome is relatively rare. To the best of our knowledge, there have been only four previous case reports. Furthermore, there have been no reports of pulmonary thromboembolism caused by nutcracker syndrome. Herein, we report a rare case of pulmonary thromboembolism caused by nutcracker syndrome and its clinical management. CASE PRESENTATION: A 40-year-old man was admitted to our hospital with acute left flank pain. Computed tomography angiography revealed compression of the left renal vein between the aorta and the superior mesenteric artery with a left renal vein thrombus. Furthermore, computed tomography revealed bilateral pulmonary thromboembolism. Rivaroxaban was administered as an anticoagulant. Twenty days after initiation, computed tomography revealed complete resolution of pulmonary thromboembolism and left renal vein thrombus, and repeated computed tomography showed no recurrence. CONCLUSION: This case report highlights nutcracker syndrome as a likely cause of pulmonary thromboembolism.

Efficacy of nivolumab plus ipilimumab as first-line therapy for primary tumors in patients with renal cell carcinoma.

OBJECTIVES: With the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors. METHODS AND MATERIALS: We retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP. RESULTS: The median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1-6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%-60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391). CONCLUSIONS: Significant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints.

Renal Mucinous Tubular and Spindle Cell Carcinoma Shows a High Uptake on 18F-FDG PET/CT.

We herein report a rare case of mucinous tubular and spindle cell carcinoma (MTSCC) in an 80-year-old woman. A well circumscribed tumor located on the right kidney was discovered incidentally as a result of screening non-contrast CT. Fluorodeoxyglucose positron emission tomography (FDG PET)/CT showed the increased tracer accumulation in the tumor. The histological diagnosis was MTSCC, which is a rare and only recently established subtype of the malignant renal cell carcinoma (RCC). The present case suggests the clinical benefit of a high uptake of FDG combined with enhanced contrast CT in the differentiation of MTSCCs and other RCCs.

Dutch Research on Beriberi: I. Christiaan Eijkman's Research and Evaluation of Kanehiro Takaki's Diet Reforms of the Japanese Navy.

Dutch researcher Christiaan Eijkman realized that a form of Polyneuritis closely resembling Beriberi occurred among chickens that were fed with cooked, instead of raw rice. He found that the cause of this illness lay in the nutritional differences between rice that still had its bran layer, and polished white rice. He also found that this bran layer had a therapeutic effect. He decided to investigate the incidence of Beriberi among humans by comparing a diet based on white rice with one based on unpolished, full-grain rice. In 1898, he published 'Beri-Beri en Voeding, Een Kritisch-Historische Studie' (Beri-beri and Feeding, An Important Historical Study), in which he discussed the diet reforms of Van Leent in the Dutch East Indian Navy, and of Kanehiro Takaki in the Japanese Navy. Notwithstanding the fact that Takaki's research was highly praised by the Lancet, Eijkman was very critical of his research methods. He was conscious, however, that a shift had occurred in the research of Beriberi from bacteria-based research to nutritional deficiencies, and discussed Takaki's findings insofar as he could.

Identification of the role of the sports pharmacist with a model for the prediction of athletes' actions to cope with sickness.

In 2009, the Japan Anti-Doping Agency (JADA) established Sports Pharmacist-a system for certified pharmacists. There are many over-the-counter drugs that contain prohibited substances in Japan, and they are easily available. In Japan, most doping violations are committed when athletes unintentionally take prohibited substances. Therefore, the Sports Pharmacist has a vital role in promoting the prevention of doping. In the present study, surveys involving a total of 350 athletes, (including 260 representatives of Ehime Prefecture in the National Athletic Meets and 90 college students who participated in the intercollegiate athletics Shikoku area meets), on awareness regarding doping and medical drugs were conducted. Using correspondence and logistic regression analyses, the results were examined to develop a model for the prediction of athletes' actions to cope with sickness based on changes in their awareness of anti-doping, and the relationship between them was also analyzed. The survey results suggested that attitudes towards doping were strongly influenced by gender, rather than the athletic ability and whether or not a doping test is scheduled. Their behavior and criteria for the selection of drugs to address sickness were strongly correlated with awareness of anti-doping. Therefore, athletes with an increased awareness of anti-doping are expected to consult a pharmacist prior to using medicine. The Sports Pharmacist should further promote environmental development, such as activities to improve awareness of doping among young athletes and the establishment of medical drug consultation services for athletes (female athletes in particular).

[Opinion survey about purchasing nonprescription drugs over the internet in remote islands--survey among internet-literate inhabitants].

The revised Pharmaceutical Affairs Act that came into force in June 2009 prohibits the sales of nonprescription drugs by mail. However, as a provisional measure, regular users and inhabitants of remote islands that do not have pharmacies or drug stores would be able to purchase nonprescription drugs by mail for two years. However, this regulation is now being discussed from the perspectives of safety and convenience. The purpose of this study was to conduct a survey on the purchasing of nonprescription drugs over the Internet by inhabitants of remote islands belonging to Goto City in Nagasaki prefecture. The results showed that approximately 78.0% of the Internet-literate respondents living on large islands (with pharmacies, drug stores, and pharmacists, e.g., Fukue-shima), 65.4% of the Internet-literate respondents living on small islands scattered around large islands (where pharmacies, drug stores, and pharmacists are not located, e.g., Mae-shima) had purchased necessities except nonprescription drugs, but the rate of purchasing nonprescription drugs over the Internet was approximately less than 10%. The results of this survey suggest that it is not necessary to purchase nonprescription drugs over the Internet. However, owing to a small but significant minority of inhabitants who need to purchase nonprescription drugs over the Internet, there is an urgent need for establishing an optimum system for supplying medicinal products to remote islands.

Preparation and characterization of gelatin sponge millispheres from air-in-water-in-oil-type emulsions.

A novel method for the preparation of gelatin sponge millispheres (GSMs) for biomaterials such as embolic agents and cell scaffolds was developed using an air-in-water-in-oil-type emulsion. The droplets, consisting of a foamy gelatin suspension in caprylic triglyceride, were gelled and rinsed with isopropanol. Sonication and depressurization were used during the rinsing process to create interconnected pores. GSMs cross-links created over 4 h at 155 degrees C without any agent were insoluble and had short and long diameters of 1.1 +/- 0.2 mm and 1.3 +/- 0.2 mm, respectively. The residual isopropanol and caprylic triglyceride were <0.05% (w/w) and <1% (w/w) respectively. The level of bacterial endotoxins in the extracts was below 0.025 EU/ml, and no bacterial or fungal growth was found during sterility testing. The GSMs produced using this method were considered to meet the basic requirements of embolic agents.

Preparation and characterization of gelatin sponge millispheres injectable through microcatheters.

OBJECTIVE: Millimeter size gelatin sponges are commonly used as an embolic agent for transcatheter arterial embolization (TAE). However the preparation of the fragments is troublesome and carries a risk of contamination. The purpose of this study was to develop gelatin sponge millispheres (GSMs), a convenient and reliable agent, and characterize them in vitro. METHOD: The size of GSMs was controlled by modifying the previously reported method to include the use of caprylic triglyceride and isopropanol. Analytical and microbiological tests were conducted to detect impurities (caprylic triglyceride, isopropanol, endotoxins, bacteria, and fungus). The effects of syringe volume (1.0 to 5.0 ml) and contrast media viscosity (1.6 to 13.6 mPa * s) on the in vitro injectability of GSMs through microcatheters of various inner diameters (ID) (0. 43 to 0.53 mm) were examined via in-line pressure monitoring. RESULTS: The GSMs were found to be water-insoluble particles containing interconnected pores. The short and long diameters of the GSMs were 1.82 ± 0.2 mm and 2.37 ± 0.3 mm, respectively. The results of tests for impurities indicated that GSMs have the general properties necessary for medical devices. The GSMs were successfully injected without clogging through a microcatheter (ID: 0.53 mm) attached to a 1.0 or 2.5 ml syringe. CONCLUSION: GSMs have the basic properties and injectability necessary to be considered reliable biomaterials (eg, embolic agents).

[Adrenal multilocular echinococcosis: a case report].

A 79-year-old man was consulted to our hospital for further examination of right adrenal tumor shown by computed tomography. Complete blood cell count, biochemical tests, hormonal examinations and urinalysis were normal. 131I-adosterol scintigram showed decreased uptake on the right adrenal. Right adrenalectomy was done in consider to adrenal cancer. By the pathological findings and the serological tests (ELISA, and Western Blot examination), the tumor was diagnosed as an adrenal multilocular echinococcosis. Mainly, Echinococcosis caused by echinococcus granulosus and echinococcus multilocularis. While E. granulosus is endemic in Europe and Mediterranean coast etc., E. multilocularis is endemic in Japan and North America etc. In E. multilocularis, about 98% of the primary cyst are localized in the liver and the cyst are localized in the lung and brain etc, are rare. In Europe, the primary hydatid cyst is found in the adrenal in only 0.05% of the total case. Moreover, adrenal multilocular echinococcosis is extremely rare case, and is not presented yet in the world. By the patient' s residential history, echinococcosis shoud be considered to differential diagnosis of the adrenal tumor in urology.

Enhanced pharmacological activity of recombinant human interleukin-11 (rhIL11) by chemical modification with polyethylene glycol.

In order to improve the pharmacological efficacy of recombinant human interleukin-11 (rhIL11) and to reduce the frequency of administration, we examined the feasibility of chemical modification of rhIL11 by polyethylene glycol. The rhIL11 was chemically modified by using branched type (PEG2), or linear type (PEG) polyethylene glycol-N-hydroxysuccinimide with various molecular weights. Plasma profiles of immunoreactive rhIL11 after i.v. injection of the 20 kDa PEG2 conjugated rhIL11 (PEG2 (20 K)-rhIL11) were determined by ELISA. Peripheral platelet counts after the administration of the various conjugates were measured. Pharmacokinetic analysis revealed that the mean residence time of PEG2 (20 K)-rhIL11 after i.v. injection extensively increased by a factor of ca 60 compared with the native rhIL11. Maximum peripheral platelet increase of 67% for PEG2 (20 K)-rhIL11 and that of 50% for PEG (20 K)-rhIL11 over the control was observed whereas no significant change was associated with the bolus i.v. injection of native rhIL11. On the other hand, the remaining biological activity of these PEGylated-rhIL11s was 14-16% of native rhIL11, suggesting that retention of rhIL11 in plasma is much effective in order to potentiate the pharmacological efficacy of the cytokine. Chemical modification of rhIL11 by PEG is a promising approach for improving the clinical efficacy of rhIL11 by prolonged retention in plasma.

Incorporation into a biodegradable hyaluronic acid matrix enhances in vivo efficacy of recombinant human interleukin 11 (rhIL11).

In order to improve the therapeutic efficacy of recombinant human interleukin 11 (rhIL11) and to reduce its frequency of administration, the feasibility of a sustained release formulation consisting of hyaluronic acid (HyA) was investigated. rhIL11 was mixed together with an aqueous solution of HyA or HyA and protamine, and the mixture was lyophilized. The resulting powder was compressed into pellet and was subcutaneously administered in the rats. The plasma profile of rhIL11 was determined by ELISA. The mean residence time and t(max) of rhIL11 were much prolonged by administration in an HyA pellet. The additional incorporation of protamine into the formulation further enhanced the plasma duration of the protein. Separately, peripheral platelet counts were measured for several rhIL11-containing solution and pellets. Platelet counts much increased after administration of rhIL11-containing pellets, whereas the effect of bolus subcutaneous administration of rhIL11 solution was limited. The degree of platelet increase in rats treated with the pellets was comparable to that for rats treated with 1- or 2-day continuous infusion from an osmotic mini-pump; these data reflect the importance of increased plasma duration of rhIL11. These data indicate that use of hyaluronic acid as a polymer matrix might enhance the therapeutic efficacy of rhIL11.

Short- and long-term amiodarone treatments regulate Cav3.2 low-voltage-activated T-type Ca2+ channel through distinct mechanisms.

Low-voltage-activated T-type Ca2+ channels have been recognized recently in the mechanisms underlying atrial arrhythmias. However, the pharmacological effects of amiodarone on the T-type Ca2+ channel remain unclear. We investigated short- and long-term effects of amiodarone on the T-type (Cav 3.2) Ca2+ channel. The Cav3.2 alpha1H subunit derived from human heart was stably transfected into cells [human embryonic kidney (HEK)-Cav3.2] cultured with or without 5 muM amiodarone. Patch-clamp recordings in the conventional whole-cell configuration were used to evaluate the actions of amiodarone on the T-type Ca2+ channel current (ICa.T). Amiodarone blockade of ICa.T occurred in a dose- and holding potential-dependent manner, shifting the activation and the steady-state inactivation curves in the hyperpolarization direction, when amiodarone was applied immediately to the bath solution. However, when the HEK-Cav3.2 cells were incubated with 5 microM amiodarone for 72 h, ICa.T density was significantly decreased by 31.7+/-2.3% for control,-93.1+/-4.3 pA/pF (n=8), versus amiodarone,-56.5+/-3.2 pA/pF (n=13), P<0.001. After the prolonged administration of amiodarone, the activation and the steady-state inactivation curves were shifted in the depolarization direction by -7.1 (n=41) and -5.5 mV (n=37), respectively, and current inactivation was significantly delayed [time constant (tau): control, 13.3+/-1.1 ms (n=6) versus amiodarone, 39.6+/-5.5 ms (n=6) at -30 mV, P<0.001)]. Nevertheless, short-term inhibitory effects of amiodarone on the modified T-type Cav3.2 Ca2+ channel created by long-term amiodarone treatment were functionally maintained. We conclude that amiodarone exerts its short- and long-term inhibitory actions on ICa.T via distinct blocking mechanisms.

Voltage-dependent and frequency-independent inhibition of recombinant Cav3.2 T-type Ca2+ channel by bepridil.

Effects of bepridil on the low voltage-activated T-type Ca2+ channel (CaV3.2) current stably expressed in human embryonic kidney (HEK)-293 cells were examined using patch-clamp techniques. Bepridil potently inhibited ICa,T with a markedly voltage-dependent manner; the IC50 of bepridil was 0.4 micromol/l at the holding potential of -70 mV, which was 26 times as potent as that at -100 mV (10.6 micromol/l). Steady-state inactivation curve (8.4 +/- 1.7 mV) and conductance curve (5.9 +/- 1.9 mV) were shifted to the hyperpolarized potential by 10 micromol/l bepridil. Bepridil exerted the tonic blocking action but not the use-dependent block. Bepridil had no effect on the recovery from inactivation of T-type Ca2+ channels. Thus, high efficacy of bepridil for terminating atrial fibrillation and atrial flutter may be considered to be attributed, at least in a part, to the T-type Ca2+ channel-blocking actions.

Selective expression of L-serine synthetic enzyme 3PGDH in schwann cells, perineuronal glia, and endoneurial fibroblasts along rat sciatic nerves and its upregulation after crush injury.

Non-essential amino acid L-serine functions as a highly potent, glia-derived neurotrophic factor, because it is a precursor for syntheses of proteins, other amino acids, membrane lipids, and nucleotides, and also because its biosynthetic enzyme 3-phosphoglycerate dehydrogenase (3PGDH) is preferentially expressed in particular glial cells within the brain. Here we pursued 3PGDH expression in peripheral nerves and its change after crush injury. In the pathway of rat sciatic nerves, 3PGDH was selectively expressed in non-neuronal elements: Schwann sheaths and endoneurial fibroblasts in sciatic nerves, satellite cells in dorsal root ganglia, and astrocytes and oligodendrocytes in the spinal ventral horn. In contrast, 3PGDH was immunonegative in axons, somata of spinal motoneurons and ganglion cells, and endoneurial macrophages. One week after crush injury, 3PGDH was upregulated in the distal segment of injured nerves, where 3PGDH was intensified in activated Schwann cells and fibroblasts. 3PGDH was still negative in activated macrophages, which were instead associated or surrounded by activated Schwann cells with intensified 3PGDH. These results suggest that in the peripheral nervous system, these non-neuronal cells synthesize and may supply L-serine to satisfy metabolic demands for maintenance and regeneration of peripheral nerves and for proliferation and activation of macrophages upon nerve injury.