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The optimal starting dose of tolvaptan to effectively improve fluid retention in patients with heart failure (HF) is unknown. This study explored the factors affecting the pharmacokinetics (PKs) and pharmacodynamics of tolvaptan in patients with decompensated HF. We prospectively enrolled patients who were slated to receive tolvaptan because of volume overload associated with chronic HF. Blood samples were collected to measure tolvaptan concentrations before and 4, 8, 12-15, 24, and 144 h after administration. Additionally, demographic parameters, coadministered drugs, and body fluid composition were evaluated. Multiple regression analysis to detect PK parameters for the prediction of body weight (BW) loss at day 7 after the initiation of tolvaptan treatment and PK analysis to explore the factors affecting the PKs of tolvaptan were performed. In total, 165 blood samples were obtained from 37 patients. The predictors of weight loss on day 7 were area under the curve (AUC 0-∞ ) of tolvaptan. PK analysis of the data revealed a strong correlation between CL/F and Vd/F, but no correlation between CL/F and kel (r = .95 and .06, respectively). A significant correlation was observed between total body fluid and Vd/F, and this correlation remained statistically significant even after adjusting for BW (r = .49, p < .05). Fat was also significantly correlated with Vd/F before adjusting for BW, on the other the correlation disappeared after adjusting BW. The optimal dose of tolvaptan based on total body fluid levels in individual patients could result in the alleviation of fluid retention in patients with HF., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Granulocyte colony-stimulating factor(G-CSF)is useful for preventing febrile neutropenia induced by chemotherapy. Recently, some cases of aortitis have been reported following administration of G-CSF. Here, we present a case of aortitis induced by pegfilgrastim(peg-G)use during neoadjuvant chemotherapy for treating breast cancer. A 61-year-old woman with breast cancer(cT2N1M0, stage ⅡB, triple negative)started neoadjuvant chemotherapy FEC(100). Eleven days after the third course of peg-G administration, the patient developed a fever and general malaise. Blood test results showed an increase in inflammatory markers and severe anemia. The symptoms were not controlled with antibiotics. Blood and urine culture test results were negative. Computed tomography revealed remarkable wall thickening of the aorta. Therefore, we suspected aortitis induced by peg-G. The symptoms rapidly improved with prednisolone therapy. The possibility of aortitis should be considered for those with fever or raised inflammatory markers following the use of G-CSF. Steroids can be used for the treatment of G-CSF-induced aortitis.

Carcinoid tumors in the ear canal are very rare. In this report, we experienced a case of carcinoid tumor of the ear canal that underwent total tumor resection. This study included a 39-year-old man presented with a chief complaint of right-sided hearing loss. Computed tomography scan showed a shadow from the ear canal to the right tympanic chamber. There were no suspicious findings of metastasis in the cervical lymph nodes or other organs. At the time of surgery, the tumor was simply removed because it was small and there was no adhesive invasion. Postoperatively, the patient has been under observation for 11.5 years without any recurrence. Carcinoid tumors in the ear canal can rarely metastasize or recur after more than 10 years. It is important to follow up with the patient for a long time after surgery, using the Ki-67 index of the removed tissue as a prognostic reference.

Human serine palmitoyltransferase (SPT) is a PLP-dependent enzyme residing in the endoplasmic reticulum. It catalyzes the synthesis of 3-ketodihydrosphingosine (3-KDS) from the substrates palmitoyl-CoA and l-serine. It is a rate-limiting enzyme for sphingolipid synthesis in cells. In the present study, we characterized and pharmacologically profiled a series of tetrahydropyrazolopyridine derivatives that potently inhibit human SPT enzymatic activity, including two cell-active derivatives and one fluorescent-labelled derivative. These SPT inhibitors exhibited dual inhibitory activities against SPT2 and SPT3. We used a fluorescent-labelled probe to molecularly assess the inhibitory mechanism and revealed its binding to the SPT2 or SPT3 subunit in the small subunit (ss) SPTa/SPT1/SPT2/or ssSPTa/SPT1/SPT3 functional complexes. One of the SPT inhibitors exhibited a significantly slow dissociation from the SPT complex. We confirmed that our SPT inhibitors suppressed ceramide content in non-small-cell lung cancer cell line, HCC4006, by performing a target engagement analysis. The potency of ceramide reduction correlated to that observed in a recombinant SPT2 enzyme assay. We thus elucidated and provided a fundamental understanding of the molecular mode of action of SPT inhibitors and developed potent, cell-active SPT inhibitors that can be used to clarify the biological function of SPT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Poly(ADP-ribose) polymerases (PARPs) use nicotinamide adenine dinucleotide (NAD + ) as a co-substrate to transfer ADP-ribose when it releases nicotinamide as the metabolized product. Enzymes of the PARP family play key roles in detecting and repairing DNA, modifying chromatin, regulating transcription, controlling energy metabolism, and inducing cell death. PARP14, the original member of the PARP family, has been reported to be associated with the development of inflammatory diseases and various cancer types, making it a potential therapeutic target. In this study, we purified the macrodomain-containing PARP14 enzyme and established an assay for detecting the auto-ribosylation activity of PARP14 using RapidFire high-throughput mass spectrometry and immunoradiometric assay using [ 3 H]NAD + . Subsequently, we performed high-throughput screening using the assays and identified small-molecule hit compounds, which showed NAD + -competitive and PARP14-selective inhibitory activities. Co-crystal structures of PARP14 with certain hit compounds revealed that the inhibitors bind to the NAD + -binding site. Finally, we confirmed that the hit compounds interacted with intracellular PARP14 by a cell-based protein stabilization assay. Thus, we successfully identified primary candidate compounds for further investigation., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

We investigated the effect of tooth absence and masticatory abnormalities due to powdered food feeding starting during the juvenile period on light and dark period activity cycles in senescence-accelerated mice (SAMP1). SAMP1 were divided into 5 groups: Group 1, maxillo-mandibular molar tooth extraction; Group 2, maxillary molar tooth extraction; Group 3, mandibular molar tooth extraction; Group 4, powdered food; and Group 5, sham-operated control. Senescence was observed earliest in the powdered food group. Total 24-hour activity was higher in the control group than in the four other groups. In the powdered food group, the dark period activity decreased to less than 60% of the total activity in the 36th week. In the tooth extraction groups (Groups 1-3), dark period activity decreased to less than 60% of the total activity in the 40th week. The control group dark period activity remained above 60% for the entire experimental period. Thus, the distinction between the light and dark periods disappeared earlier in the four experimental groups compared with the control group. Significant correlations were noted among total activity, degree of senescence, and percent dark period activity in each experimental group. Functional masticatory insufficiency promoted dementia and behavioral abnormalities in SAMP1.

The patient was a 79-year-old woman. We became introduction consultation than a nearby doctor in alpha-fetoprotein(AFP)high level. Abdominal ultrasonography showed 30mm great tumor in liver lateral segment area and gastric fiber showed type2 tumor which is AFP producing gastric cancer. On admission AFP level is high(403ng/ml). Multiple liver metastases were noted it by abdominal angiography. We started FLAP(5-fluorouracil, leucovorin, etoposide, cisplatin)combination chemotherapy by a diagnosis of AFP producing gastric cancer StageIV. It is reduction of a liver tumor after one course, and the stomach lesion almost disappeared after three courses end points.

Background/aims: Schönlein-Henoch purpura (SHP) is a systemic condition characterized by purpura associated with leukocytoclastic vasculitis. SHP diagnosis is more difficult in infrequent cases where gastrointestinal (GI) symptoms precede purpura. This report examines 11 cases of SHP at our hospital with specific regard to the incidences and details of GI symptoms., Methods: The clinical manifestations and endoscopic findings were investigated for their utility in SHP diagnosis., Results: Among the 11 cases, 3 showed GI symptoms prior to other manifestations. In terms of GI symptoms, abdominal pain was reported in all 11 cases, diarrhea in 4 cases, and bloody stools in 3 cases. Endoscopic findings were seen in the stomach in 7/10 cases, in the small intestine including the duodenum in 10/11 cases, and in the large intestine in 6/10 cases. The frequency of ulcer formation was significantly higher in the small intestine (including the duodenum) than in the stomach. Multiple specific erythematosus lesions were observed in the stomach and large intestine., Conclusion: Familiarity with characteristic endoscopic findings and careful observation of all GI findings are essential for diagnosing SHP in cases in which GI tract symptoms precede cutaneous findings., (Copyright 2008 S. Karger AG, Basel.)

Children with severe motor and intellectual disabilities (SMID) find it almost impossible to communicate whether they are feeling comfortable or uncomfortable. Most of the children with SMID rely on medical care involving disposable-type life support devices such as tracheostomy tubes or gastric tubes. It is believed that the insertion and removal of these medical devices could cause extreme physical pain under certain circumstances. The authors have previously reported a hand-held type salivary amylase (AMY) activity monitor that can be used to evaluate the sympathetic nervous system. This report proposes a nonverbal communication procedure based on a biochemical measurement using AMY activity for children with SMID. The physiological conditions of these children were evaluated using a hand-held type AMY activity monitor that we fabricated. The AMY activity and heart rate of six subjects, who required daily insertion and removal of tracheostomy tubes or gastric tubes, were simultaneously measured before and after medical care. Apart from one subject who required a respirator due to severe cerebral palsy, the experimental results showed that the AMY value increased sharply by 200 400% after medical care compared to the resting state. Furthermore, the rate of change of AMY activity was 10 times larger than the change in heart rate. Therefore, it is suggested that using these biochemical measurements a nonverbal communication tool for children with SMID can be established.

Objective: To determine the long term prognosis of children of patients with systemic lupus erythematosus (SLE)., Methods: Children of patients with SLE were invited to attend our clinic for physical examination and laboratory tests. A total of 195 children (aged 4 months to 26 years; male = 82, female = 113) were examined in 1991, 1995, 1997, and 1998., Results: Two cases were diagnosed as SLE at the first visit and were excluded from the second visit. A significantly higher percentage (52/195 (27%)) of patients were positive for antinuclear antibodies (ANA) at a cut off serum dilution of 1/40 compared with controls (4/57 (7%)). ANA were detected more frequently in female subjects than in men (p<0.05). Forty four subjects were examined on more than two occasions. Nine of the 10 patients who were positive for ANA at the second visit were girls aged 4-8 years. The incidence of anti-DNA and antiphospholipid antibodies in children of patients with SLE was similar to that in the controls., Conclusions: The finding that children, especially girls, born to maternal lupus patients had a high positive rate for ANA suggests that a genetic factor is involved in SLE pathogenesis. Longitudinal observation of these patients may provide important clinical information and clues to the pathogenesis of SLE.

Tacrolimus (TAC) is a useful immunosuppressive agent in the prevention of rejection. However, the blood level between its therapeutic and toxic levels is narrow such that its nephrotoxicity is a problem. Moreover, its bioavailability and pharmacokinetics are highly variable. We experienced a case of acute nephrotoxicity, in which the blood level rose about 10 times above the expected level. We found a peculiar vacuolization in the transplant biopsy specimen. This change showed a marked vacuolization of the tubular cells, suggestive of acute nephrotoxicity by TAC.

The variations of environmental gamma radiation flux were observed by using a new portable spectrometry recording system for 1 year. Spectrum analyses by the response matrix method have provided much information, and the artificial contribution can be separated from natural back ground dose by using the Th-method or the three component method.

We describe a new low density lipoprotein (LDL) apheresis system using dextran sulfate cellulose column in an automated column regenerating unit (LDL continuous apheresis). Two columns containing 150 ml of dextran sulfate cellulose were used, and the whole extracorporeal circulation was about 400 ml in volume. After 600 ml of plasma was adsorbed into the first column, the second column was used as an adsorbent and meanwhile the first column was regenerated. Thus, the 2 columns were used alternately without losing the potency of the columns. As the apparatus was automatically controlled by a computerized unit, no extra manipulation is necessary compared with the conventional single-column method. By treating 4-5 liters of plasma, non-high density lipoprotein (HDL)-cholesterol levels decreased by 63-71%, and HDL-cholesterol levels remained unchanged. Thus, this new method of LDL apheresis can safely reduce LDL-cholesterol to any desired level and will be applicable for the treatment of child and adult family hypercholesterolemic patients with severe coronary heart disease.

A retrospective analysis of CT images in 138 histologically proven ovarian masses in 100 patients was undertaken to evaluate the usefulness and limitation of CT in the diagnosis of ovarian tumors. Benign masses were purely cystic in 98 (94.2%) and had solid component (including thickened walls, thickened septa, papillary projections) in five of 104 lesions (4.8%) on CT. These five masses, which are classified as benign solid tumors, could not be differentiated from malignant tumors by either the size of the solid portion or the intensity of contrast enhancement. In the malignant tumors a solid portion was detected in 32 of 34 tumors (94%). When a solid component is detected in an ovarian mass, the mass should be considered malignant although a few cases will be benign solid tumors. In Krukenberg tumors, which were all of gastric origin, the solid component was so large that it occupied more than one-half the mass. Therefore, if the solid portion of the ovarian mass is large on CT, upper gastrointestinal study should be performed to rule out Krukenberg tumor.