Pharmacokinetics and tissue distribution of uraemic indoxyl sulphate in rats

The purpose of the present study was to examine the pharmacokinetic properties of indoxyl sulphate, a harmful uraemic toxin that accumulates during chronic renal failure. The pharmacokinetics and tissue distribution of indoxyl sulphate were examined in normal and 5/6 nephrectomized (CRF) rats. The uptake process of indoxyl sulphate by rat renal cortical slices in vitro was also investigated. Endogenous indoxyl sulphate was found to be mainly distributed in the kidney. The rate of elimination of indoxyl sulphate from plasma was lower in CRF rats compared with sham-operated rats. The majority of intact indoxyl sulphate was excreted in the urine. In renal cortical slice experiments, uptake of indoxyl sulphate was a saturable process with a K(m) of 43.0 microm. Furthermore, sulphate conjugates, such as oestrone sulphate and dehydroepiandrosterone sulphate, inhibited the uptake of indoxyl sulphate to a greater extent than PAH. Thus, indoxyl sulphate is primarily eliminated from the plasma via the kidney by active tubular secretion, and renal uptake of indoxyl sulphate appears to be mediated by an organic anion transport system with a high affinity for oestrone sulphate and dehydroepiandrosterone sulphate.     

Removal of Toxin (Tetrodotoxin) from Puffer Ovary by Traditional Fermentation

The amounts of puffer toxin (tetrodotoxin, TTX) extracted from the fresh and the traditional Japanese salted and fermented “Nukazuke” and “Kasuzuke” ovaries of Takifugu stictonotus (T. stictonotus) were quantitatively analyzed in the voltage-dependent sodium current (I_Na) recorded from mechanically dissociated single rat hippocampal CA1 neurons. The amount of TTX contained in “Nukazuke” and “Kasuzuke” ovaries decreased to 1/50–1/90 times of that of fresh ovary during a salted and successive fermented period over a few years. The final toxin concentration after fermentation was almost close to the TTX level extracted from T. Rubripes” fresh muscle that is normally eaten. It was concluded that the fermented “Nukazuke” and “Kasuzuke” ovaries of puffer fish T. Stictonotus are safe and harmless as food.     

Case of cutaneous malignant melanoma surviving 16 years with late recurrence

Late recurrence, defined as that occurring 10 or more years after diagnosis, is an unusual event in cutaneous malignant melanoma (MM). A 59-year-old woman presented with a black nodule measuring 10 mm × 9 mm on the sole of her right foot. She was diagnosed with MM and the tumor was totally excised with 5 cm of the normal surrounding skin. Eleven years after the operation, five in-transit metastases were found in her right limb. They were all excised and β-interferon (IFN-β) was injected into the skin around the postoperative scars. However, numerous new in-transit skin metastases have been emerging every year in her right limb. Fifty-four in-transit skin metastases have so far been found. Recently, there have been few in-transit metastases. All in-transit metastatic lesions were excised and local IFN-β injections were conducted continuously. There is no evidence of metastases to the internal organs or lymph nodes. This report describes this case with a brief review of the published work concerning the rare late recurrences of MM.     

Chronopharmacology of analgesic effect and its tolerance induced by morphine in mice

The influence of morphine dosing time on analgesic effect after acute or chronic treatment, recovery of analgesic effect after once developed tolerance, and their pharmacological mechanisms were investigated in ICR male mice under a 12-h light/dark cycle (light on from 7:00 AM to 7:00 PM). There was a significant 24-h rhythm in the latency of thermal response at 30 min after morphine injection. The analgesic effect was significantly greater at the dark phase than at the light phase. The rhythmic pattern resembled overall the rhythm occurring in the latency of thermal response under non-drugged state. The absolute value of morphine analgesic effect (the real time spent on the hot-plate) on days 1 and 2 after morphine daily injection was significantly larger after morphine injection at 9:00 PM than after saline injection at 9:00 PM or after morphine injection at 9:00 AM. The recovery from tolerance of analgesic effect was significantly faster at the dark phase than at the light phase. The time-dependent difference in the analgesic effect after chronic treatment or recovery from tolerance is closely related to that in the expression of mu-opioid receptor. The present study suggests that 24-h rhythm of morphine analgesic effect is consistent with 24-h rhythm of mu-opioid receptor expression.     

Renal clearance of endogenous hippurate correlates with expression levels of renal organic anion transporters in uremic rats

Hippurate (HA) is a harmful uremic toxin that accumulates during chronic renal failure, and failure of the excretion system for uremic toxins is thought to be responsible. Recently, we reported that rat organic anion transporter 1 (rOat1) is the primary mediator of HA uptake in the kidney, and so now we have studied the pharmacokinetics and tissue distribution of HA after a single i.v. dose of HA to normal and 5/6 nephrectomized rats (5/6Nx rats). In control rats, the renal and biliary clearances of HA were 18.1 and 0.1 ml/min/kg, respectively. Plasma clearance decreased as dosage increased from 0.1 to 5 mg/kg, which suggests that renal tubular secretion is the primary route for elimination of HA. The plasma clearance of HA was significantly decreased in 5/6 Nx rats compared with normal rats. In 5/6 Nx rats, renal clearance of endogenous HA correlated more closely with clearance of p-aminohippurate than with that of creatinine. Protein expression of rOat1 and rOat3, assessed by Western blot analysis, was decreased in 5/6 Nx rats. Furthermore, in 5/6 Nx rats, the renal secretory clearance of endogenous HA correlated closely with protein expression of renal rOats. Thus, HA is primarily eliminated from the plasma via the kidney by active tubular secretion. The renal clearance of endogenous HA seems to be a useful indicator of changes in renal secretion that accompany the reduced levels of OAT protein in chronic renal failure.     

Challenging behavior of patients with frontal dysfunction managed successfully with behavioral intervention

Herein, we report on two clinical cases in which behavioral disturbances occurred due to frontal dysfunction. Both patients were treated successfully with behavioral intervention. In the first case, the patient's challenging behavior of repeatedly entering his wife's workplace and interrupting her work was reduced after the patient's wife changed her response to the behavior and her schedule prior to work to ensure that she spent time with him in the morning. In the second case, the patient's challenging behavior of urinating in the street was reduced by changing his walking route. The successful outcome in both cases suggests that behavioral intervention based on Antecedents, Behavior, and Consequences (ABC) analysis is useful in the management of behavioral disturbance due to frontal dysfunction.     

Differential inductions of small heat shock protein 27 and 1-Cys peroxiredoxin in reactive astrocytes in sulfatide-deficient mouse spinal cord

In myelinated fibers, various interactions among axons, oligodendrocytes, and astrocytes are present, particularly around the node of Ranvier. In the present study, we examined the protein composition of cerebroside sulfotransferase knockout (CST KO) mouse spinal cord by two-dimensional gel electrophoresis to examine the molecular changes resulting from the disruption of paranodal junctions in addition to the sulfatide-deficient condition. Interestingly, heat shock protein 27 (Hsp27) and 1-cys peroxiredoxin (1-Cys Prx) were both elevated in CST KO mice. Hsp27 was increased specifically in reactive astrocytes in the white matter, and the elevation was well correlated to the progression of neurologic symptoms. In contrast, 1-Cys Prx was elevated both in white and gray matter astrocytes in CST KO mice. These results suggest that astrocytes do not always respond stereotypically, as they display differences in their activation in these two regions. To determine whether these changes are specific to the sulfatide-deficient condition, spinal cords from CST KO mice and the hypomyelinating mutant shiverer mice were compared. The same distribution patterns of Hsp27 and 1-Cys Prx were found in reactive astrocytes in both CST KO and shiverer mice, suggesting that paranodal disruption with progressive nodal changes may underlie the similar reaction of white matter astrocytes. In contrast, CST KO and shiverer mice showed distinctly different localization patterns of connexin 43 and connexin 47, suggesting that intercellular communication between astrocytes and oligodendrocytes was different in these mutants. These results suggest that astrocytes may respond differentially to individual white matter abnormalities and may modulate specific axonal functions.     

Infusion of neuropeptide Y into CA3 region of hippocampus produces antidepressant-like effect via Y1 receptor

A couple of papers indicate that patients with depression show a decrease in serum neuropeptide Y (NPY). To study the role of NPY in depression, we examined the effects of infusion of NPY into the hippocampus of learned helplessness (LH) rats (an animal model of depression). Infusion of NPY into the cerebral ventricle of LH rats showed antidepressant-like effects. Infusion of NPY into the CA3 region, but not the dentate gyrus (DG), produced antidepressant-like effects in the LH paradigm. Infusion of NPY did not affect locomotor activity or aversive learning ability. Coadministration of BIBO3304 (a Y1 receptor antagonist) with NPY to the CA3 region blocked the antidepressant-like effects of NPY, whereas coadministration of NPY with BIIE0246 (a Y2 receptor antagonist) to the CA3 region failed to block antidepressant-like effects. Furthermore, infusions of [Leu(31) Pro(34)]PYY (a Y1 and Y5 receptor agonist) alone and BIIE0246 alone into the CA3 region produced the antidepressant-like effects in LH rats. These results suggest that infusion of NPY into the CA3 region of hippocampus of LH rats produces antidepressant-like activity through Y1 receptors and attenuating effects through Y2 receptors.     

First Case Report of Sepsis Due to Rothia aeria in a Neonate

Rothia aeria, a gram-positive coccoid- to rod-shaped bacterium with irregular morphology, is an extremely rare causative organism of infections in humans. We report the first case of R. aeria sepsis clinically manifested in a female neonate soon after birth.