Relationship between dose of mycophenolate mofetil and the occurrence of cytomegalovirus infection and diarrhea in renal transplant recipients

To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.     

Treatment of nevus using medical tattooing

Medical tattooing is used to color skin with a pigment loss. Currently, however, a trial-and-error scheme is employed to obtain the desired color appearance of tattooed skin because prediction of the color appearance is dependent on the experiences of medical doctors. We propose a method for predicting the color appearance of tattooed skin. Two trial dyes are first injected in the area of pigment loss, and the color appearance of a third dye to be injected can be predicted using measured spectrocolorimeter data and mathematical formula. The spectrocolorimeter measures the color appearances of the skin before and after tattooing using the first two dyes, and the mathematical formula calculates the color appearance of the tattooed skin using any third dye. In the derivation of the mathematical formula, light propagation in the skin has been modeled using the modified Lambert-Beer law considering the strong scattering of light by biological tissues. The proposed method was successfully validated by a preliminary tattooing of the skin to an area with pigment loss. Predicting the color appearance of tattooed skin significantly reduces the number of trial-and-error attempts required in the current methods. Medical tattooing using this method can also be applied to treat various skin color abnormalities such as leukoderma, intradermal nevi, and reconstructed nipples.     

Neuronal lineage-specific induction of phospholipase Cepsilon expression in the developing mouse brain

Phospholipase C is a key enzyme of intracellular signal transduction in the central nervous system. We and others recently discovered a novel class of phospholipase C, phospholipase Cepsilon, which is regulated by Ras and Rap small GTPases. As a first step toward analysis of its function, we have examined the spatial and temporal expression patterns of phospholipase Cepsilon during mouse development by in situ hybridization and immunohistochemistry. Around embryonic day 10.5, abundant expression of phospholipase Cepsilon is observed specifically in the outermost layer of the neural tube. On embryonic day 12 and later, it is observed mainly in the marginal zone of developing brain and spinal cord as well as in other regions undergoing neuronal differentiation, such as the retina and olfactory epithelium. The phospholipase Cepsilon-expressing cells almost invariably express microtubule-associated protein 2, but hardly express nestin or glial fibrillary acidic protein, indicating that the expression of phospholipase Cepsilon is induced specifically in cells committed to the neuronal lineage. The expression of phospholipase Cepsilon persists in the terminally differentiated neurons and exhibits no regional specificity. Further, an in vitro culture system of neuroepithelial stem cells is employed to show that abundant expression of phospholipase Cepsilon occurs in parallel with the loss of nestin expression as well as with the induction of microtubule-associated protein 2 expression and neuronal morphology. Also, glial fibrillary acidic protein-positive glial lineage cells do not exhibit the high phospholipase Cepsilon expression. These results suggest that the induction of phospholipase Cepsilon expression may be a specific event associated with the commitment of the neural precursor cells to the neuronal lineage.     

Immunohistochemical fluorescence intensity reduction of brain somatostatin in the impairment of learning and memory-related behaviour induced by olfactory bulbectomy

The role of brain somatostatin (SST) on memory function after olfactory bulbectomy (OBX) was investigated by using the passive-avoidance task and immunohistochemical analyses in mice. The present study indicated that the learning and memory-related behaviour was impaired on the 7th and 14th day, but not on the 1st day after OBX. The impairment of learning and memory-related behaviour on the 14th day after OBX was dose-dependently reversed by intracerebroventricularly administered SST (1 microg per mouse). To ascertain the correlation between SST in mouse brain and the impairment of learning and memory-related behaviour induced by OBX, the immunohistochemical distribution of brain SST was determined by fluorescence intensity using two-dimensional microphotometry. The intensity of SST fluorescence was low in the hippocampus on the 14th day after OBX in comparison with Sham controls. These results suggest that SST in the hippocampus is related to the impairment of learning and memory-related behaviour induced by OBX.     

Pigmented villonodular synovitis of the knee with lesions of the bursae

Five patients with pigmented villonodular synovitis of the knee associated with lesions of the posterior periarticular bursae were treated by posterior exploration, excision of the bursal tissue, and routine anterior synovectomy of the knee. It was hypothesized that complete excision of the posterior periarticular bursae would reduce the high recurrence rate of pigmented villonodular synovitis of the knee. To completely excise the periarticular lesions, two posterior oblique skin incisions were used. In all patients, periarticular lesions were seen clearly on computed tomography scans after air arthrography and on magnetic resonance imaging scans. The patients were followed up for 6.9 years on average (range, 3.3-8.1 years) after surgery. One of five patients required reoperation because of recurrence. Two of five patients required manual mobilization after release of the intraarticular adhesion. However, in the remaining three patients, who started continuous passive motion exercise immediately after surgery, full range of motion was restored within 3 months after the operation. Complete excision of the periarticular lesions is recommended to reduce the high recurrence rate, and continuous passive motion exercise immediately after surgery also is recommended to prevent reduction of range of motion.     

Antinociceptive effect of cilnidipine, a novel N-type calcium channel antagonist

We investigated the antinociceptic effects of cilnidipine, a dihydropyridine derivative which acts on both L- and N-type voltage-dependent calcium channels, in mice. Intrathecally injected cilnidipine showed significant analgesic effect in formalin test. Cilnidipine significantly suppressed N-type currents in dorsal root ganglion (DRG) cells. Our findings apparently support the idea that cilnidipine attenuates synaptic neurotransmission by inhibiting N-type calcium channels in DRG neurons.     

Effects of diethyldithiocarbamate on ejaculatory inhibition and change in monoamine levels of accessory glands (author's transl)]

Effects of diethyldithiocarbamate(DDC) on erection and ejaculation were investigated and monoamine levels in central nervous system, gonad and accessory glands were determined in dogs. Intraperitoneal administration of 50, 75 and 100 mg/kg of DDC suppressed ejaculation 1 hour after administration, although penial erection did occur. This suppression of ejaculation was recovered to some extent 3 hours after DDC and completely recovered 24 hours after DDC. One hour after the administration of 100 mg/kg of DDC, noradrenaline (NA) level in the caudate and serotonin (5-HT) level in the posterior hypothalamus decreased significantly, as compared with the control. However, there were no significant changes in the regions of anterior hypothalamus and hippocampus which are known to play an important role in sexual behavior. In the epididymis, NA and adrenaline levels decreased significantly, though 5-HT levels increased, as compared with those of the control. In the prostate and posterior urethra, NA levels decreased significantly, as compared with the control. The seminal emission induced by hypogastric nerve stimulation induced a gradual rise in the posterior urethral pressure. When the pressure reached the maximum level, rhythmic alterations of the pressure considered to be a phenomenon associated with ejaculation occurred. DDC (100 mg/kg) abolished both seminal emission and rhythmic alterations of the posterior urethral pressure. These findings indicate that the sperm transport may be inhibited by decrease of NA level in accessory glands.     

Abnormal expression and function of Fas ligand of lacrimal glands and peripheral blood in Sjögren's syndrome patients with enlarged exocrine glands

The objective of our study was to investigate the possibility of Fas ligand protein abnormalities in certain types of Sjögren's syndrome patients with enlarged exocrine glands. Fas ligand expression by lymphocytes infiltrating the lachrymal glands and by peripheral blood monocytes in Sjögren's syndrome patients with enlarged exocrine glands was assessed immunohistologically and by immunoblotting. Cytotoxicity of peripheral blood monocytes and sensitivity to steroids in Sjögren's syndrome patients with enlarged exocrine glands were studied by functional assay. Minimal Fas ligand expression was detected in the lymphocytes of the lachrymal glands and a decreased level of Fas ligand was found in peripheral blood monocytes as assessed by immunoblotting. Functional assay confirmed the decreased cytotoxicity of lymphocytes in Sjögren's syndrome patients with enlarged exocrine glands, and that it is not affected by anti‐Fas ligand antibody. By contrast, the sensitivity of lymphocytes in Sjögren's syndrome patients with enlarged exocrine glands to steroids was increased. These observations suggest that abnormal expression and function of Fas ligand occurs in Sjögren's syndrome patients with enlarged exocrine glands.     

Pharmacological studies of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., in the central nervous system

The pharmacological properties of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., were analyzed in vitro and in vivo using mice central serotonin neurons. In the in vitro experiment, geissoschizine methyl ether inhibited [3H]8-hydroxy-2-(di-n-propylamino)tetralin) ([3H]8-OH-DPAT) (K(i)=0.8 microM), [3H]mesulergine (K(i)=0.9 microM) and [3H]ketanserin (K(i)=1.4 microM), but had less affinity toward [3H]prazosin (K(i) > 10 microM) and [3H]spiperone (K(i) >15 microM) binding to mouse brain membranes. The in vivo studies showed that geissoschizine methyl ether dose-dependently reduced 5-hydroxy-L-tryptophan (I-5-HTP) plus clorgyline-induced head twitch response without inhibiting the I-5-HTP plus clorgyline and 8-OH-DPAT-induced head weaving. On the other hand, geissoschizine methyl ether also decreased the rectal temperature of mice (hypothermic response) in a dose-dependent manner. These results suggest that geissoschizine methyl ether possesses mixed 5-HT(1A) receptor agonist/5-HT(2A/2C) receptor antagonist activities and inhibits the head twitch response by blocking the 5-HT(2A) receptors, and possibly, at least in part, by stimulating the 5-HT(1A) receptors in the central nervous system.