Absence of effect of SLC22A2 genotype on cisplatin-induced nephrotoxicity in oesophageal cancer patients receiving cisplatin and 5-fluorouracil: report of results discordant with those of earlier studies.

WHAT IS KNOWN AND OBJECTIVE: Cancer patients treated with cisplatin chemotherapy frequently experience drug-induced nephrotoxicity. Clinical studies using a single chemotherapeutic regimen or large sample sizes for patients with the SLC22A2 808T allele have not been reported. Here, we examined 95 patients with oesophageal cancer who received 5-fluorouracil and cisplatin (FP) to determine whether nephrotoxicity was affected by SLC22A2 808G>T polymorphism. METHODS: The change rate of the estimated glomerular filtration rate (eGFR) was used for the evaluation of cisplatin-induced nephrotoxicity and calculated for each patient according to the following formula: change rate = (prechemotherapy value - post-chemotherapy value)/prechemotherapy value. Genotyping of SLC22A2 808G>T was carried out using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The eGFR after FP chemotherapy was significantly lower than that before chemotherapy, and the mean difference in eGFR was 25·7 mL/min (P < 0·01). There was no significant difference in the mean change rate of the eGFR following FP chemotherapy between the SLC22A2 808GG genotype (n = 70) and the 808GT+TT genotypes (n = 25) (27·9% and 27·8%, respectively). In multiple regression analyses, the change rate of eGFR following FP chemotherapy was associated with the eGFR value prior to chemotherapy (P = 0·04). WHAT IS NEW AND CONCLUSION: In FP chemotherapy for oesophageal cancers, cisplatin-induced nephrotoxicity seems to be unaffected by the SLC22A2 808G>T polymorphism. The eGFR prior to chemotherapy might be an important risk factor for cisplatin-induced nephrotoxicity. Our present study was estimated with a single chemotherapeutic regimen, eGFR, and was calculated using serum creatinine, age and the sex of the patient and sample sizes of 25 patients with SLC22A2 808T allele. However, further examinations with a larger sample size to corroborate the study results might be necessary.

Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. METHODS: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12-hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). RESULTS: There were no significant differences in the dose-adjusted area under the plasma concentration-time curve (AUC(0-12)) and maximum plasma concentration (C(max)) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co-administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose-adjusted AUC(0-12) and C(max) of tacrolimus were associated with CYP3A5*3/*3 and co-administration with lansoprazole. WHAT IS NEW AND CONCLUSION: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long-term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.

Occurrence of parasympathetic vasodilator fibers in the lower lip of the guinea-pig.

The present study was designed to examine whether there are parasympathetic vasodilator fibers in the lower lip of the guinea-pig. Electrical stimulation of the central cut end of the lingual nerve of guinea-pigs evoked intensity- and frequency-dependent decreases in lower lip blood flow and systemic arterial blood pressure (SABP). Pretreatment with guanethidine, a postganglionic sympathetic nerve blocker and antihypertensive drug (30 mg kg(-1), s.c., 24 h prior to experiments), reduced the magnitude of the decrease in SABP while the intensity- and frequency-dependent increases of the lip blood flow occurred by the lingual nerve stimulation only on the side ipsilateral to stimulation. Increases in the lip blood flow evoked by lingual nerve stimulation in guanethidine pretreated guinea-pigs were reduced by hexamethonium (an autonomic ganglion cholinergic blocker) in a dose-dependent manner. When fluoro-gold (a retrograde neural tracer) was injected into the lower lip, labeled neurons were observed in the ipsilateral otic ganglion. The present study indicates the presence of parasympathetic vasodilator fibers originating from the otic parasympathetic ganglion in the guinea-pig lower lip, similar to those reported previously in rats, cats, rabbits and humans.

Effects of isoflurane on parasympathetic vasodilatation in the rat submandibular gland.

Volatile anesthetics have been known to suppress parasympathetic reflex vasodilatation in the lower lip and palate. However, in the submandibular gland, little is known about the effects of these anesthetics on the parasympathetic vasodilatation elicited by reflex and direct (i.e., non-reflex) activation of the parasympathetic vasodilator mechanisms. Although both parasympathetic vasodilatations were inhibited by isoflurane in a concentration- and time-dependent manner, the effects of continuous administration of the alpha(1)-adrenoceptor agonist methoxamine were markedly different: The reflex vasodilatation was not affected by methoxamine, while the direct vasodilatation was significantly reduced. Picrotoxin (GABA(A) receptor antagonist) attenuated the inhibitory effect of isoflurane on direct vasodilatation and the systemic arterial blood pressure. These findings suggest that the isoflurane-induced inhibitory effects on direct vasodilatation are produced by a decrease of peripheral vascular tone by GABAergic mechanisms, whereas those on the reflex vasodilatation are produced exclusively by the inhibition of the reflex center.

Hepatic clearance improves after angioplasty of the hepatic vein.

Anastomotic stricture sometimes causes hepatic congestion leading to decreased hepatic clearance of drugs. We herein describe a correlation between trough levels of tacrolimus and an anastomotic stricture of the hepatic vein. A 13-year-old boy underwent living donor liver transplant with a left lobe graft from his mother. Outflow blockage due to an anastomotic stricture of the hepatic vein developed 3 months after transplant. His anastomotic site had been repeatedly treated with percutaneous transvenous angioplasty (PTA) by balloon dilation. About 1 year after transplant, his trough level of tacrolimus promptly decreased after balloon dilation (from 15.7 to 5.6 ng/dL). Liver function tests showed abnormalities, which were diagnosed as acute cellular rejection, and he was treated with pulse steroid therapy. The calculated half-life of tacrolimus (T1/2) showed marked improvement after PTA (from 35 to 22 hours). A 45-year-old woman underwent living donor transplantation due to alcoholic liver cirrhosis with a left lobe graft from her brother. An anastomotic stricture of the hepatic vein developed 4 months after transplant. She was treated with balloon dilation, which caused an abrupt decrease in the trough level of tacrolimus (12 to 4 ng/dL). Her alkaline phosphatase was elevated and she was diagnosed with rejection, which was treated with an increase of dosage of tacrolimus. In outflow block, the T1/2 of tacrolimus increases probably due to decreased hepatic clearance by stagnation or congestion of the liver. However, hepatic clearance of drugs quickly recovers after PTA. Close monitoring of immunosuppressive agents is fundamental at the time of angioplasty to avoid acute cellular rejection as developed in our two cases.

Distribution of zinc-binding metallothionein in cirrhotic liver of rats administered zinc.

This study was undertaken in order to investigate the effect of zinc (Zn) administration on induction of Zn-binding metallothionein in rat liver with thioacetamide-induced cirrhosis, and the localization of metallothionein in the liver. Normal and cirrhotic rats received intraperitoneal injections with or without Zn. Subsequently, metal analyses, purification of metallothionein by gel filtration and immunohistochemical assessments of metallothionein were carried out. Although in Zn-injected cirrhotic rats, the Zn contents in the liver and plasma increased significantly depending upon the dose of Zn, the Zn contents in the liver and plasma of the cirrhotic rats were lower than those of normal rats after the same dose of Zn. The results of gel filtration also showed that the levels of Zn-metallothionein in the cirrhotic liver were reduced in comparison with those of the normal liver. By the immunohistochemical method, the presence of metallothionein in the parenchymal areas but not in the fibrotic areas of the cirrhotic liver was confirmed. These results suggested that the induced metallothionein was only located in the parenchymal areas. The metallothionein induced in the parenchymal areas was considered to play a role in protecting the parenchymal cells against the progression of fibrosis, because metallothionein has been thought to be involved in the cellular defense against oxidative stress.

[Toward the promotion of researches utilizing microgravity].

Although many opportunities to make experiments under microgravity conditions have been given in the recent decade, it does not seem that a dramatic or decisive result has been obtained by use of microgravity. Promising some experiments in the space station are now near at hand, but it may be necessary to reconsider what the microgravity experiment is or how the microgravity field should be effectively utilized.

Isolation of tick-borne encephalitis virus from Ixodes ovatus (Acari: Ixodidae) in Japan.

A case of tick-borne encephalitis (TBE) was found in a farming area located in the southern part of Hokkaido, Japan, in 1993. TBE viruses were isolated from sentinel dogs in the area where the human case occurred in 1995. Ticks were collected in the area by 2 collection methods in 1995 and virus isolation was conducted on ticks in 1995 and 1996. Ixodes ovatus Neumann was found to be the predominant tick species in the area. In 1996, 2 virus strains were isolated from 600 I. ovatus ticks (300 females and 300 males), giving the minimum infection rate of 0.33% (2 of 600). The 2 virus strains were identified as TBE virus by antigenic analysis using monoclonal antibodies and the indirect immunofluorescent antibody test. The results showed that I. ovatus was a suspected vector of the emerging TBE virus in Hokkaido.

Histochemical localization of superoxide dismutase activity in rat brain.

Histochemical localization of superoxide anion (O2.-) scavenging activity in rat brain was visualized by the tissue-blotting technique. The activity was thought to mainly depend on Cu/Zn-SOD, because the localization of the activity was identical with the immunohistochemistry of Cu/Zn-SOD and the localization of its mRNA in the brain. Moreover, the activity was dramatically decreased after treatment of Cu (I) chelater. The activity was detected in pyramidal cells of the cortex, granular, and mitral cells of the olfactory bulbs, pyramidal cell layer CA1 to CA3, and dentate gyrus of hippocampus formation and granular cells of the cerebellum. Moreover, the activity was detected in the pontine nuclei of brain stem. Olfactory bulbs, hippocampus, and cerebellum were believed to be bestowed high brain functions, i.e., long-term potentiation and long-term depression. A part of the function was regulated by a retrograde neurotransmitter, nitric oxide (.NO). Our findings suggest that the SOD is colocalized with NO synthase in olfactory bulbs, hippocampus, and cerebellum, where .NO plays the important roles. In contrast, low SOD activity was observed in the axonal neurofiber bundles, although the regions contain a lot of membrane lipids, which was thought to be peroxidized by O2.- and related radicals such as .OH in the regions. From these findings, it was suggested that the SOD did not only play a role in protecting the neurons from endogenously formed O2.-, but also play a role in preservation of beneficial natures of .NO in the brain.

[Particle numbers in classified sizes of roadside dust caused by studded tires in the air at different heights from the pavement surface].

Increased use of motor vehicles has produced various risks to human health due to air pollution by noxious gases, heavy metals and roadside dust. Since the late 1970s, the wide spread use of studded tires for cars has caused pavement wear, resulting in not only economic losses, but also roadside air pollution in cold and snowy regions in Japan. The most serious environmental problem in Sapporo, a city with heavy snowfall, in the 1980s, was roadside dust derived from studded tires. The inhabitants suffered from this dust in the early winter and in the early spring when the streets were not covered with snow. To investigate the influence of such roadside dust upon human health, particle numbers in classified sizes of roadside dust were counted after the roadside dust in the air was collected with a device we constructed at 30, 60, 90, 120, 150, and 180 cm above the pavement surface. The results indicated that the concentration of roadside dust in the air did not greatly vary according to the height from the pavement surface. The results also suggested that xenogranuloma, reported in lungs of stray dogs, under roadside dust-pollution conditions such as those examined here, may occur in humans in the future.

Electrocardiogram monitoring at rest and during exercise in 31P magnetic resonance spectroscopy studies of the human heart at 1.9 tesla.

An electrocardiogram (ECG) monitoring system has been developed and evaluated in normal volunteers (n = 7) and patients with various cardiac diseases (n = 24) in a 1.9 tesla magnet during magnetic resonance spectroscopy studies. To minimize an ECG signal path, and thus to reduce motion-related artifacts on the ECG during a dynamic exercise test, one coaxial cable was used to obtain the ECG signal from two electrodes placed parallel to the longitudinal body axis on the left side of the chest. A fiber optic link and an inductor-capacitor low-pass filter were used to remove extraneous radiofrequency (RF) noise and RF pulse artifacts respectively, and the examination bed was solidly supported on the base of the magnet. The ECG monitoring system provided a useful means for continuous recording of the ECG independently of the R-R interval in the high magnetic field, and permitted reliable monitoring of the QRS complex of the subject at rest and during exercise.

Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy.

Phosphorus-31 magnetic resonance spectroscopy can be used to study intracellular biochemistry non-invasively by measuring the relative proportions of high energy phosphates. Study of deteriorating cardiac metabolism might be useful in the management of hypertrophy and heart failure. 31P magnetic resonance spectroscopy was carried out in fourteen patients with aortic valve disease (six with aortic stenosis, eight with aortic incompetence). Six patients were receiving treatment for symptoms of heart failure. The phosphocreatine (PCr) to ATP ratio in these patients (1.1 [SD 0.32]) was significantly lower than that in thirteen controls (1.5 [0.2], p less than 0.001) or in the eight patients who did not have symptoms of heart failure (1.56 [0.15], p less than 0.0035). These findings indicate that heart failure in aortic valve disease is associated with low PCr, which could be due to loss of intracellular creatine. The measurement could eventually have a role in helping to determine the optimum timing for aortic valve replacement.

Urinary 3-methylthiopropionate excretion and the effect of D- or L-methionine ingestion studied in healthy subjects.

After overnight fasting, the urinary concentrations of 3-methylthiopropionate in 23 healthy male subjects aged from 17 to 72 were studied by gas chromatography and flame photometry. The urinary 3-methylthiopropionate concentrations after fasting showed an approximately normal distribution in the logarithmic scale (M +/- SD = 0.953 +/- 0.394): 10M = 8.97, 10M-SD = 3.62 and 10M + SD = 22.23 ng/mg Creatinine. In 6 volunteers, a 2g D- or L-methionine loading test was also performed. Following D-methionine ingestion, urinary 3-methylthiopropionate concentrations over a 1-hour period increased 22- to 95-fold above those of the pre- loading values and then decreased in an approximately linear manner on semilogarithmic graph paper during a further 2- or 3-hour observation period, after which the examination ended. The mean amount of 3-methylthiopropionate excreted in the urine 3 hrs after loading was 147.7 micrograms (n = 6). Following L-methionine ingestion, by contrast, the increases in 3-methylthiopropionate concentrations over a 1-hr period were 0.3- to 8.3-fold above those of the preloading values. The mean urinary excretion of 3-methylthiopropionate 3 hrs after loading was 3.58 micrograms (n = 4). Because of the simple and specific analytical procedure, quantitative determination of urinary 3-methylthiopropionate is useful in the study of human methionine metabolism.

Increased lipoperoxide value and glutathione peroxidase activity in blood plasma of type 2 (non-insulin-dependent) diabetic women.

The lipoperoxide values and glutathione peroxidase activity in blood plasma, along with the glutathione peroxidase, catalase and cupro-zinc superoxide dismutase activities in erythrocytes were investigated in 60 women with Type 2 (non-insulin-dependent) diabetes mellitus and in 71 healthy women. The mean lipoperoxide value and the mean plasma glutathione peroxidase activity in the diabetic patients were significantly higher than those in the control subjects (lipoperoxide p less than 0.001, plasma glutathione peroxidase activity p less than 0.01). The plasma glutathione peroxidase activities did not, however, correlate with the plasma lipoperoxide values. The erythrocyte glutathione peroxidase activity was approximately ten times higher than that of the plasma glutathione peroxidase activity, nor did they correlate with each other. In contrast to the findings of other authors on the activities of the protective enzymes in erythrocytes against oxidative damage, there were no significant differences of erythrocytes glutathione peroxidase, catalase and superoxide dismutase activities between diabetic and control women.

[The recent status of vibration hazards among workers at the state forests in Hokkaido (author's transl)].

In order to make clear the recent status of vibration hazards among workers belonging to the national forestry bureau in northern Hokkaido, a special health examination was carried out on 417 chain saw operators and 443 bush cutter operators. The results obtained are as follows: 1. Seven point seven percent of chain saw operators and 5.6% of bush cutter operators were diagnosed as suffering from vibration hazards. Distribution of the cases in chain saw operators was 50% in grade I, 31.2% in grade II and 18.8% in grade III, while in bush cutter operators it was 20% in grade I, 60.0% in grade II and 20.0% in grade III. 2. Six new patients were found in this special health examination. 3. Twenty-two of 76 authorized patients, who had been treated with periodical therapy and prohibited from the operation of vibratory tools until this special health examination, were diagnosed as having recovered their health because of the existance of no symptoms concerning vibration hazards. 4. Pains on pressure of the muscles were complained of at the upper arm, forearm, chest and at the back in 12.4% of chain saw and bush cutter operators. Deformities of the elbow, hand and finger joints were recognized in 12.6% of the workers, and ulnar nerve paralysis was recognized in 1.0% of them. 5. Occupational hearing loss and lumbago were diagnosed in 20.2% and 14.7% of the chain saw and bush cutter workers, respectively.

[Studies of the propriety of the items adopted for the special health examination of vibration hazards at present (author's transl)].

Skin temperature, vibratory sense, nail press test and pain sense are customarily used as the items in the special health examination for finding vibration hazards at present. These items are measured under the condition of room temperature at 20 to 23 degrees c and after 10-minute immersion in cold water at 5 degrees C or 10 degrees C. In this report, the propriety of these items was investigated on the basis of measurements in 274 healthy chain saw operators and 294 healthy bush cutter operators. The 10-minute immersion test in cold water at 10 degrees C was adopted in this experiment. The results obtained are as follows: Skin temperatures of the chain saw and bush cutter operators did not show any significant difference by age under the condition at the room temperature, but the recovery in the subjects in the twenties was faster than in the other. Skin temperatures at the 10th minute after the 10-minute immersion test in cold water at 10 degrees C showed very wide deviations among the subjects. Vibratory senses of the aged subjects markedly lowered in comparison with those of the younger subjects. Recovery of vibratory sense after the immersion in cold water showed a tendency which is faster than that of the skin temperature. Correlation between the skin temperature and the vibratory sense at the 10th minute after the immersion was statistically significant. Most of the subjects showed the recovery time within 2 sec with the nail press test under the condition of the room temperature and at the 10th minute after the immersion. Above 95% of subjects complained pain sense with one gram weight at the measurement under the all conditions except immediately after the 10-minute immersion test. From the above results, it should be considered that the value of these measurement may be dominated by the age of the subjects and that the immersion test in cold water to the tests of vibratory sense and pain sense may not have important role in the diagnosis of vibration hazards.