Effect of cinacalcet on bone mineral density of the radius in hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND/AIM: Cinacalcet, an allosteric modulator of the calcium sensing receptor, effectively reduces serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. It is not well known whether bone mineral density (BMD) of hemodialysis patients with secondary hyperparathyroidism is altered after cinacalcet treatment. METHODS: The BMD in the distal 1/3 of the radius and in the ultradistal radius, which are enriched with cortical and cancellous bone, respectively, was examined by dual X-ray absorptiometry, 1 year prior to, at the start, and 1 year after cinacalcet treatment, in 61 patients. RESULTS: The BMD of both the distal 1/3 and ultradistal radius decreased significantly in the year prior to cinacalcet treatment (p < 0.01). However, the BMD at either site did not change significantly in the year after cinacalcet treatment. The annual changes in the BMD of the distal 1/3 radius increased significantly from -0.023 ± 0.029 g/cm2/year to -0.002 ± 0.033 g/cm2/year, prior to and after cinacalcet treatment, respectively; however, the annual changes in the BMD of the ultradistal radius did not change significantly prior to and after cinacalcet treatment. CONCLUSION: There was a significant association between cinacalcet treatment and reduction in BMD loss in patients with secondary hyperparathyroidism. Cortical bone, rather than cancellous bone, was particularly affected by cinacalcet treatment.

Promotion by histamine of carcinogenesis in the forestomach and protection by histamine against carcinogenesis induced by N-nitroso-N-methylnitroguanidine in the glandular stomach in W rats.

The effect of histamine on induction of tumors in the forestomach and the glandular stomach after N-nitroso-N-methylnitroguanidine (MNNG) administration was studied in male inbred W rats. Animals were given 50 micrograms MNNG solution/ml orally for 25 weeks and then 4 mg histamine dihydrochloride sc per day in depot form. Administration of histamine in depot form after MNNG significantly increased the incidence of tumors in the forestomach, but it significantly decreased the incidence of adenocarcinomas in the glandular stomach. All of the tumors induced in the forestomach were of the squamous cell type, and 50% of them were squamous cell carcinomas. Histamine alone had no apparent carcinogenicity in rats.

Inhibitory effects of tetragastrin and histamine on carcinogenesis in the small intestines of W rats by N-methyl-N'-nitro-N-nitrosoguanidine.

The effects of tetragastrin and histamine on the incidence and histology of tumors induced in the small intestine by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] were investigated in male W rats. Animals were given MNNG at 150 micrograms/ml in their drinking water for 25 weeks and then 300 micrograms tetragastrin or 4 mg histamine dihydrochloride sc per day in depot form. Administration of tetragastrin or histamine after MNNG treatment resulted in a significant increase in gastric acid secretion and a significant reduction in the incidence of tumors in the duodenum; however, only histamine decreased the incidence of tumors in the jejunum. Histologically, the tumors induced in the small intestine were mostly adenocarcinomas, and their histologic type was not affected by either tetragastrin or histamine.

Photodynamic effects of exposure to hematoporphyrin derivatives and dye-laser radiation on human gastric adenocarcinoma cells.

The phototoxicity of hematoporphyrin derivatives (HPD) and dye-laser radiation on adenocarcinoma cells of the human stomach was examined by light and electron microscopy. Adenocarcinoma cells were obtained from human stomach tissue by endoscopic biopsy. The cells were incubated for 5 minutes in the patient's own serum that contained 0.6 mg HPD/ml and then were exposed to dye-laser radiation at 630 nm at an irradiance of 15 mW/cm2. Electron microscopy showed that cytotoxicity was mediated by mitochondrial damage, dilatation of the rough endoplasmic reticulum, and alterations of the nuclear membrane. The degenerative changes were greater and more frequent in poorly differentiated adenocarcinoma cells than in well-differentiated ones. No marked temperature rise was detected during irradiation. Neither the dye alone nor light alone had any effect. A singlet oxygen-trapping agent, 1,3-diphenylisobenzofuran, prevented adenocarcinoma cell degeneration that otherwise would result from exposure to HPD and dye-laser radiation. Thus singlet oxygen may be the cytotoxic agent in this system.

Effect of a chemically defined diet in liquid form on colon carcinogenesis in rats.

The effects of ad libitum feeding of a chemically defined diet in liquid form on the incidence and histology of colon cancer induced by 10 weekly sc injections of 7.4 mg/kg of azoxymethane [(AOM) CAS: 25843-45-2] were investigated in W-rats. The chemically defined diet was adjusted once every 24 hours from 4 weeks before injection of the carcinogen to the end of the experiment at week 40. Oral administration of the defined diet resulted in significant increase in the incidence of colon cancer at week 40. Histologic examination showed that unlike adenocarcinomas with high mucin-producing activity, which were common in rats on pellet diet, most of the adenocarcinomas that developed in rats fed on defined diet were highly or well differentiated, with a typical glandular pattern. Administration of the chemically defined diet also resulted in marked colon mucosal hypoplasia and reduced gastrin levels in the serum at weeks 4 and 40.

Effect of prolonged administration of gastrin on experimental carcinogenesis in rat colon induced by intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine.

The effect of tetragastrin on the incidence and histology of colonic tumors induced by intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine was investigated in Wistar rats. Prolonged administration of tetragastrin in depot form during and after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant reduction in the incidence of colonic tumors in Experimental Week 35. Histological examinations showed that, unlike the well-differentiated adenocarcinomas with a typical glandular pattern in control groups, the adenocarcinomas that developed in rats treated with tetragastrin had high mucin-producing activity.

Effect of tetragastrin on the colonic mucosa of rats during intrarectal administration of N-methyl-N'-nitro-N-nitrosoguanidine.

The effects of the C-terminal tetrapeptide of gastrin, tetragastrin, on the colonic mucosa on Days 15 and 25 during intrarectal administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and its effects on the incidences of colonic tumors in experimental Wk 20 and 35 were investigated in Wistar rats. Administration of tetragastrin in depot form during instillation of MNNG resulted in significant decreases in the incidences of mucosal erosions, ulcerations, and atypical regenerative glandular hyperplasias in the colonic mucosa, most of these lesions being greater in the distal half of the colon. Administration of tetragastrin also significantly decreased the incidences and/or numbers of colonic tumors in Wk 20 and 35. The distribution of colonic tumors induced in Wk 20 and 35 corresponded well to those of erosions, ulcerations, and atypical regenerative glandular hyperplasias induced during the administration of MNNG. These findings suggest that the effect of tetragastrin in decreasing the incidences of erosions, ulcerations, and atypical regenerative glandular hyperplasias in the colonic mucosa during instillation of MNNG is related to its effect in reducing the development of colonic tumors.

Inhibition by gamma-amino-n-butyric acid and baclofen of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of gamma-amino-n-butyric acid (GABA), the GABA(A) receptor agonist muscimol (5-aminomethyl-3-hydroxyisoxazole), and the GABA(B) receptor agonist baclofen [4-amino-3-(4-chlorophenyl)butanoic acid] on the incidence and number of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in Wistar rats. Rats received alternate-day i.p. injections of 500 or 1000 mg/kg of body weight GABA, 0.25 or 0.5 mg/kg of body weight muscimol, or 4 or 8 mg/kg of body weight baclofen after 25 wk of p.o. treatment with the carcinogen. Prolonged administration of GABA at 1000 mg/kg of body weight, but not at 500 mg/kg of body weight, and of baclofen at 4 and 8 mg/kg of body weight significantly decreased the incidence and number of gastric cancers of the glandular stomach in Wk 52, but long-term muscimol administration had no influence. Histologically, GABA at the high dosage and baclofen at both dosages significantly decreased the labeling index of the antral mucosa and significantly increased the serum gastrin level. Furthermore, baclofen at both dosages significantly decreased antral pH and significantly increased gastric acid secretion. These findings indicate that GABA inhibits gastric carcinogenesis via the GABAB receptor and that this effect may be related to its effect in decreasing the proliferation of antral mucosa.

Promotion by bombesin of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effects of bombesin on the incidence, number, histological type, and depth of involvement of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in male Wistar rats. Rats received alternate-day s.c. administration of 20 or 40 micrograms/kg body weight of bombesin in depot form after p.o. treatment with the carcinogen for 25 weeks. Prolonged administration of bombesin at 40 micrograms/kg led to a significant increase in the incidence and number per rat of gastric cancers of the glandular stomach at Week 52. In rats that had received alternate-day injections of 20 micrograms/kg of bombesin, the number of gastric cancers per rat, but not the incidence of cancer, was significantly more than in untreated rats. However, bombesin at both dosages did not affect the histological appearance of the lesions or their depth of involvement. At Weeks 30 and 52, norepinephrine concentrations in the fundic and antral portion of the gastric walls and labeling indices in the antral and fundic mucosae were significantly higher in rats treated with bombesin at both dosages than in untreated rats. These findings indicate that bombesin enhances gastric carcinogenesis after administration of N-methyl-N'-nitro-N-nitrosoguanidine is stopped and that this effect may be related to its effects in increasing tissue norepinephrine concentrations in the stomach wall and increasing cell proliferation in the gastric mucosa.

Attenuating effect of bromocriptine on cysteamine anticarcinogenesis of stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine.

The effect of bromocriptine on inhibition by cysteamine of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. After 25 weeks of p.o. treatment with N-methyl-N'-nitro-N-nitrosoguanidine, rats were given injections every other day: cysteamine (50 mg/kg body weight); cysteamine (50 mg/kg body weight) plus bromocriptine (0.5 or 0.25 mg/kg body weight); or bromocriptine (0.5 or 0.25 mg/kg body weight). In week 52, the group treated with cysteamine showed a significantly decreased incidence of gastric cancers. Concomitant treatment with bromocriptine at 0.5 but not at 0.25 mg/kg body weight significantly attenuated the inhibitory effect of cysteamine on gastric carcinogenesis. Administration of bromocriptine alone at either dosage had no influence on gastric carcinogenesis. The labeling index of the antral mucosa was significantly reduced in rats treated with cysteamine and significantly higher in those treated concomitantly with bromocriptine at 0.5 mg/kg body weight than in those treated with cysteamine alone. These findings indicate that cysteamine suppressed gastric carcinogenesis and that bromocriptine at high dosage attenuated this inhibition. These findings also suggest that dopamine is involved in the mechanism of inhibition of gastric carcinogenesis by cysteamine.

Promotion by vagotomy of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effects of truncal vagotomy after administration of N-methyl-N'-nitro-N-nitrosoguanidine on the incidence and number of gastric carcinomas and gastric acid secretion, gastrin secretion, antral pH, and duodenal reflux were investigated in inbred Wistar rats. Rats were subjected to truncal vagotomy after N-methyl-N'-nitro-N-nitrosoguanidine treatment. Vagotomy significantly increased the incidence and number of adenocarcinomas of the glandular stomach. It also resulted in significantly more atypical glandular hyperplasias, which are precursors of gastric cancer. Furthermore, it caused a decrease in gastric secretion and an increase in mucosal pH in the antrum but did not increase duodenal reflux. These findings indicate that vagotomy has a promoting effect on the development of gastric cancers. The reduced gastric acid secretion, but not duodenal reflux, may be related to this increased incidence of gastric cancer.

Detection of platinum in the brain of mice treated with cisplatin and subjected to short-term hypoxia.

Cisplatin is widely used for cancer treatment but has strong side-effects, including nephrotoxicity. Neurotoxicity has been thought to be limited to peripheral damage because the blood-brain barrier is thought to be impervious to hydrophilic substances such as cisplatin. Because anoxic ischaemia has been associated with lesions of the barrier, inductively coupled plasma mass spectrometry has been used to monitor the accumulation of platinum in the brains of mice treated with cisplatin and exposed to oxygen-deficient atmospheres. Platinum was detected in the cerebral cortex of mice 24 h after the administration of cisplatin (3 mg kg-1) followed by exposure for 60 s to an atmosphere containing 7% oxygen, but not in the cerebral cortex of mice exposed to normal atmospheres. Platinum was also observed in the cerebral cortex after exposure for 120 s to an atmosphere containing 14% oxygen, and platinum levels increased as the concentration of oxygen was reduced. The highest platinum levels were obtained 10 h after administration of cisplatin and exposure for 120 s to an atmosphere containing 7% oxygen. Platinum was still retained in the cerebral cortex one week after administration. In contrast, platinum levels in the blood and kidney decreased with time. Platinum levels were measured in seven regions of the brain: the right and left cerebral cortices, the basal ganglia, the thalamus and hypothalamus, the bulbus olfactorius, the cerebellum, and the mesencephalon. When cisplatin was administered to mice not subjected to hypoxia, platinum was not detected in the right and left cerebral cortices, basal ganglia or the thalamus and hypothalamus, but was detected in the bulbus olfactorius, cerebellum and mesencephalon. When such mice were exposed to low levels of oxygen, however, platinum was detected in the right and left cerebral cortices, the basal ganglia and the thalamus and hypothalamus. Platinum levels in the cerebellum and mesencephalon of mice exposed to low levels of oxygen were higher than those of mice exposed to normal air. In addition, platinum levels in the bulbus olfactorius were significantly higher than those in the other regions, although the platinum content of the bulbus olfactorius was not affected by hypoxia. From these observations, it is concluded that platinum is easily accumulated in the bulbus olfactorius after the administration of cisplatin, and that after exposure to atmospheres containing low levels of oxygen, platinum easily passes through the blood-brain barrier and accumulates in all parts of the brain.

Accumulation of mercury in excavated bones of two natives in Japan.

Mercury content of excavated bones and surrounding soil was compared between the two areas of Shikoku, Tokushima and Matsuyama. Results show a high variance of mercury content between localities and between ages of the burials. There was a high mercury occurrence in the 6-7th century in Tokushima and a moderate one in Matsuyama, and a trace in the 12-17th century in both places. Moreover, a low level of mercury was observed in the soil samples of Tokushima, and mercury was not detected in any of the Matsuyama soil samples. Therefore, these occasions of high mercury content may be due to artificial uptake, and may relate to differences in conventions and customs.

Comparison of three different methods for measurement of tissue platinum level.

We attempted to make a comparison of three methods for tissue platinum; atomic absorption spectrometry (AAS), inductively coupled plasma atomic emission spectrometry (ICP-AES), and inductively coupled plasma mass spectrometry (ICP-MS). The determination limits were 0.05 ng/mL on ICP-MS, 50 ng/mL on ICP-AES, and 200 ng/mL on AAS, and the recovery rates were 97.7 +/- 6.9% on ICP-MS, 69.0 +/- 3.0% on ICP-AES, and 102.4 +/- 4.0% on AAS, respectively. Platinum was detected by ICP-AES and ICP-MS in human vertebrae, but the level was higher by ICP-AES than by ICP-MS. In the mouse kidney treated with cisplatin, platinum was detected by ICP-MS, but not by ICP-AES. As cadmium gives the absorption peak close to platinum, cadmium was measured together with platinum by ICP-AES in the vertebrae. From these, ICP-MS is the most sensitive for measurement at tissue platinum. The sensitivity of ICP-AES looks worse for measuring the tissue platinum, and it is necessary to take care of the contaminant of metals, especially cadmium. AAS is not suitable for measurement of tissue platinum as in the vertebrae and kidneys, because platinum was not detectable by AAS.

Free radical scavengers suppress the accumulation of platinum in the cerebral cortex.

We investigated whether free radical scavengers and antioxidants inhibit the accumulation of platinum (Pt) in the cerebral cortex. Pt was detected in the cerebral cortex of mice after administration of cisplatin and exposure to short-term hypoxia. When mice were treated with either allopurinol (20 mg/kg) or catalase (100 mg/kg) before cisplatin administration and low oxygen exposure, Pt was not detected in the cerebral cortex. However, Pt was detected in the cerebral cortex of mice pretreated with either a low dosage of allopurinol or heat-denatured catalase. Furthermore, Pt was detected in the cerebral cortex of mice preadministered vitamin C, vitamin E, or deferoxamine. Lipid peroxide levels in the cerebral cortex increased 10 min after the treatment of hypoxia, and peaked 30 min after the treatment. These results suggested that short-term hypoxia produces free radicals, which allows Pt to pass through the blood-brain barrier and accumulate in the cerebral cortex, and that the production of free radicals is reduced by the administration of either allopurinol or catalase, which prevents Pt from passing through the barrier.

Difference of mineral contents in human intervertebral disks and its age-related change.

To establish a difference of the relative contents (RCs) of elements among the cervical, thoracic, and lumbar intervertebral disks and its age-related change, the intervertebral disks between the axis and the sacrum, which were resected from the nine cadavers who died at 53 to 99 yr old, were analyzed by inductively coupled atomic plasma emission spectrometry. It was found that both the RCs of calcium and phosphorus were high in the cervical disks, especially the highest in the disk between the 6th and 7th cervical vertebrae, and lower in the order of the cervical, thoracic, and lumbar intervertebral disks. In regard to the RCs of sulfur and magnesium, there were no significant differences among the cervical, thoracic, and lumbar intervertebral disks. In addition, it was found that both the RCs of calcium and phosphorus in the cervical intervertebral disks started to increase in the sixth decade of life, became the highest in the eighth decade of life, and then decreased.

An improved method for estimating original mineral contents in excavated bone using sulfur.

Trace element analysis in excavated bones is complicated by the lack of a reliable index for estimating the original amount of bone material. In this study, we subjected modern human bones to alkali treatment to simulate aging. Alkali treatment of vertebrae with attached muscle did not affect sulfur (S) content; it increased the magnesium (Mg), phosphorus (P), and zinc (Zn) contents, and tended to decrease iron (Fe) content of the bones. When vertebrae cleaned of muscle were used, alkali treatment did not affect S and Fe contents but increased Mg, P, Ca, and Zn contents. Ca and S contents were higher in excavated bones (200-1300 yr old) than in their surrounding soils. In contrast, S, Mg, and Ca contents per dry weight did not differ between the excavated bones and the alkali-treated modern bones. These results indicate that S can provide a more accurate index of excavated bones than the often-used Ca content or dry wt measures, especially for bones excavated from calcium-rich soils.

Age-dependent aluminum accumulation in the human aorta and cerebral artery.

The purpose of this study was to determine the extent of aluminum (Al) accumulation in the human aorta and cerebral arteries. The Al contents in the aortae and in the cerebral arteries from 23 human subjects was determined by inductively coupled plasma atomic emission spectrophotometry (ICP-AES). The subjects' age range was 45-99-yr-old; 15 of the subjects were males and 8 were females. Al was detected in twelve aortae and in six cerebral arteries, when the entire specimen was analyzed. Two specimens where Al was found in the cerebral arteries contained no Al in the aorta. No relationship to the subject's sex was found. When related to age, two groups were established. Group L (45-75 yr old) and group H (> 75 yr old), which exhibited aortal Al concentrations of 33.3 and 72.7%, respectively. When the aortic wall was dissected into the tunica intima, media, and adventitia, Al was found mainly in the tunica media. In the aorta, significant relationships were found between Al and phosphorus (P) levels (r = 0.801, p < 0.01) and between Al and calcium (Ca) (r = 0.661, p < 0.05). We have concluded that Al accumulation is age-dependent and that it occurs both in the aorta and in the cerebral artery. In the aorta, accumulation occurs mainly in the tunica media. Both P and Ca appear to enhance aortal Al accumulation.

Accumulation of platinum in the intervertebral discs and vertebrae of ovarian tumor-bearing patients treated with cisplatin.

Platinum was determined by the inductively coupled plasma mass spectrometry (ICP-MS) in the intervertebral discs and vertebrae of ovarian tumor bearing patients treated with cis-diamminedichloro-platinum (II) (cisplatin). Platinum was 0.05 ng/mL at the absolute detection limit, and platinum was undetectable in the intervertebral discs and vertebrae of human specimens without cisplatin treatments. On the other hand, platinum was detected in the intervertebral discs and vertebrae of patients administered cisplatin, and platinum concentration was at levels of 1.06-10.31 micrograms/g dry tissue in the intervertebral discs and 0.60-1.28 micrograms/g dry tissue in the vertebrae, respectively. The platinum level of intervertebral discs was 4.3-fold higher than that of the vertebrae. Thus, platinum accumulates greatly in the intervertebral discs and somewhat in the vertebrae after administering cisplatin to patients for therapy.

Age-related change of mineral content in the human thoracic aorta and in the human cerebral artery.

The relative contents (RCs) of mineral elements in aortae and cerebral arteries from 23 subjects, with ages ranging between 45 and 99 yr, were analyzed by inductively coupled plasma atomic emission spectrometry. The RCs of calcium, phosphorus, and magnesium in the aortae increased markedly after the age of 70. While the RC of sulfur in aortae decreased gradually after that age. It was found that accumulation of calcium and phosphorus occurred primarily in the tunica media of aorta, and secondarily in the tunica intima. Furthermore, the RCs of calcium, phosphorus, and magnesium in cerebral arteries increased markedly after the age of 70, whereas the RC of sulfur in cerebral arteries decreased after age 70. It was found that accumulation of calcium and phosphorus in the cerebral arteries were 30 and 60%, respectively, lower than those in the aortae with ages ranging between 45 and 99 yr.