Pharmacokinetic change of nanoparticulate formulation "Lactosome" on multiple administrations

Lactosome, which is a polymer micelle composed of poly(lactic acid)-b-poly(sarcosine), was applied successfully for solid tumor imaging. Lactosome is considered to escape from the reticuloendothelial system recognition, and shows prolonged in vivo blood clearance time. In vivo disposition of Lactosome, however, changed upon multiple dosages. Lactosome at the 2nd dosage was cleared from the blood stream by trapping at liver. This accelerated blood clearance (ABC) phenomenon is explained by production of anti-Lactosome IgM and IgG(3) through the immune response related with B-lymphocyte cells. The memory effect of B-lymphocyte cells lasted nearly for six months in mouse. The epitope moiety of Lactosome is concluded to be poly(sarcosine) based on the competitive inhibition assay. Since the ABC phenomenon was also reported with PEGylated liposome, nanoparticles in general may be potential in triggering the immune system.     

Impact of walking upon medical care expenditure in Japan: the Ohsaki Cohort Study

BACKGROUND: Physical activity is expected to reduce medical costs by lowering the risk for a variety of chronic diseases. However, little is known about the actual magnitude of medical cost saved by physical activity. We attempted to quantify the association between time spent walking and medical care costs, based on a 4-year prospective observation of National Health Insurance (NHI) beneficiaries in rural Japan. METHODS: In 27 431 Japanese men and women, aged 40-79 years, who had no functional limitation or conditions interfering with physical activity at the baseline survey in 1994, we ascertained all hospitalizations, outpatient visits, and the costs through computerized linkage with NHI claims history files between January 1995 and December 1998. RESULTS: Medical costs significantly reduced with longer time spent walking. Per capita medical cost was pound 111.80 per month (95% CI: 109.3, 114.2) in those who walked for < or =30 minutes/day, pound 108.10 (95% CI: 105.7, 110.5) in those who walked for 30 minutes-1 hour, and pound 97.30 (95% CI: 95.5, 99.0) in those who walked for > or =1 hour, after multivariate adjustment of potential confounders. CONCLUSIONS: This prospective study in Japan indicated that time spent walking was significantly associated with lower medical costs.     

Effect of the PPARG2 Pro12Ala Polymorphism and Clinical Risk Factors for Diabetes Mellitus on HbA1c in the Japanese General Population

Background

Although the peroxisome proliferator-activated receptor-γ2 (PPARG2) Pro12Ala gene variant is associated with diabetes mellitus, the associations and interactions of this polymorphism and known clinical risk factors with glycated hemoglobin (HbA1c) remain poorly understood. We investigated if carrying the Ala allele was inversely associated with HbA1c level and examined possible interactions.

Methods

This cross-sectional analysis used data collected from 1281 men and 1356 women aged 40 to 69 years who completed the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. PPARG2 polymorphism was determined by multiplex polymerase chain reaction (PCR)-based Invader assay. Multiple linear regression and ANCOVA were used to control for confounding variables (age, body mass index [BMI], energy intake, alcohol, smoking, physical activity, and family history of diabetes) and examine possible interactions.

Results

After adjustment, the Ala allele was significantly inversely associated with HbA1c in women but not in men. Older age, BMI, and family history of diabetes were associated with higher HbA1c in both sexes. When stratified by PPARG2 genotype, these associations were observed in subjects with the Pro12Pro genotype but not in Ala allele carriers. A significant interaction of genotype and BMI on HbA1c was observed in women. Older age, BMI, and family history of diabetes were significantly associated with high-normal HbA1c (≥5.7% NGSP), whereas PPARG2 polymorphism was not.

Conclusions

Although PPARG2 Pro12Ala polymorphism might attenuate associations between known risk factors and HbA1c level, it had a small effect on high-normal HbA1c, as compared with clinical risk factors, in the general population.Key words: peroxisome proliferator-activated receptor-γ2, polymorphism, glycated hemoglobin, interaction     

Ingestion of water-soluble soybean fiber prevents gastrectomy-induced iron malabsorption,anemia and impairment of voluntary running exercise performance in rats

We examined the effects of feeding water-soluble soybean fiber (WSSF), a highly fermentable dietary fiber, on gastrectomy-induced iron malabsorption, anemia and impairment of exercise performance in rats in two separate experiments. The study was designed as a 2 x 2 factorial arrangement with operation (total gastrectomy) and diet (WSSF) under sedentary (Experiment 1) and exercised (Experiment 2) conditions. In Experiment 1, gastrectomy reduced net iron absorption, hemoglobin concentration, hematocrit and hemoglobin regeneration efficiency (P < 0.01). However, in rats fed a WSSF diet (50 g/kg diet), iron absorption and the hematological variables of the gastrectomized rats were comparable to those in the sham-operated rats, demonstrating that ingestion of WSSF promotes iron absorption and prevents anemia after gastrectomy. Feeding WSSF increased pools of organic acids and soluble iron in cecal contents and decreased the pH of the cecal contents (P < 0.001). Of the many cecal variables measured, net iron absorption in gastrectomized rats was most closely correlated (r = 0.614, P < 0.01) with the short-chain fatty acid pool in the cecum. Cecal fermentation of WSSF may contribute to improvements in gastrectomy-induced nutritional defects. In Experiment 2, we examined voluntary running exercise performance in totally gastrectomized rats fed diets with or without WSSF. Total gastrectomy severely impaired running performance (P < 0.001), and WSSF feeding largely restored the lowered performance. We conclude that feeding WSSF improves anemia and impaired voluntary running performance in totally gastrectomized rats.     

Effect of lactulose on calcium and magnesium absorption: a study using stable isotopes in adult men

To evaluate the effect of lactulose on calcium (Ca) and magnesium (Mg) absorption, we performed a clinical trial with a double-blind, randomized, crossover design in 24 healthy adult male volunteers. The absorptions of Ca and Mg were evaluated by a single-labeling method using stable isotopes. The test foods, containing lactulose at a dose of 0 g (placebo), 2 g (low-dose), or 4 g (high-dose) together with 300 mg of Ca containing 20 mg of 44Ca, and 150 mg of Mg containing 28 mg of 25Mg, were administered orally. Urine samples were collected for 8 h after the ingestion of the test food. The ratios of stable isotopes in urine (44Ca/40Ca and 25Mg/24Mg) were measured by ICP-MS (inductively coupled plasma-mass spectrometry). The urinary stable-isotopes ratios (44Ca/40Ca and 25Mg/24Mg) increased with lactulose dosage. Significant differences were observed in the Ca ratio between placebo and high-dose lactulose (p<0.01), and in the Mg ratio between placebo and low-dose lactulose and between placebo and high-dose lactulose (p<0.01). Lactulose ingestion did not change the levels of bone-resorption markers (type I collagen cross-linked N-telopeptide and deoxypyridinoline) in urine. The test foods did not cause any side effects. This study demonstrates that lactulose enhances the absorptions of Ca and Mg in adult men.     

Effect of bis (tributyl tin) oxide on permeability of the blood-brain barrier: a transient increase.

OBJECTIVES--To study the effect of bis (tributyl tin) oxide (TBTO) on permeability of the blood-brain barrier. METHODS--Electron microscopy and an x ray microanalyser with lanthanum chloride as a tracer were used, and blood tin concentrations were determined with an atomic absorption spectrophotometer. Adult male wistar rats received 0.05 ml/kg body weight of TBTO orally. RESULTS--A transient increase in paracellular permeability at the blood-brain barrier was found 2 h after the dose of TBTO. Electron dense lanthanum deposits penetrated tight junctions of the endothelia and permeated the subendothelial space. The x ray microprobe data showed an accumulation of TBTO at the tight junctions at 2 h. Leakage of tracer did not occur at 4 h, but oedematous changes in the surrounding glial cells were prominent between 4 and 8 h and had almost returned to normal by 24 h. By atomic absorption analysis, it was seen that blood tin concentrations rapidly increased at 1 h and rose to a maximum peak at 8 h, then gradually decreased to reach zero at 24 h. CONCLUSIONS--Accumulated TBTO at tight junctions could have caused the temporary replacement of calcium ion by tin, which induces a transient increase in paracellular permeability throughout the blood-brain barrier.     

Successful treatment of an infected wound in infants by a combination of negative pressure wound therapy and arginine supplementation

ObjectiveWound dehiscence caused by surgical site infection (SSI) presents a complicated problem. Negative pressure wound therapy (NPWT) was developed to treat wound dehiscence. Nutritional treatment using arginine has also been recently shown to be effective for the treatment of pressure ulcers. Therefore, wound complications due to SSI were treated using NPWT combined with nutritional therapy with an arginine-rich supplement (ARS).MethodsSix pediatric patients with wound dehiscence due to SSI received this combined therapy.ResultsThe average age of the patients was 12.2 mo. The operations that these patients underwent included laryngotracheal separation, radical operation for spinal bifida, gastrostomy, colostomy, anorectoplasty, and tumor extirpation. A local wound infection induced wound dehiscence in all patients. Therefore, NPWT was introduced with an enteral administration of ARS. All wounds completely healed within 1 mo after the introduction of this combined therapy without any other complications from the NPWT or ARS. A follow-up study at 6 mo after this therapy was completed showed no complications associated with the wounds.ConclusionThis combination therapy using NPWT and ARS administration was effective in inducing early healing of infected wound complications after surgery.     

Characterization of an immortalized hepatic stellate cell line established from metallothionein-null mice

Hepatic stellate (HS) cells were isolated from the livers of metallothionein (MT)-null and control mice and used to establish IMS/MT(-) and IMS/N cell lines, respectively, using SV40 virus transformation. Cellular morphology, incorporation of vitamin A and expression of alpha-SMA, desmin and SV40 T-antigen were used to confirm that both cell lines were immortal HS cells. The growth rates of both cell lines were similar and there was little difference between cell line sensitivity to zinc. MT-null IMS/MT(-) cells were more sensitive to cadmium and mercury, although both cell lines accumulated almost equal amounts of cadmium during a 24-hr culture period. As HS cells play an important role in hepatic fibrosis and are activated by heavy metals such as cadmium or reactive oxygen, the MT-null HS cell line derived in this study should be a useful experimental model for examination of the role of MT in HS cell activation.     

Estimation of aldehyde oxidase activity in vivo from conversion ratio of N1-methylnicotinamide to pyridones, and intraspecies variation of the enzyme activity in rats.

The in vivo conversion ratio of N1-methylnicotinamide (NMN) to N1-methyl-2-pyridone-5-carboxamide (2-PY) and N1-methyl-4-pyridone-3-carboxamide (4-PY) as a parameter for the estimation of aldehyde oxidase level in rats was examined. NMN and its pyridones (2-PY and 4-PY) are usually detected in the urine of rats. When we measured the ratio of the amount of pyridones to the total amount of NMN and pyridones (RP value) in the urine of rats, marked intraspecies variations were observed. The variation in RP value among strains was closely related to the differences of liver aldehyde oxidase activity measured with NMN as a substrate. RP values after administration of NMN to different strains of rats confirmed the existence of strain differences of aldehyde oxidase activity in vivo. We demonstrated that measurements of NMN and its pyridones usually excreted in the urine can be used to predict the in vivo level of aldehyde oxidase.     

Substrate specificity of a mouse aldo-keto reductase (AKR1C12)

AKR1C12, a mouse member of the aldo-keto reductase (AKR) superfamily, is highly expressed in the stomach and is identical to a protein encoded in an interleukin-3-regulated gene in mouse myeloid cells, but its function remains unknown. In this study, the recombinant AKR1C12 was purified to homogeneity and the specificity for coenzymes and substrates was examined at a physiological pH of 7.4. The enzyme reduced various alpha-dicarbonyl compounds, several ketosteroids, aldehydes and some ketones using NADH as the preferred coenzyme. In the reverse reaction, the enzyme showed coenzyme preference for NAD+, and oxidized 3alpha-, 17beta- and 20alpha-hydroxysteroids, and non-steroidal aliphatic and alicyclic alcohols, of which many hydroxysteroids and geranylgeraniol were good substrates, exhibiting low Km and high kcat/Km values. The results, together with the intracellular high ratio of NAD+/NADH, suggest that AKR1C12 functions as a dehydrogenase for the endogenous hydroxysteroids and geranylgeraniol in mouse stomach and myeloid cells.