A case of secondary hyperparathyroidism with an ectopic intrathyroid gland successfully diagnosed and controlled by percutaneous ethanol injection therapy (PEIT)

Secondary hyperparathyroidism (II HPT) is a major complication in chronic dialysis patients, and percutaneous ethanol injection therapy (PEIT) has become a useful alternative treatment for II HPT. However, the existence of ectopic parathyroid glands is a major problem when conducting PEIT. Ectopic parathyroid gland accepts 10-35% of II HPT, and the missing glands cannot be detected consistently by any imaging techniques, including scintigraphy. Intrathyroid parathyroid gland is as rare as about 1% and recurrence of missing glands after parathyroidectomy (PTx) has been reported in some cases. We report here a 52-year-old female in whom an ectopic parathyroid gland was defected successfully and intact-PTH controlled by tentative PEIT. At the first examination, a left parathyroid adenoma and a right thyroid goiter were pointed out by ultrasonography, CT and scintigraphy. PEIT was applied twice to the left parathyroid adenoma, but intact-PTH was not decreased. Ultrasonography, CT, 201Tl-99mTc subtraction scintigraphy and fine needle aspiration biopsy (FNAB) were performed again to search for the existence of ectopic glands. The results suggested that the right intrathyroid tumor was an ectopic parathyroid gland. Consequently, tentative PEIT was applied to the right intrathyroid tumor, and successful control of intact-PTH and serum Ca was eventually achieved. To our knowledge, this is the first reported case of secondary hyperparathyroidism with an ectopic intrathyroid gland that was successfully controlled by PEIT. In this case, it was suggested that tentative PEIT of intrathyroid tumor was a useful method for detecting an ectopic parathyroid gland.     

Inhibition of murine corneal allograft rejection by treatment with antibodies to CD80 and CD86

The purpose of this study was to investigate the role of CD80 and CD86 costimulatory molecules in corneal allograft rejection. Anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) were administered after orthotopic corneal allograft transplantation. Graft rejection was observed by biomicroscopy. Population and localization of CD80(+)and CD86(+)cells in the cornea, cervical lymph nodes, and spleen were examined by flow cytometry and immunohistochemistry. The combined use of anti-CD80 and anti-CD86 mAbs was effective in prolonging corneal allograft survival. In the untreated mice bearing rejected graft, many CD86(+)and CD80(+)cells were found around the host-graft junctional area in the cornea, and CD86(high)cells were found in the cervical lymph node and spleen. In contrast, few CD86(+)or CD80(+)cells were observed in the cornea, cervical lymph node, and spleen from the mice treated with anti-CD80/CD86 mAbs. These results demonstrated a significant role of CD80 and CD86 costimulatory molecules in corneal allograft rejection.     

Intraocular dexamethasone delivery system for corneal transplantation in an animal model

PURPOSE: To assess the efficacy of a new intraocular biodegradable polymer dexamethasone drug delivery system (DEX DDS) in a high-risk corneal transplantation model. METHODS: Lewis rats that received orthotopic corneal transplants (Balb/c mice donors) were divided into three groups (six rats in each); group 1 received no treatment and served as controls, group 2 was treated with 0.1% betamethasone eyedrops three times daily for 6 weeks, and group 3 received DEX DDS in the anterior chamber at the time of transplantation. RESULTS: All grafts in the untreated control group were rejected within 8 days. In the betamethasone eyedrop group, five eyes (83%) were rejected during the 8-week study period. None of the grafts in the DEX DDS group was rejected. The administration of DEX DDS significantly prolonged the survival rate of the corneal grafts (p < 0.001, log-rank test). CONCLUSION: DEX DDS is effective in suppressing graft rejection in high-risk corneal transplantation.     

Quinapril treatment restores the vasodilator action of insulin in fructose-hypertensive rats

1. Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve insulin-resistance both experimentally and clinically. We therefore investigated the effects of quinapril, which has high tissue specificity for ACE, regarding the contribution of insulin to vascular contractions, as well as insulin sensitivity in a dietary rat model of insulin resistance. 2. Male Sprague-Dawley rats were divided into three groups: (i) rats fed normal chow (normal diet group); (ii) rats fed fructose-rich chow containing 40% fructose and 7% lard (fructose diet group); and (iii) rats fed fructose-rich chow plus quinapril (10 mg/kg per day; quinapril-treated group). 3. After 2 weeks, we evaluated systolic blood pressure, insulin sensitivity as assessed by steady state plasma glucose (SSPG) levels, response of aortic rings to phenylephrine (10-9 to 10-6 mol/L) in the presence or absence of insulin and the response of aortic rings to acetylcholine. 4. Feeding rats fructose-rich chow resulted in an elevation of blood pressure (P < 0.01) and SSPG levels (P < 0.01). Quinapril treatment significantly prevented increases in both blood pressure and SSPG, with a return to the levels seen in the normal diet group. 5. In the absence of insulin, the maximal contractile response to phenylephrine did not differ between the three groups. However, in the presence of insulin (100 mU/mL), the contractile response to phenylephrine (10-6 mol/L) was reduced by 22.8 +/- 1.2% in the normal diet group, although no insulin effects were observed in the fructose diet group (P < 0.01). Quinapril restored the inhibitory effect of insulin on phenylephrine-induced contractions. 6. In addition, the reduction in relaxation induced by acetylcholine in the fructose diet group was significantly reversed by quinapril treatment. 7. It is concluded that the fructose diet impairs the vasodilator effects of insulin as well as acetylcholine-induced relaxation in rat thoracic aortas. Quinapril prevented deterioration in the responses of the aortic rings, suggesting that ACE inhibitors may be useful for treating vascular insulin resistance.     

Estimation of intradermal disposition kinetics of drugs: II. Factors determining penetration of drugs from viable skin to muscular layer

To develop a more efficient transdermal delivery system, it is very important to regulate the intradermal disposition of drugs after topical application. We tried to elucidate the factors determining the intradermal disposition kinetics, especially drug penetration from the viable skin to the muscular layer, mainly based on the six-compartment model, including the contralateral skin and muscle for ten model drugs with different physicochemical characteristics. In vivo transdermal absorption study was performed for six model drugs using the stripped-skin rats. The fitting analyses by the six-compartment model gave the theoretical curves describing the observed data very well and the reasonable pharmacokinetic parameters, showing the pharmacokinetic model should be useful for the estimation of the intradermal disposition kinetics of drugs applied topically again. The simulation study using the pharmacokinetic parameters obtained above could show the relative contribution of the direct penetration and the distribution from the systemic circulation to the muscular distribution of drugs. The largest contribution of direct penetration was observed for antipyrine (90.8%) and the smallest was for felbinac (43.3%). Among the pharmacokinetic parameters obtained above, the clearance from the viable skin to the muscle (CL(vs-m)) was found to be significantly correlated with the unbound fraction of drugs in the viable skin (fu(vs)). Although the clearance from the viable skin to the plasma (CL(vs-p)) also tended to increase as fu(vs) increased, the ratio of CL(vs-m) to CL(vs-p) was significantly correlated with fu(vs), meaning that the larger amount of unbound drug in the viable skin significantly contributes to the direct penetration into the muscle more than to the systemic absorption. On the other hand, k(direct) values obtained in in vitro penetration study-the penetration rate constant of drugs from the viable skin to the muscular layer-were found to be correlated with CL(vs-m) values for seven model drugs. Therefore, adding the in vitro experiments for the other three model drugs, the multiple linear regression analysis of k(direct) was performed for ten model drugs in terms of fu(vs), logarithm of the partition coefficient (Log P) and molecular weight. The results clearly showed the largest and significant contribution of fu(vs) to the direct penetration of drugs from the viable skin to the muscular layer, indicating that a drug with the higher value of fu(vs) in the viable skin can penetrate more into the muscular layer.     

Twenty-six week carcinogenicity study of ampicillin in CB6F1-TgrasH2 mice

As a part of the ILSI-HESI Alternative to Carcinogenicity Testing (ACT) program, we performed a 26-week carcinogenetic study of nonmutagenic drug, ampicillin (ABPC) in Tg-rasH2 mice. ABPC was given to Tg-rasH2 mice (0, 350, 1000, 3000 mg/kg, p.o.) and Non-Tg mice (0, 3000 mg/kg, p.o.) daily for 26 weeks. As a positive control, a single dose of MNU was administered once to Tg-rasH2 mice (75 mg/kg, i.p.). In this study, Tg-rasH2 mice did not demonstrate any increases in tumor development in response to ABPC. Thus, ABPC had no carcinogenicity in the 26-week carcinogenesis study in Tg-rasH2 mice or in a 2-year carcinogenesis study in B6C3F1 mice.     

Platelet activation in patients with obstructive sleep apnea syndrome and effects of nasal-continuous positive airway pressure

OBJECTIVE: Our study was undertaken to determine whether increased platelet activation occurs in patients with obstructive sleep apnea syndrome (OSAS) and whether a therapy with nasal-continuous positive airway pressure (N-CPAP) alters this activation. METHODS: We measured the positive rate of activated platelets using activation-dependent monoclonal antibodies (MoAb) and flow cytometry in whole blood from 94 patients with OSAS, and from 31 age-matched controls. Thrombotic vascular diseases were surveyed as a background of alternative of platelet activation. RESULTS: The positive rate for activated platelets was significantly higher in patients with OSAS ( PAC1 52.6 +/- 22.9 %, CD62P 6.8 +/- 7.1%, mean +/- SD), as compared with healthy control subjects ( PAC1 16.7 +/- 8.6 %, CD62P 0.7 +/- 0.5 %, p < 0.001). The activation indexes were significantly reduced after 1 month with N-CPAP treatment as a whole (PAC1; from 52.6 +/- 22.9 to 44.2 +/- 22.4, p < 0.05, CD62P; from 6.8 +/- 7.1 to 5.3 +/- 5.5, p < 0.05). In nearly 60 % of patients, platelets activation remained high despite significant improvement of sleep apnea-episodes after N-CPAP. These patients had significantly higher incidence of previous myocardial infarction and/or cerebral infarction and abnormalities of head MRI and carotid sonograpy; indicating that the platelet activation appears to be induced by existing atheroma plaque and not by sympathetic activity in OSAS. CONCLUSION: In conclusion, patients with OSAS have increased percentages of activated platelets as assessed by flow cytometrical analysis of activation dependent surface markers, and were divided into two groups, one group with response to N-CPAP treatment in the reduction of platelet activation and the other without. One possible reason of no response to N-CPAP treatment in the reduction of platelet activation was suggested to be thrombotic diseases.     

Catechol and hydroquinone have different redox properties responsible for their differential DNA-damaging ability.

We examined the redox properties of the "carcinogenic" catechol and the "noncarcinogenic" hydroquinone in relation to different DNA damaging activities and carcinogenicity using 32P-labeled DNA fragments obtained from the human genes. In the presence of endogenous NADH and Cu2+, catechol induces stronger DNA damage than hydroquinone, although the magnitudes of their DNA damaging activities were reversed in the absence of NADH. In both cases, DNA damage resulted from base modification at guanine and thymine residues in addition to strand breakage induced by Cu+ and H2O2, generated during the oxidation of catechol and hydroquinone into 1,2-benzoquinone and 1,4-benzoquinone, respectively. EPR and 1H NMR studies indicated that 1,2-benzoquinone is converted directly into catechol through a nonenzymatic two-electron reduction by NADH whereas 1,4-benzoquinone is reduced into hydroquinone through a semiquinone radical intermediate through two cycles of one-electron reduction. The reduction of 1,2-benzoquinone by NADH proceeds more rapidly than that of 1,4-benzoquinone. This study demonstrates that the rapid 1,2-benzoquinone two-electron reduction accelerates the redox reaction turnover between catechol and 1,2-benzoquinone, resulting in the enhancement of DNA damage. These results suggest that the differences in NADH-mediated redox properties of catechol and hydroquinone contribute to their different carcinogenicities.