Spontaneous regression of multicentric pilocytic astrocytoma with CSF dissemination in an adult

We present a case of spontaneous regression of multicentric pilocytic astrocytoma with cerebrospinal fluid (CSF) dissemination without neurofibromatosis type 1 (NF1) in an adult, the first such case reported. Magnetic resonance imaging (MRI) showed multiple low signal intensity lesions on T1-weighted images and high signal intensity areas on T2-weighted images in the bilateral thalamus, basal ganglia and midbrain. Contrast-enhanced MRI revealed that small, enhanced lesions were seen in the basal ganglia and the pineal region. Neuroendoscopic biopsy and third ventriculostomy were performed. Intraoperative findings demonstrated CSF dissemination. Histologically, the specimens showed pilocytic astrocytoma. Serial MRIs showed regression of the tumor without any additional treatment. The clinical features of spontaneous regression of pilocytic astrocytoma are discussed.     

Mode of action of trifluorothymidine (TFT) against DNA replication and repair enzymes

Trifluorothymidine (TFT) is well known to be converted to TFT-monophosphate by thymidine kinase and to inhibit thymidylate synthase. In addition, TFT-triphosphate (TFT-TP) is also incorporated into DNA, resulting in cytocidal effects. However, the precise mechanism of TFT-induced DNA damage is still unclear. Therefore, we investigated the modes of action of TFT against DNA replication and repair enzymes, as compared with those of 5FU and FdUrd. When HeLa cells were treated with TFT at a concentration of 1 μM (IC50 value), the concentration of TFT in the DNA was calculated as 62.2±0.9 pmol/1x106 cells for 4 h. On the other hand, following treatment of the cells with FdUrd (0.5 μM) and 5FU (10 μM) at their IC50 doses, the drug concentrations in the DNA were 7.53, and 0.17 pmol/1 x 10? cells for 4 h, respectively. These results show the markedly greater degree of incorporation of TFT into the DNA of the HeLa cells compared with that of 5FU (approximately more than 300-fold for 4 h) or FdUrd (approximately more than 8-fold for 4 h). The primer extension assay demonstrated that TFT-TP was also incorporated into the T-sites of the growing DNA strand, however, it competed only weakly with thymidine triphosphate. The DNA glycosylase assay was performed using commercially available DNA glycosylase and fractionated HeLa cell extracts obtained by gel filtration. There was no detectable excision of the TFT pairing to adenine by uracil DNA glycosylase (UDG), thymine DNA glycosylase (TDG), methyl-CpG binding domain 4 (MBD4) or the fractionated HeLa cell extracts, however, TDG and MBD4 were able to excise the TFT pairing to guanine. Additional data indicate that small-interfering RNA-mediated knockdown of TDG or MBD4 significantly increased the resistance to the cytotoxic effects of FdUrd, but not to that of TFT. These studies show the greater degree of incorporation of TFT into the DNA than that of 5FU or FdUrd, and that such a high degree of incorporation of TFT residues into the DNA might be related to exhibit potent cytotoxic activity to be refractory to cleavage by these DNA glycosylases; thus, the DNA-directed cytotoxic effect of the compound is quite different from that of 5FU.     

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination

Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. siRNA for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair.     

Investigation of trends and characteristics in patients with obstructive sleep apnea

Background

Oral appliance (OA) therapy for obstructive sleep apnea (OSA) has only been part of Japan’s National Health care coverage plan since 2004. Subsequently, not enough time has passed to establish the medical trends and characteristics of OSA patients in Japanese Dental Hospitals.

Aim

The aim of this study was to investigate the medical trends and the characteristics in patients with OSA who visited our clinic, and to compare our findings with previous studies.

Setting and design

Epidemiological survey (retrospective study).

Materials and methods

Two hundred and one patients were recruited at the Internal Medicine Division in the Tsurumi University Dental Hospital from February 2006 to December 2008, consecutively. Patients received a medical interview, and a detailed sleep analysis that included a polysomnography (PSG) to verify the exact nature of their condition. The efficacy of OA was assessed in 49 patients who wore an OA and underwent PSG.

Results

Of all subjects, 141 patients visited the Prosthodontic Division to receive OA therapy, 38 patients were treated or received a follow up examination in the Internal Medicine Division. The dropout rate was 10.4% in the all subjects, 17.0% in patients who visited the Prosthodontic Division. The male-to-female ratio was 3.3:1, 3.0:1 in patients who visited the Prosthodontic Division. In addition, females had a lower rate of OAS severity than males. In our patients, the major complication was hypertension and cardiac disease. The success rate of OA was 75.5%.

Conclusion

This approach allowed us to reveal some of the trends and characteristics in our patients.     

Effect of overglazed and polished surface finishes on the compressive fracture strength of machinable ceramic materials

Controversy prevails over the effect of overglazing on the fracture strength of ceramic materials. Therefore, the effects of different surface finishes on the compressive fracture strength of machinable ceramic materials were investigated in this study. Plates prepared from four commercial brands of ceramic materials were either surface-polished or overglazed (n=10 per ceramic material for each surface finish), and bonded to flat surfaces of human dentin using a resin cement. Loads at failure were determined and statistically analyzed using two-way ANOVA and Bonferroni test. Although no statistical differences in load value were detected between polished and overglazed groups (p>0.05), the fracture load of Vita Mark II was significantly lower than those of ProCAD and IPS Empress CAD, whereas that of IPS e.max CAD was significantly higher than the latter two ceramic materials (p<0.05). It was concluded that overglazed and polished surfaces produced similar compressive fracture strengths irrespective of the machinable ceramic material tested, and that fracture strength was material-dependent.     

Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Background and purpose:

Various complications consequent on disordered calcium and phosphate homeostasis occur frequently in chronic kidney disease (CKD) patients. Particularly, vascular calcification has high morbidity and mortality rates. There is a clear need for a better CKD model to examine various aspects of this disordered homeostasis.

Experimental approach:

Oral dosing with adenine induced CKD in rats in only 10 days. Serum calcium, phosphate and parathyroid hormone were measured and calcification in aorta was assessed histologically. The effects of varying phosphorus content of diet or treatment with phosphate binders or active vitamin D₃ on these parameters were examined.

Key results:

After adenine dosing, significant hyperphosphatemia, hypocalcemia and secondary hyperparathyroidism (2HPT) were observed during the experimental period of 15 weeks. Aortic calcification was detected in only some of the animals even at 15 weeks (∼40%). Treatment with vitamin D₃ for 18 days, even at a low dose (100 ng·kg⁻¹, 3–4 times week⁻¹, p.o), caused aortic calcification in all animals and increases in serum calcium levels up to the normal range. The vitamin D₃-induced calcification was significantly inhibited by phosphate binders which lowered serum phosphate levels and the calcium × phosphate product, although serum calcium levels were elevated.

Conclusions:

These data suggest that rats dosed orally with adenine provide a more useful model for analysing calcium/phosphate homeostasis in severe CKD. Controlling serum calcium/phosphate levels with phosphate binders may be better than vitamin D₃ treatment in hyperphosphatemia and 2HPT, to avoid vascular calcification.     

Carcinogenicity studies of 1,4-dioxane administered in drinking-water to rats and mice for 2 years

The carcinogenicity of 1,4-dioxane was examined by giving groups of 50 F344/DuCrj rats and 50 Crj:BDF₁ mice of each sex 1,4-dioxane in the drinking-water for 2 years. The concentrations of 1,4-dioxane were 0 (control), 200, 1000 and 5000 ppm (wt./wt.) for rats and 0, 500, 2000 and 8000 ppm for mice. The highest dose levels did not exceed the maximum tolerated dose. In the rat, there was significant induction of nasal squamous cell carcinomas in females and hepatocellular adenomas and carcinomas in males and females, peritoneal mesotheliomas in males, and mammary gland adenomas in females. In the mouse, there was significant induction of hepatocellular tumors in males and females. Two nasal tumors occurring in the 8000 ppm-dosed groups were spontaneously rare and, thus, were attributed to 1,4-dioxane exposure. The present studies provided clear evidence of carcinogenicity in rats and mice. Lifetime cancer risk of humans exposed to 1,4-dioxane through drinking-water was quantitatively estimated with a non-threshold approach by application of a linearized multistage model to dose–carcinogenic response relationships, in addition to a threshold approach for estimation of the tolerable daily intake using no-observed- or lowest-observed-adverse-effect levels of the carcinogenic responses and uncertainty factors.     

Overview of the clinical reference guides for the idiopathic hematopoietic disorders

The research committee for idiopathic hematopoietic disorders, which has been supported by the government over the past 35 years, has recently worked out a series of reference guide for the management of diseases under investigation to provide aids for better understanding of pathophysiology of diseases and appropriate clinical decision making. Such attempts covered aplastic anemia, Fanconi anemia, pure red cell aplasia, autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes and primary myelofibrosis, and included diagnostic criteria and severity classification as well as clinical pictures derived from nationwide survey studies. Therapeutic measures were evaluated according to the concepts of evidence-based medicine, when applicable. This report presents an overview of these guides and summarizes key issues in each disease entity.