Myosin heavy chain composition of tongue muscle in microphthalmic (mi/mi) mice before and after weaning.

To elucidate the effects of teeth on muscle fibers in the tongue during the developmental process, we examined the expression of muscle contractile proteins and the genes for those proteins in normal mice and microphthalmic (mi/mi) mice with impaired tooth eruption. The mice were observed during the growth period, including weaning, which is when feeding movements undergo major changes. Expression of the myosin heavy chain (MyHC)-2a protein, whose contraction speed is relatively slow, disappeared after weaning in normal mice, while it remained in high concentrations even after weaning in mi/mi mice. The presence of MyHC-2a after weaning in mice with no tooth eruption was attributed to a compensation for lack of proper masticatory function and sucking-like movements, as MyHC-2a is necessary for these movements.     

Sclerosing mucoepidermoid carcinoma of the oral cavity

Sclerosing mucoepidermoid carcinoma (SMEC) with eosinophilia is a rare but distinctive tumor usually affecting the thyroid. SMEC involvement of salivary gland is exceptional, with only six cases in the literature. We present here the first case of an intermediate-grade SMEC, arising from the intraoral minor salivary glands. A particularly interesting finding is the cytoplasmic accumulation of eosinophilic hyaline granules in carcinoma cells, similar to aberrant zymogen-like granules previously described in salivary sclerosing polycystic adenosis.     

Enhancement of bradykinin-induced prostacyclin synthesis in porcine aortic endothelial cells by pertussis toxin Possible implication of lipocortin I

Bradykinin-stimulated prostacyclin synthesis in porcine aortic endothelial cells was enhanced by pretreatment of the cells with pertussis toxin or islet-activating protein (IAP) for 5 hr or longer. Although ADP-ribosylation of a protein with a molecular weight of 41–42 kD in the cell membranes was completed by 3 hr after the addition of IAP into the incubation medium, there was good correlation between enhancement of bradykinin-induced prostacyclin synthesis and ADP-ribosylation of the IAP substrate over a wide range of IAP concentrations. Furthermore, even if IAP was removed from the incubation medium at 3 hr, bradykinin-induced prostaglandin synthesis at 24 hr was still potentiated. Cycloheximide and actinomycin D enhanced bradykinin-induced prostacyclin synthesis and apparently blocked the effect of IAP. Since this result suggested the involvement of an inhibitor protein(s) of prostacyclin synthesis in the IAP effect, we studied the effect of IAP on the level of lipocortin I which is known to inhibit phospholipase A₂. Western and Northern blot analyses revealed that IAP decreased the amounts of protein and mRNA of lipocortin I. These results suggest that the enhancement of bradykinin-induced prostacyclin synthesis by IAP is associated with a decrease in the level of lipocortin I.     

Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.     

Identification of new immunogenic peptides in conserved regions of hepatitis C virus (HCV) 1b with the potentiality to generate cytotoxic T lymphocytes in HCV1b+ HLA-A24+ patients

Aim: Hepatitis C virus (HCV) 1b is resistant to standard interferon therapy and has a high risk of developing into hepatocellular carcinoma at the late stage of infection. Therefore, new therapeutic modalities for HCV1b infection must be developed. One approach would be active specific immunotherapy with highly immunogenic HCV1b peptides. Methods: HCV1b-derived 44 synthetic peptides were selected based on their binding scores to HLA-A24. Peptide-specific IgG were measured by ELISA. Peptide-specific cytotoxic T-lymphocytes (CTLs) were induced in vitro by repeated peptide-stimulation. Results: We identified three novel candidate peptides of HCV1b proteins containing HLA-A24 binding motifs. Each of them had the ability to induce HLA-A24-restricted and peptide-specific CTL activity, and IgGs specific to each of them were detected in the plasma of HCV1b patients. Among these three peptides, a peptide NS5A 2132-2142 was recognized by both cellular and humoral immunities in the majority of blood samples of patients tested. More importantly, the peptide-stimulated peripheral blood mononuclear cells (PBMCs) showed cytotoxicity against cells cotransfected with NS5A and HLA-A2402 genes in an HLA-restricted manner. This is an additional report to our previous study. Conclusion: These findings may provide a new insight into the development of a peptide-based specific immunotherapy for HCV1b-infected patients.     

Ameloblastoma ex calcifying odontogenic cyst (dentinogenic ghost cell tumor)

Calcifying odontogenic cyst (COC) has shown to be of extensive diversity in its clinical and histopathological features, as well as in its biological behavior. In this report, a rare case is described of ameloblastoma ex COC (dentinogenic ghost cell tumor) and the relevant literature is briefly reviewed.     

Traumatic degeneration of transected myelinated fibers of the mouse sciatic nerve.

Traumatic degeneration of myelinated fibers was studied by electron microscopy over 5 days following transection of mouse sciatic nerve. Special attention was paid to the mechanism which separates the degenerating part, while preserving the viable part of the axon. Immediately after transection, the opened end of the proximal stump revealed extensive subcellular changes including the disorganization of neurofilaments, and disruption of mitochondria and axonal endoplasmic reticulum (SER). Subsequently, vesicles of round and tubular profiles filled up the whole area of the stump end, and proximal to it appeared a neurofilament-predominant area characterized by randomly oriented neurofilaments and normally appearing mitochondria and SER. Characteristic membranous demarcations occurred in early periods at the border between the vesicle accumulation and the neurofilament-predominant areas, and later also within these areas. The demarcation membranes formed both by invagination of the surface plasma membrane and, probably, by fusion of the large vesicles. These became prominent with time, dividing the axoplasm into compartments of varying sizes, which gradually underwent degeneration and were liberated from the parent axon. Occurrence of autophagic vacuoles was characteristic of the degenerating portions of the parent axon. Thus, by the function of demarcation membranes, the parent axon to be preserved could remain membrane-bound, while the degenerating parts were shed off.     

Coats'-type retinitis pigmentosa

Coats'-like changes (i.e., retinal telangiectasia and/or exudative detachment) have been reported in as many as 1.2 to 3.6 percent of patients with retinitis pigmentosa. In severe cases this disorder may progress to total retinal detachment and visual loss in the context of longstanding retinitis pigmentosa. Forty-six cases of Coats'-type retinitis pigmentosa gathered from the literature are reviewed. Historical and epidemiological features, hereditary factors, clinical features, histopathological findings, pathogenesis, differential diagnosis, prognosis and possible treatment are discussed.     

Effect of sevoflurane on diaphragmatic contractility in dogs.

The effect of sevoflurane on diaphragmatic contractility was investigated in 12 anesthetized, mechanically ventilated dogs with the thorax opened. Animals were divided into two groups of six each: the sevoflurane and time control groups. We assessed contractility by the transdiaphragmatic pressure (Pdi) during supramaximal stimulation of the phrenic nerve at frequencies of 0.5, 10, 20, 50, and 100 Hz under quasiisometric conditions. The integrated electrical activity (Edi) of the crural and costal parts of the diaphragm (Edi cru, Edi cost) was also measured. In the sevoflurane group, diaphragmatic contractility was determined during three levels of anesthesia, specifically 0, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC). Measurements were made at the start of the stimulation (initial) and at the end of the 2-s period (2-s). Increasing the depth of sevoflurane anesthesia did not cause any significant differences in Pdi and Edi at 0.5-, 10-, and 20-Hz stimulation. By contrast, at 50- and 100-Hz stimulation, initial Pdi during 1.0 and 1.5 MAC sevoflurane exposure decreased significantly compared with the 0 MAC value (P less than 0.05). In addition, there was a statistical difference in 2-s Pdi between 1.0 and 1.5 MAC at 100-Hz stimulation (P less than 0.05). The Edi cru showed similar changes in Pdi at both measurements, whereas there was no remarkable change in Edi cost. There was no significant change either in Pdi or in Edi with respect to time in the time control group. We conclude from these results that sevoflurane impairs diaphragmatic contractility through its inhibitory effect on neuromuscular transmission, predominantly of the crural part.