Clinical and histopathological features of progressive-type familial amyloidotic polyneuropathy with TTR Lys54

The purpose of this study was to evaluate the clinical and pathological features in patients with progressive-type familial amyloidotic polyneuropathy (FAP) using autopsy and biopsy specimens. A proband is a 33-year-old man with FAP type I who developed motor, sensory and autonomic impairments with neuropathy, heart failure, and anorexia. Genetic findings of transthyretin (TTR) revealed G to A transition in codon 54 causing a rare mutation of TTR Lys54. He died of pneumonia and severe cardiac failure 4 years after onset. Autopsy showed heavy amyloid deposition in the heart, peripheral nerves, thyroid, skin, fat tissue, prostate and testis, moderate in the sympathetic nerve trunk, vagal nerve, celiac plexus, pelvic plexus, bladder, gastrointestinal tract, tongue, pancreas, lung, pituitary, blood vessel, gall bladder, adrenals and muscles, and free in the central nervous system, liver, kidney and spleen. Sural nerve biopsy in a sibling confirmed TTR amyloidosis immunohistochemically. Electronmicroscopic findings of amyloid fibrils were similar to that of FAP Met30. Immunoelectronmicroscopic findings indicated the relationship between amyloid fibrils or non-fibrillar structure and collagen fibers. The distribution of amyloid deposition, heavy in the heart and lacking in the kidney, is a characteristic feature and reflected severity of FAP with TTR Lys54.     

Influence of oral health on febrile status in long-term hospitalized elderly patients

Many elderly patients have various health problems and are susceptible to recurrent fever. We examined the influence of oral health on the febrile status of 271 long-term hospitalized elderly patients over 1 year. In dentate patients, those with > or =20 teeth had a significantly higher risk for fever than those with 1-9 teeth; multivariate logistic regression analysis: odds ratio (OR)=5.44, 95% confidence interval (CI)=1.37-21.66. In edentate patients, those with moderate or much tongue plaque had a significantly higher risk for fever than those with no or slight tongue plaque; multivariate analysis: OR=5.14, 95% CI=1.77-14.88. These results suggest that oral health status related to febrile status differs between dentate and edentate patients in the elderly population.     

Developmental changes in frontal lobe function during a verbal fluency task: A multi-channel near-infrared spectroscopy study

Objective: Near-infrared spectroscopy (NIRS) is commonly used to investigate continuous changes of brain activation and has excellent time resolution. Verbal fluency task (VFT) is widely used as a neuropsychological test of frontal lobe function. The aim of this study was to investigate normal developmental change in frontal lobe function during VFT performance using multi-channel NIRS, specifically focusing on oxygenation hemoglobin (oxyHb) changes. Methods: The subjects were 9 adults and 37 childrens who were all healthy right-handed volunteers. Children were divided into four age groups (group A, 6–8 years; group B, 9–11 years; group C, 12–14 years; group D, 15–18 years). The [oxyHb] changes were measured with 22 channels of NIRS during VFT. We defined the frontopolar region as the region of interest for analysis, and calculated the Z-score to compare the data between groups. Results: The task performance changed with age. There were significant differences between group A and other groups. The Z-score of [oxyHb] also significantly increased with age, when comparing adults to groups A and B. The task performances decreased with time in all groups. In contrast, [oxyHb] only continued to increase in the adult group. Conclusion: The verbal retrieval functions begin to mature in early adolescence and continue to grow up to adulthood.     

Correlation of high density lipoprotein (HDL)-associated sphingosine 1-phosphate with serum levels of HDL-cholesterol and apolipoproteins

BACKGROUND: Extracellular sphingosine 1-phosphate (S1P) has been shown to contribute to the action of high density lipoprotein (HDL) on endothelial and smooth muscle cells. We examined the relationship of lipoprotein-associated S1P concentrations with cholesterol (C) and apolipoprotein (apo) contents of lipoprotein and lipoprotein subfractions characterized by capillary isotachophoresis (cITP). METHODS: Blood samples were drawn from 16 volunteers. S1P concentrations were quantified by bioassay based on the ability of S1P to stimulate its receptor. cITP was performed using plasma that had been prestained with NBD-ceramide. RESULTS: In plasma, S1P was concentrated in HDL and associated with LDL at a much lower concentration. HDL-S1P was the major determinant of the plasma S1P concentration. HDL-S1P was strongly and positively (p<0.001) correlated with serum levels of HDL-C (r=0.82), apo A-I (r=0.91) and apo A-II (r=0.92). HDL-S1P was strongly and positively (p<0.01) correlated with the apo A-I- and apo A-I/apo A-II-containing cITP HDL subfractions [fast HDL-C (r=0.66) and intermediate HDL-C (r=0.80)], but was not significantly correlated with apo E-containing slow HDL, suggesting that S1P is associated with both apo A-I HDL and apo A-I/A-II HDL. LDL-S1P was positively correlated (p<0.01) with levels of LDL-C (r=0.65) and apo B (r=0.85). CONCLUSION: Lipoprotein-associated S1P was related to the lipoprotein composition of cholesterol and apolipoproteins, suggesting that extracellular S1P may play different roles depending on the particles with which it is associated.     

Size of noncancerous hilomediastinal lymph nodes measured on coronal and sagittal reconstruction CT images

Purpose  

To determine the sizes of hilomediastinal lymph nodes on coronal and sagittal reconstruction computed tomographic images of subjects without known malignancies.     

Comparison of 18F-FDG PET and MRI in assessment of uterine smooth muscle tumors.

The purpose of this study was to prospectively determine whether combined MRI and (18)F-FDG PET is more accurate than MRI in assessing nonbenign uterine smooth muscle tumors (USMTs). METHODS: Seventy patients (mean age, 49+/-10 y; range, 28-77 y) suspected of having nonbenign USMTs underwent both MRI and (18)F-FDG PET before surgery. Results were evaluated using receiver-operating-characteristic (ROC) analyses and the Cochran Q test. RESULTS: The area under the ROC curve for MRI with (18)F-FDG PET was significantly higher than that for MRI (0.97 vs. 0.89, P<0.05). Although multiple comparisons using the Cochran Q test were not significant, the sensitivity, specificity, and accuracy for MRI with (18)F-FDG PET with probable nonbenign USMT cases considered to be positive were higher than those for MRI (93.3% vs. 73.3%; 92.7% vs. 85.5%; and 92.9% vs. 82.9%, respectively). CONCLUSION: MRI with (18)F-FDG PET is useful in assessing nonbenign USMTs, as compared with MRI.     

Expression of chemoresistance-related proteins in alpha-fetoprotein-producing adenocarcinoma of the digestive organs

alpha-fetoprotein-producing adenocarcinoma of the digestive organs (APAD) is known to show a poor prognosis. To clarify the characteristics of chemoresistance in APAD, three proteins of fluoropyrimidine chemotherapy association [dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and thymidylate synthase (TS)] and one protein of cisplatin association [metallothionein (MT)] were immunohistochemically evaluated. Tissue samples were taken from 12 AFP-positive gastric cancers and 94 AFP-negative gastric cancers. Four AFP-positive cancer xenografts (one colonic, two pancreatic, and one biliary tract) and 17 AFP-negative cancer xenografts were also examined. In gastric cancers, high expression of TP was observed in 30% of AFP-negative tumors but in none of AFP-positive tumors (p=0.03). High expression of MT was found in 30% of AFP-negative tumors but in only one of the AFP-positive tumors. The TP-low and MT-low phenotype was noted in 92% of AFP-positive tumors and in 46% of AFP-negative tumors (p=0.004). None of the AFP-positive cancer xenografts revealed high TP expression and only one showed high MT expression. In the cellular level, TP and MT were scarcely co-expressed with AFP in either gastric cancer or xenograft series, using double immunostaining and serial sectioning techniques. There were no significant differences in the expression of DPD and TS between AFP-positive group and -negative group. However, DPD was frequently co-expressed with AFP in poorly differentiated medullary areas of the AFP-positive gastric cancers. The data presented herein suggest that APAD should be sensitive to cisplatin, but resistant to capecitabine and 5'-deoxyfluorouridine, fluoropyrimidines which are converted to 5-fluorouracil by TP. S-1, a fluoropyrimidine containing a strong DPD inhibitor, may be effective for AFP-positive gastric cancers with poorly differentiated medullary growth pattern.     

Phosphodiesterase inhibitors as anti-cancer drugs

It is well known that high intracellular levels of cAMP can effectively kill cancer cells in vitro. Unfortunately substances elevating cAMP such as forskolin, 8-bromo-cAMP, 8-chloro-cAMP, monobutiryl or dibutiryl cAMP are not recommended to be used as anti-cancer drugs because of their high cytotoxicity. In contrast blockers of phosphodieterases such as theophylline and aminophylline, which could elevate intracellular cAMP, are commonly used as anti-asthma drugs reaching concentrations in the blood of 10-20 microg/ml. We tested the effectiveness of theophylline and aminophylline to induce cell death alone or in combination with common anti-cancer drugs such as cisplatin and gemcitabine (gemzar). We examined such drug combinations in the induction of cell death in a variety of carcinoma cell lines derived from human ovarian, prostate and lung cancer and in granulosa cell line transformed by SV40 and Ras oncogene. While theophylline could induce moderate cell death alone, at 20-25 microg/ml concentrations, aminophylline was ineffective at this concentration. Theophylline (at 15-25 ng/ml) was found in all four representative cell lines to synergize with gemcitabine or cisplatin to induce programmed cell death, which permits a reduction in the effective doses of cisplatin and gemcitabine by 2-3-fold. The effect of theophylline in induction of apoptosis involved reduction of intracellular levels of Bcl2. Such a reduction was proportional to the extent of apoptosis induced by theophylline as well as by the combined drug treatments. Therefore, we propose that theophylline should be considered as a potential anti-cancer drug in combination with other chemotherapeutic drugs. Screening of other phosphodiesterase blockers, which are not severely toxic, could open a possibility to improved chemotherapeutic cancer treatments with reduced undesired side-effects. A clinical trial, using theophylline as an anti-cancer drug, is currently being conducted in lung cancer patients.     

Evaluation of positron emission tomography with tracer 18-fluorodeoxyglucose in addition to magnetic resonance imaging in the diagnosis of ovarian cancer in selected women after ultrasonography

OBJECTIVE: To determine whether positron emission tomography (PET) with tracer 18-fluorodeoxyglucose (FDG-PET) yields additional information in the diagnosis of malignancy compared with magnetic resonance imaging (MRI) findings in selected women after screening for ovarian masses by ultrasonography (US). METHODS: After 49 patients were screened by US and physical examination (including a pelvic examination) by 2 experienced gynecologic oncologists, 38 patients suspected of having ovarian cancer were enrolled in the study. All 38 underwent MRI and FDG-PET. The results of the histologic findings were used to assess the accuracy of the imaging findings. RESULTS: Of the 38 women, 23 had malignant lesions and 15 had benign lesions. Magnetic resonance imaging, PET, and MRI with FDG-PET diagnoses had sensitivities of 91%, 78%, and 91%, respectively; specificities of 87%, 87%, and 87%, respectively; and diagnostic accuracy of 92%, 82%, and 92%, respectively. CONCLUSION: The addition of FDG-PET to MRI does not yield significant additional information for differentiation of benign from malignant ovarian masses in selected women after US.     

Sphingosylphosphorylcholine antagonizes proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1)-mediated inositol phosphate production and cAMP accumulation

Ovarian cancer G-protein-coupled receptor 1 (OGR1), previously proposed as a receptor for sphingosylphosphorylcholine (SPC), has recently been identified as a proton-sensing or extracellular pH-responsive G-protein-coupled receptor stimulating inositol phosphate production, reflecting the activation of phospholipase C. In the present study, we found that acidic pH stimulated cAMP accumulation, reflecting the activation of adenylyl cyclase, in addition to inositol phosphate production in OGR1-expressing cells. The cAMP response was hardly affected by the inhibition of phospholipase C. SPC inhibited the acidification-induced actions in a pH-dependent manner, while no OGR1-dependent agonistic action of SPC was observed. Thus, the dose-response curves of the proton-induced actions were shifted to the right in the presence of SPC regardless of stereoisoform. The antagonistic property was also observed for psychosine and glucosylsphingosine. In conclusion, OGR1 stimulation may lead to the activation of adenylyl cyclase in addition to phospholipase C in response to extracellular acidification but not to SPC. However, SPC and related lysolipids antagonize the proton-induced and OGR1-mediated actions.