Large-vessel vasculitis associated with PEGylated granulocyte-colony stimulating factor.

A 71-year-old female with advanced endometrial cancer was treated with pegfilgrastim. She developed a fever within seven days, and contrast-enhanced computed tomography scans repeated within three days revealed rapidly progressive thickening of the aortic wall. When clinicians administer PEGylated granulocyte-colony stimulating factor (G-CSF) to cancer patients, drug-associated vasculitis should be suspected. This report discusses the manifestation of G-CSF-associated large-vessel vasculitis (LVV).

Tumour necrosis factor α augments the inhibitory effects of CTLA-4-Ig on osteoclast generation from human monocytes via induction of CD80 expression.

Cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) exerts anti-rheumatic action via negative regulation of the co-stimulation process between antigen-presenting cells and T cells. CTLA-4-Ig also binds to CD80/CD86 on monocytes of osteoclast precursors. However, little is known about the effect of CTLA-4-Ig on osteoclastogenesis in rheumatoid arthritis (RA). In this study we evaluated the effects of CTLA-4-Ig on osteoclast generation from human blood monocytes (PBM) and rheumatoid synovial fluid monocytes (RSFM). Highly purified monocytes were cultured with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of CTLA-4-Ig. CTLA-4-Ig inhibited RANKL-induced osteoclast generation in PBM and RSFM, as determined by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay using osteo assay surface plates. In addition, CTLA-4-Ig reduced the gene and protein expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and cathepsin K during osteoclastogenesis. Furthermore, CTLA-4-Ig significantly inhibited cell proliferation during osteoclastogenesis. Interestingly, the gene expression of indoleamine 2,3-dioxygenase-1, an inducer of apoptosis, was enhanced by CTLA-4-Ig. We next examined the effect of tumour necrosis factor (TNF)-α, a major inflammatory cytokine in rheumatoid synovium, on the expression of CD80 and CD86 by flow cytometric analysis. TNF-α potently induced the surface expression of CD80, which is known to have much higher affinity to CTLA-4-Ig than CD86, and this induction was observed at mRNA levels. Interestingly, freshly prepared rheumatoid synovial monocytes also expressed CD80 as much as TNF-α-treated PBM. Furthermore, TNF-α enhanced CTLA-4-Ig-induced inhibition of osteoclastogenesis and cell proliferation. Taken together, the TNF-α-induced CD80 may augment CTLA-4-Ig-induced inhibition of osteoclastogenesis, suggesting that CTLA-4-Ig potently inhibits osteoclast differentiation and protects bone destruction in rheumatoid inflamed joints.

Specific downregulation of death-associated protein kinase enhances Fas-mediated apoptosis in the human differentiated endometrial adenocarcinoma cell line, HHUA.

PURPOSE OF INVESTIGATION: Death-associated protein kinase (DAPK) is a serine/threonine kinase that is well-known as a positive mediator of Fas-mediated apoptosis. Previous reports have shown that DAPK and Fas are expressed in human endometrial adenocarcinoma cells. In this study, we examined the effects of specific downregulation of DAPK expression on Fas-mediated apoptosis in the human endometrial adenocarcinoma cell line, HHUA. METHODS AND RESULTS: Transfection of DAPK small-interfering RNAs (siRNAs) into the HHUA cells reduced DAPK protein expression, and enhanced Fas-mediated apoptosis, in a dose-dependent manner. CONCLUSIONS: These results indicate that, in contrast to cases with other malignant tumor cells, DAPK negatively regulates Fas-mediated apoptosis in these human differentiated endometrial adenocarcinoma cells.

Simultaneous, laser-sintered, three-dimensional modelling of bony structures and soft tissue for surgical navigation of extended cholesteatoma.

AIM: To examine the usefulness of a three-dimensional model for surgical navigation of cholesteatoma. MATERIALS AND METHOD: A three-dimensional model was prototyped using selective laser sintering. Based on detailed computed tomography data, powder layers were laser-fused and accumulated to create a three-dimensional structure. The computed tomography threshold was adjusted to simultaneously replicate bony structures and soft tissues. RESULTS: The cholesteatoma, major vessels and bony structures were well replicated. This laser-sintered model was used to aid surgery for recurrent cholesteatoma. The cholesteatoma, which extended from the hypotympanum through the styloid process sheath and the internal carotid artery sheath, was removed safely via a minimal skin incision. CONCLUSION: The laser-sintered model was useful for surgical planning and navigation in a cholesteatoma case involving complex bony structures and soft tissue.

Radiation reduces carboplatin sensitivity and enhances nedaplatin sensitivity in cervical squamous cell carcinoma in vitro.

BACKGROUND: The study was performed to examine how the platinum anticancer drugs other than cisplatin, such as carboplatin (CBDCA) and nedaplatin (NEP) can be effectively used in chemoradiotherapy for cervical squamous cell carcinoma patients. MATERIALS AND METHODS: The radiosensitive human cervical squamous cell carcinoma cell line ME180 was examined to investigate the radiation effects on CBDCA and NEP sensitivities of the cells. RESULTS: Irradiation significantly reduced cellular CBDCA sensitivity. There were no significant changes in CBDCA sensitivity between the cells concurrently irradiated and those treated with CBDCA 8 h before or 8 h after irradiation. However NEP sensitivity of the cells treated 8 h before or 8 h after irradiation was significantly higher than that in cells concurrently irradiated. CONCLUSIONS: Although CBDCA sensitivity in the concurrently irradiated cells is reduced, NEP sensitivity is enhanced by irradiation. NEP, but not CBDCA, therefore, may be a candidate anticancer drug for concurrent chemoradiotherapy for cervical cancer. For the greatest efficacy, NEP should be administered to patients several hours before or after irradiation.

Irradiation reduces bleomycin sensitivity in cervical squamous cancer cells in vitro.

PURPOSE OF INVESTIGATION: The study was performed to examine how bleomycin (BLM) and peplomycin (PEM) should be effectively used in radiotherapy for cervical squamous cancer patients. METHODS: The effects of BLM on radiosensitivity and the effects of radiation on the sensitivity to BLM of cancer cells were investigated using the radiosensitive human cervical squamous cell carcinoma cell line ME180. RESULTS: BLM treatment did not affect radiosensitivity. However, irradiation significantly reduced cell BLM sensitivity in a dose-dependent manner. There was no significant difference in BLM sensitivity and PEM sensitivity between cells concurrently irradiated and those treated with BLM or PEM 8 h before or 8 h after irradiation. CONCLUSION: Since sensitivity to BLM is reduced during irradiation, BLM should be administered to cervical cancer patients as an adjuvant chemotherapeutic drug after completion of radiotherapy.

Effective chemoradiotherapy protocol with 5-fluorouracil for cervical squamous cell carcinoma in vitro.

PURPOSE OF INVESTIGATION: 5-Fluorouracil (5FU) is frequently used in concurrent chemoradiotherapy for patients with advanced cervical cancer, although its optimal chemoradiotherapy protocol has not yet been established. In search of an optimal chemoradiotherapy protocol, some in vitro experiments were carried out. METHODS: The radiosensitive human cervical squamous cell carcinoma cell line ME180 was examined to investigate the effects of 5FU on radiosensitivity and the effects of irradiation on 5FU-sensitivity. RESULTS: 5FU dose-dependently enhanced cellular radiosensitivity at therapeutic concentrations. Although high doses of y-ray irradiation significantly reduced the 5FU-sensitivity, a low dose of irradiation at therapeutic doses (< 2.5 Gy) had no effect on 5FU-sensitivity of the irradiated cells. Cells pretreated with 5FU eight hours before irradiation showed significantly higher 5FU-sensitivity than cells concurrently treated with 5FU and irradiation. In contrast, cells treated with 5FU eight hours after irradiation showed significantly lower 5FU-sensitivity than cells concurrently treated with 5FU and irradiation. Moreover, all four post-irradiation surviving subclones obtained from repeatedly irradiated ME180 cells showed significantly lower 5FU-sensitivity than the non-irradiated parent cells. CONCLUSION: 5FU acts as a radiosensitizer for cervical squamous cell carcinoma and 5FU-sensitivity is reduced in irradiated cells. Therefore, 5FU administration immediately before irradiation may be a more effective treatment than concurrent chemoradiotherapy or post-irradiation chemotherapy with 5FU.

Radiation enhances cisplatin-sensitivity in human cervical squamous cancer cells in vitro.

UNLABELLED: PURPOSE AND METHODS OF INVESTIGATION: Cisplatin (CDDP) is regularly used in concurrent chemoradiotherapy in patients with advanced cervical cancer although an effective protocol of chemoradiotherapy with CDDP has not yet been established. In search of a better chemoradiotherapy protocol, we investigated both CDDP effects on radiosensitivity and irradiation effects on CDDP-sensitivity using the radiosensitive human cervical squamous cell carcinoma cell line ME180. RESULTS: We found that CDDP did not affect cellular radiosensitivity, and that irradiation significantly enhanced CDDP-sensitivity. Moreover, all the four post-irradiation surviving subclones obtained from repetitively irradiated ME180 cells showed significantly higher CDDP sensitivities than those of the non-irradiated parent cells. CONCLUSION: These results suggest that an effective protocol would involve the concurrent administration of CDDP with radiotherapy and further administration following completion of radiotherapy in order to achieve higher CDDP-sensitivities.

Age-related pattern of body density and body composition in Japanese males and females, 11 and 18 years of age.

The age-related pattern of body density and body composition in Japanese males (n = 266) and females (n = 318), 11.00 to 18.99 years of age was studied. Body density (BD) as well as height, body weight, and seven skinfold thicknesses were measured. Percentage fat (%Fat) was calculated using the age- and sex-specific equation of Lohman. Fat mass (FM), fat-free mass (FFM), and the body mass index (BMI) were calculated. The trend for BD in males was lowest at 11 years (1.0530 g/ml) and increased to 1.0695 g/ml at 14 years, and then decreased slightly at 15 to 17 years. In female, BD decreased from 1.0530 g/ml at 13 years to 1.0424 g/ml at 17 years. Mean %Fat was highest in males at 11 years (15.8%), and lowest at 14 years (10.1%). The highest mean %Fat in females occurred at 16 years (22.8%), and the lowest at age 11 years (15.2%). Overall, only 6.8% of males and 3.1% of females were classified as obese. Between 11 and 18 years, FFM of males differed by 20.7 kg or 67.9%, whereas females showed a difference of only 10.8 kg or 34.7%. Consequently, age effects explained approximately 60% of the male variance of FFM but only 26% in females. Body density of each sex and age group in this study did not differ significantly from previous Japanese studies, and the pooled BD data for 1,457 Japanese including the present study are reported as a reference.

The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice.

The class IV semaphorin CD100/Sema4D differentially utilizes two distinct receptors: plexin-B1 in nonlymphoid tissues, such as brain and kidney, and CD72 in lymphoid tissues. We have generated CD100-deficient mice and demonstrated that they have functional defects in their immune system, without apparent abnormalities in other tissues. The number of CD5(+) B-1 cells was considerably decreased in the mutant mice, whereas conventional B cells and T cells appeared to develop normally. In vitro proliferative responses and immunoglobulin production were reduced in CD100-deficient B cells. The humoral immune response against a T cell-dependent antigen and in vivo priming of T cells were also defective in the mutant mice. These results demonstrate nonredundant and essential roles of CD100-CD72 interactions in the immune system.

[Validity of various obesity indices calculated from height and weight in adult females using the underwater-weighing method as a reference].

We evaluated association between excess percent body fat (%Fat) and various obesity indices calculated from height and weight in 322 adult females. %Fat was measured by the underwater-weighing method, and obesity indices were based on the following 5 methods; Broca-Katsura method (Katsura method), Kato-Wataya method (Kato method), Japan Society for the Study of Obesity method (BMI method; based on the body weight at which BMI is 22), Meiji Life Insurance Co. method, and Table and Figure for the Assessment of Obesity and Leanness by the Ministry of Health and Welfare (MHW method). %Fat was 30% or more (obese) in 73 females (22.7%), 25-30% in 97 (30.1%), 20-25% in 88 (27.3%), and less than 20% in 64 (19.9%). The correlation coefficient between the obesity indices and %Fat were 0.71 for the Katsura method, 0.70 for the Kato-method, 0.72 for the BMI method, 0.70 for the Meiji Life Insurance Co. Method, and 0.63 for the MHW method, being significant for all methods (P < 0.01). When the cut-off point was set as 110% for each obesity index, sensitivity was the highest for the Katsura method (67.1%), and specificity was the highest for the Meiji Life Insurance Co. method (95.2%). Receiver operating characteristic (ROC) curves were similar in figure for the Katsura method, Kato-method, BMI method, and Meiji Life Insurance Co. method. For the MHW method, however, the curve was slightly farther from the point of sensitivity of 100% and 1-specificity of 0% than the others. Excess fat accumulation could not be accurately assessed by the obesity indices calculated from body height and weight. Validity was similar among the obesity indices except for the MHW method.

Regulation of transcription factor C/ATF by the cAMP signal activation in hippocampal neurons, and molecular interaction of C/ATF with signal integrator CBP/p300.

The CCAAT/enhancer binding proteins related activating transcription factor, C/ATF, is a mouse leucine-zipper transcription factor which is structurally homologous to ApCREB2, a suppressor integral to long-term synaptic plasticity in Aplysia. To gain a clue to whether C/ATF is involved in long-term plasticities of brain, we examined if the expression levels of C/ATF are modulated by cAMP, an inducer crucial for memory formation in Aplysia, Drosophila and mice. Our in situ hybridization analysis revealed the expression of C/ATF mRNA in hippocampal neurons. C/ATF protein levels increased after the cAMP signal stimulation in hippocampal neurons, while C/ATF mRNA levels remained constant. The human activating transcription factor 4 (hATF4), another homolog of ApCREB2, interacts with multiple domains of the coactivator CREB-binding protein (CBP), resulting in the potentiation of its ability to activate transcription. As expected, C/ATF was found to interact with three domains of CBP including CREB binding domain or kinase-inducible interaction (KIX) domain, the third cysteine-histidine-rich region (CH3 domain) and the nuclear receptor coactivator p160/SRC-1-interacting domain. Interestingly, C/ATF was further found to interact strongly with CREB binding protein/p300 (CBP/p300) CH1 domain. Mammalian two hybrid assays indicated that the interaction between C/ATF and CBP/p300 can occur in mammalian cells, and that the p300 CH1 domain is critical for the interaction. Thus, C/ATF may be implicated in transcription-dependent phase of hippocampal long-term plasticities through the modulation of its protein level under cAMP signal and the interaction with signal integrator, CBP/p300.

Clinical features of paroxysmal positional vertigo presenting combined lesions.

Benign paroxysmal positional vertigo (BPPV) is one of the common vestibular disorders. Canalolithiasis is thought to be a likely lesion. A canalith repositioning procedure (CRP by Epley) generally yields good resolution of vertigo and nystagmus. The authors confirmed the efficacy of this procedure on typical BPPV of the posterior semicircular canal type. We designed a new procedure for BPPV of the lateral canal type, which also yielded satisfactory results. BPPV sometimes presents a nystagmus pattern, which suggests multiple lesions. We have seen eight cases of BPPV showing nystagmus that combines both the posterior and the lateral canal types. Combined CRP was performed on these cases, which again gave good clinical results. Other BPPV cases were associated with central lesions. We must be aware that BPPV may involve multiple canals and may be associated with central lesions.

Expressions of CCAAT/Enhancer-binding proteins beta and delta and their activities are intensified by cAMP signaling as well as Ca2+/calmodulin kinases activation in hippocampal neurons.

The transcription factor, Aplysia CCAAT enhancer-binding protein (ApC/EBP), plays a crucial role in long term facilitation, a synaptic mechanism of long term memory in Aplysia. To gain a clue to whether the mammalian C/EBP family of transcription factors are also involved in long term memory, we examined how C/EBP activities in hippocampal neurons can be modulated in response to cAMP and Ca2+, crucial inductive signals for memory formation. As a result, stimulation of either cAMP or Ca2+ signals in hippocampal neurons was found to enhance mRNA expressions and DNA binding activities of C/EBPbeta and C/EBPdelta. Furthermore, it is indicated that CaM kinases have essential roles for increasing the expression and DNA binding activities of C/EBPbeta in hippocampal neurons activated by membrane depolarization. Overexpression of constitutively active calcium/calmodulin-dependent kinase IV was found to directly stimulate either C/EBPbeta-dependent or C/EBPdelta-dependent transcription, reinforcing the evidence that C/EBP family members contribute to Ca2+-dependent transcription. Thus, these results suggest that C/EBPbeta and C/EBPdelta may be involved in the transcription-dependent phase of memory formation by increasing the expression of both the DNA binding and the transcriptional activities under the direction of cAMP and/or Ca2+ signaling in hippocampal neurons.

Hypotensive effects of an angiotensin II type 1 receptor antagonist differ between exercised and sedentary rats aged from 4 to 19 weeks.

The hypotensive effects of an angiotensin II type 1 receptor antagonist TCV-116 were accelerated by swimming training in the early period of chronic administration in young rats. In the latter period, however, a severe decrease in blood pressure that appeared during long-term administration of TCV-116 was prevented by swimming training. Therefore exercise may contribute to the stabilization of blood pressure in young rats treated with TCV-116.

Regulation of human papillomavirus transcription by the differentiation-dependent epithelial factor Epoc-1/skn-1a.

Human papillomavirus (HPV) early gene expression is closely linked to the differentiation status of infected epithelial cells. Typically, HPV type 16 (HPV16) or HPV18 E6 and E7 transcripts are only barely detectable within the undifferentiated basal cell layer, but their levels increase concomitantly with higher degrees of epithelial cell differentiation in suprabasal cells. A similar differentiation-dependent distribution of expression has been reported for the recently cloned epithelial cell specific transcription factor Epoc-1/skn-1a. We therefore examined whether Epoc-1/skn-1a may be directly involved in the activation of HPV E6/E7 transcription. Transient transfection studies showed that Epoc-1/skn-1a specifically stimulated the HPV16 and HPV18 E6/E7 promoters. Moreover, ectopically expressed Epoc-1/skn-1a was sufficient to stimulate HPV transcription also in nonepithelial cells. By deletion analyses, the Epoc-1/skn-1a-responsive element was mapped to the promoter-proximal portion of the HPV18 transcriptional control region. Footprint analyses and gel retardation assays demonstrated direct binding of Epoc-1/skn-1a to a hitherto uncharacterized site within this region. Mutation of the Epoc-1/skn-1a recognition site within the context of the complete HPV18 upstream regulatory region inhibited Epoc-1/skn-1a-mediated transactivation. These results show that Epoc-1/skn-1a can directly activate the E6/E7 promoter by binding to the viral transcriptional control region. Thus, Epoc-1/skn-1a may be involved in the differentiation-dependent regulation of HPV transcription.

[Hydrostatic weighing, skinfold thickness, body mass index relationships in high school girls].

A study was conducted to evaluate body composition by hydrostatic weighing, skinfold thickness, and body mass index (BMI) in 102 senior high school girls, aged 15 to 18 in Nagasaki City. Body density measured by the underwater weighing method, was used to determine the fat weight (Fat) and lean body mass (LBM. or fat free weight: FFW) utilizing the formulas by Brozek et al. The results were as follows; 1. Mean values of body density were 1.04428 in the first grade girls, 1.04182 in the second grade, and 1.04185 in the third grade. 2. Mean values of percentage body fat (%Fat) were 23.5% in the first grade, 24.5% in the second and 24.5% in the third. 3. Percentage body fat (%Fat), lean body mass (LBM) and LBM/Height were not significantly with different advance of grade from the first to the third. 4. The correlation coefficients between percent body fat and the sum of two skinfold thicknesses, the sum of three skinfold thicknesses and the sum of seven skinfold thicknesses was 0.78, 0.79, and 0.80 respectively and were all statistically significant (p < 0.001). 5. The correlation coefficients between BMI and the sum of two skinfold thicknesses, the sum of three skinfold thicknesses and the sum of seven skinfold thicknesses was 0.74, 0.74, and 0.74 respectively and were all statistically significant (p < 0.001). 6. Mean values of BMI, Rohrer index and waist-hip ratio (WHR) in all subjects (n = 102) were 20.3, 128.2 and 0.72 respectively.

[Body density assessment utilizing skinfold thickness and age in Japanese men].

A study was conducted to investigate the validity of skinfold-based prediction equations for body density (g/ml) by Nagamine and Suzuki (1964), and to formulate more convenient and more useful equations for predicting body density from skinfold and age in men. Subjects of the study were 257 healthy men aged 19-60 years in or near Nagasaki City. The regression equation for the dependent variable, body density, was determined by hydrostatic weighing. Independent variables included eight skinfolds, the sum of two skinfolds (triceps, subscapular), the sum of three skinfolds (triceps, subscapular, and abdominal), age, and body surface area. Skinfolds were measured with an Eiken-model skinfold caliper. Age (mean 33.1, range 19-60 yrs.), weight (mean 65.3, range 46.6-107.7 kg), height (mean 168.8, range 152.3-185.4 cm), and body density (mean 1.05874, range 1.00860-1.09020 g/ml) were also recorded. Percent body fat was calculated using the formula by Brozek et al. and ranged from 6.1% to 38.9%. Multiple correlation coefficients (MR) and standard error (SE) of 10 regression equations (A-J) for predicting body density in men were obtained. The best-fitting and the most convenient prediction equation for body density was equation-E.: body density = 1.09556-0.00062 x sum of three skinfolds (mm)-0.00028 x age (MR = 0.815 and SE = 0.0087 g/ml). The equation was cross-validated on a different sample of 45 men. The correlation coefficient between predicted and hydrostatically determined body density was 0.781 (p < 0.001). Equation-E (Tahara's equation) appears to be useful in body density analysis particularly when the subjects are Japanese men, aged 18-50 yrs, with percent body fat 10 to 30%.

Changes in body shape of young individuals from the aspect of adult physique model by factor analysis.

The purpose of this study was to clarify characteristics of age-related changes in body shape in adolescence, in 11- to 19-year-old boys and girls, by using previously reported physique models of adult men and women as the scale. The scale consisted of four factors obtained by factor analysis using 30 items as variables, such as the values measured for the physique, skinfold thickness and body composition. The four factors were Factor 1: body fat, Factor 2: mass, Factor 3: leg length to height ratio, and Factor 4: length, and were interpreted in the men and women in a similar manner. The subjects were 307 boys and 368 girls; all were healthy. Thirty items were measured and included the values measured for the physique, skinfold thickness and body composition, as in the men and women. Factor scores in the subjects were standardized by mean and standard deviation for each item in the adult subjects, and calculated for individuals by using the coefficient of factor score in the adult subjects. The body shapes of the boys and girls were investigated from the factor score by age calculated for each factor. The following results were obtained: 1. Factor 1 tended to gradually decrease and reached the adult level at 15 years of age in the boys.(ABSTRACT TRUNCATED AT 250 WORDS)