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Objective The majority of uterine cervical cancer is known to be related to human papillomavirus (HPV), and HPV-related tumors are known to be radio-sensitive. In the management of HPV-related oropharyngeal cancer, de-intensification of treatment has been attempted; however, no such attempt is performed in the management of cervical cancer. The aim of this study was to identify a group of patients who can safely be treated by de-escalated treatment intensity. Methods From the Asian international multi-institutional retrospective study involving 13 Japanese, one Thailand, and one Korean institutions based on 469 patients, squamous cell carcinoma (Scc), tumor reduction ratio ≥29%, tumor size before brachytherapy ≤4 cm, and total treatment time (TTT) Results Among 469 patients, 162 patients (34.5%) met the criteria of low-risk group, and 63, 41, 43, and 15 patients were categorized in CTVHR D90 50–60 Gy, 60–70 Gy, 70–80 Gy, and >80 Gy, respectively. While 4-y progression-free survival ranged from 66 to 80%, 4-y local control was consistently over 90% in every dose group. Rectum and bladder D2cc and incidence of late adverse events decreased as CTVHR D90 decreased. Conclusions The low-risk patients achieved favorable local control with CTVHR D90

There are currently no reliable, established serum biomarkers to predict the prognosis of radiotherapy for advanced cervical cancer. We aimed to identify serum biomarkers for survival after radiotherapy for cervical cancer. In this multicenter prospective cohort study, the usefulness of pre- and posttreatment serum protein levels of potential biomarkers, including squamous cell carcinoma antigen (SCC-Ag), apolipoprotein C-II (ApoC-II), matrix metalloproteinase (MMP)1, and MMP2, were evaluated together with clinical factors in 145 cervical cancer patients in order to determine their suitability to predict survival. Progression-free survival (PFS) was the primary endpoint, and overall survival (OS), pelvic PFS (PPFS), and distant metastasis-free survival (DMFS) were the secondary endpoints. Blood samples were collected before and 1 month after radiotherapy to measure serum biomarker levels. ApoC-II was measured using a monoclonal antibody-based enzyme-linked immunosorbent assay, which was developed for this purpose. Kaplan-Meier method, log-rank test, and univariate and multivariate Cox proportional hazards models were used for statistical analyses. In multivariate analysis, larger tumor size was independently associated with shorter PFS, OS, PPFS, and DMFS, while longer overall treatment time was independently associated with shorter PPFS. Higher pretreatment SCC-Ag (P < 0.001) was associated with shorter DMFS. Higher posttreatment SCC-Ag (P = 0.017) was also associated with shorter DMFS. Pretreatment ApoC-II was associated with PPFS in univariate analysis (P = 0.048), but not in multivariate analysis. Patients with pretreatment ApoC-II levels ≤ 25.8 μg/ml had shorter PPFS than those with pretreatment ApoC-II levels > 25.8 μg/ml (P = 0.023, log-rank test). Pre- and posttreatment serum SCC-Ag and pretreatment serum ApoC-II levels may be important biomarkers to predict survival outcomes of patients with cervical cancer after radiotherapy. Pre- and posttreatment SCC-Ag and pretreatment ApoC-II might be useful in clinical settings for screening patients to improve treatment strategies in cervical cancer.

Summary Background & aims The associations between dietary magnesium intake and stroke and coronary heart disease (CHD) incidences are inconsistent and not established in Asian. We aimed to determine the association between dietary magnesium intake and the risk of stroke and CHD in a Japanese population. Subjects/Methods We studied 85,293 Japanese subjects by questionnaire at baseline (age 45–74 years, without cardiovascular disease or cancer in 1995 and 1998 for Cohorts I and II, respectively). The participants were followed until the end of 2009 and 2010 in Cohorts I and II, respectively. Dietary magnesium intake was estimated from a self-administered 138-item food-frequency questionnaire. Results After 1,305,738 person-years of follow-up, 4110 strokes and 1283 cases of CHD were documented. The multivariable-adjusted hazard ratios (HRs, 95% confidence intervals, 95%CIs) of CHD for the fourth and fifth quintiles of dietary magnesium intake were 0.70 (0.50–0.99) and 0.66 (0.44–0.97) in men (P for trend = 0.036), respectively, and third quintile of dietary magnesium intake was 0.61 (0.39–0.96) in women (P for trend = 0.241), compared with the lowest quintile in men and women. We observed no decreased risks of incident stroke in men or women with higher dietary magnesium intakes. Conclusions Higher dietary magnesium intake was associated with a reduced risk of CHD in Japanese men.

Aims Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. Methods and results The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000–04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50–79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality. The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73–1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55–0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64–0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01–4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07–11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03–1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40–0.99), respectively. Conclusion An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

Background and aims Higher intake of fish or n-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of coronary heart disease (CHD). However, it is unclear whether increased blood levels of n-3 PUFAs are associated with reduced risk of CHD in the Japanese population. Methods The relationship between circulating levels of n-3 PUFAs (eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid) and risk of CHD was examined in a nested case-control study among participants in the Japan Public Health Center (JPHC)-based Study Cohort. Plasma n-3 PUFA phospholipid levels were measured at baseline by gas chromatography in 209 cases with CHD and 418 controls matched for sex, age, date of blood draw, time elapsed since last meal before blood collection, and study location. The CHD cases (n = 209) comprised 168 cases of myocardial infarction and 41 of sudden cardiac death, otherwise classified as 157 non-fatal and 52 fatal coronary events, respectively. Mean duration of follow-up was 13.5 years. Results Multivariate conditional logistic analysis showed no significant association between n-3 PUFAs and risk of total CHD. The odds ratio (OR) for the highest versus lowest quartiles of plasma n-3 PUFAs was 0.79 (95% confidence interval [95% CI]: 0.41–1.51, p for trend = 0.51). Subtype analysis of CHD revealed that the multivariate ORs for the highest versus lowest quartiles for n-3 PUFAs were 0.91 (95% CI: 0.43–1.89, p for trend = 0.90) for myocardial infarction, 0.08 (95% CI: 0.01–0.88, p for trend = 0.04) for sudden cardiac death, 0.89 (95% CI: 0.42–1.89, p for trend = 0.97) for nonfatal coronary events, and 0.12 (95% CI: 0.02–0.75, p for trend = 0.03) for fatal coronary events. Conclusions Plasma n-3 PUFA levels were not associated with risk of total CHD but were inversely associated with risks of sudden cardiac death and fatal coronary events among middle-aged Japanese individuals.

The purpose of this study is to investigate changes in lung tumor internal target volume during stereotactic body radiotherapy treatment (SBRT) using magnetic resonance imaging (MRI). Ten lung cancer patients (13 tumors) undergoing SBRT (48 Gy over four consecutive days) were evaluated. Each patient underwent three lung MRI evaluations: before SBRT (MRI‐1), after fraction 3 of SBRT (MRI‐3), and three months after completion of SBRT (MRI‐3m). Each MRI consisted of T1‐weighted images in axial plane through the entire lung. A cone‐beam CT (CBCT) was taken before each fraction. On MRI and CBCT taken before fractions 1 and 3, gross tumor volume (GTV) was contoured and differences between the two volumes were compared. Median tumor size on CBCT before fractions 1 (CBCT‐1) and 3 (CBCT‐3) was 8.68 and 11.10 cm3, respectively. In 12 tumors, the GTV was larger on CBCT‐3 compared to CBCT‐1 (median enlargement, 1.56 cm3). Median tumor size on MRI‐1, MRI‐3, and MRI‐3m was 7.91, 11.60, and 3.33 cm3, respectively. In all patients, the GTV was larger on MRI‐3 compared to MRI‐1 (median enlargement, 1.54 cm3). In all patients, GTV was smaller on MRI‐3m compared to MRI‐1 (median shrinkage, 5.44 cm3). On CBCT and MRI, all patients showed enlargement of the GTV during the treatment week of SBRT, except for one patient who showed minimal shrinkage (0.86 cm3). Changes in tumor volume are unpredictable; therefore, motion and breathing must be taken into account during treatment planning, and image‐guided methods should be used, when treating with large fraction sizes. PACS number: 87.53.Ly

Seafood/fish intake has been regarded as a protective factor for coronary heart disease (CHD), while smoking is a strong risk factor. To examine whether associations between smoking and risk of CHD are modified by seafood/fish intake, we studied 72,012 Japanese men and women aged 45-74 years who completed 2 food frequency questionnaires, 5 years apart, during the period 1995-2009. After 878,163 person-years of follow-up, 584 incident cases of CHD (101 fatal and 483 nonfatal), including 516 myocardial infarctions, were documented. There was a clear dose-response association between smoking and CHD risk among subjects with a low seafood/fish intake (

Organophosphate esters are used as additives in flame retardants and plasticizers, and they are ubiquitous in the indoor environment. Phosphorus flame retardants (PFRs) are present in residential dust, but few epidemiological studies have assessed their impact on human health. We measured the levels of 11 PFRs in indoor floor dust and multi-surface dust in 182 single-family dwellings in Japan. We evaluated their correlations with asthma and allergies of the inhabitants. Tris(2-butoxyethyl) phosphate was detected in all samples (median value: 580 μg/g in floor dust, 111 μg/g in multi-surface dust). Tris(2-chloro-iso-propyl) phosphate (TCIPP) was detected at 8.69 μg/g in floor dust and 25.8 μg/g in multi-surface dust. After adjustment for potential confounders, significant associations were found between the prevalence of atopic dermatitis and the presence of TCIPP and tris(1,3-dichloro-2-propyl) phosphate in floor dust [per log10 -unit, odds ratio (OR): 2.43 and 1.84, respectively]. Tributyl phosphate was significantly associated with the prevalence of asthma (OR: 2.85 in floor dust, 5.34 in multi-surface dust) and allergic rhinitis (OR: 2.55 in multi-surface dust). PFR levels in Japan were high compared with values reported previously for Europe, Asia-Pacific, and the USA. Higher levels of PFRs in house dust were related to the inhabitants' health status.

Total body irradiation (TBI) is an important component of conditioning regimens for Allogeneic bone marrow transplantation (BMT). Interstitial pneumonitis (IP) and other pulmonary disorders are known regimen-related complications. The incidence of IP is related to the dose rate and dose fractionation; however, there is a paucity of clinical data regarding the optimal dose fractionation. This retrospective study evaluated patients to determine the influence of dose fractionation during TBI in preparation for allogeneic BMT on the subsequent development of IP and other pulmonary complications. Fifty-six patients were treated with TBI followed by BMT at our institute. All patients received a total TBI dose of 12 Gy given in 6 fractions over 3 days or in 4 fractions over 2 days. The prevalence of unrelated donors in the 4-fraction group was higher than that in the 6-fraction group. The overall and freedom from progression rates for patients in the 4-fraction group were better than those for patients in the 6-fraction group, but the difference did not reach significance. Clinically significant lung complications occurred in 19 (10: infectious and 9: non-infectious diseases) of 33 patients in the 6-fraction group and 12 (7: infectious and 5: non-infectious diseases) of 23 in the 4-fraction group. There was no significant difference between the two groups. There was no significant difference in pulmonary complications between patients treated with a TBI dose of 12 Gy in 6 fractions over 3 days and patients treated with a TBI dose of 12 Gy in 4 fractions over 2 days.

Radiotherapy is one of the major methods for treating cancer, but many patients undergoing radiotherapy have deep concerns about receiving radiation treatment. This problem is not generally appreciated and has not been adequately studied.The objective of this investigation was to empirically investigate the anxieties that cancer patients feel towards radiotherapy by using questionnaires to classify and quantitatively measure their concerns. A preliminary interview to develop a questionnaire was carried out with 48 patients receiving radiotherapy to discover their anxieties about on-going treatments. Subsequently, a main study was performed using a questionnaire with 185 patients to classify their types of anxiety and to ascertain the reliability and validity of the responses. Confirmatory factor analysis was then carried out with a 17-item Radiotherapy Categorical Anxiety Scale.Three anxiety factors were abstracted by factor analysis: (1) adverse effects of radiotherapy, (2) environment of radiotherapy, and (3) treatment effects of radiotherapy. Reliability, content validity, and concurrent validity were obtained. The adequacy of the three-factor model of anxiety concerning radiotherapy was confirmed.A 17-item Radiotherapy Categorical Anxiety Scale was formulated to quantitatively measure the specific types of anxiety among cancer patients receiving radiotherapy.

Purpose To characterize the magnitude of volume change in the postoperative tumor bed before and during radiotherapy, and to identify any factors associated with large volumetric change. Methods and Materials Thirty-six consecutive patients with early-stage or preinvasive breast cancer underwent breast-conserving therapy at our institution between June 2006 and October 2007. Computed tomography (CT) scans of the breast were obtained shortly after surgery, before the start of radiotherapy (RT) for treatment planning, and, if applicable, before the tumor bed boost. Postoperative changes, seroma, and surgical clips were used to define the tumor bed through consensus agreement of 3 observers (B.P., D.I., and J.L.). Multiple variables were examined for correlation with volumetric change. Results Between the first and last scan obtained (median time, 7.2 weeks), the tumor bed volume decreased at least 20% in 86% of patients ( n = 31) and at least 50% in 64% of patients ( n = 23). From the postoperative scan to the planning scan (median time, 3 weeks), the tumor bed volume decreased by an average of 49.9%, or approximately 2.1% per postoperative day. From planning scan to boost scan (median interval, 7 weeks), the median tumor bed volume decreased by 44.6%, at an average rate of 0.95% per postoperative day. No single factor was significantly associated with a change in tumor bed volume greater than 20%. Conclusions The average postlumpectomy cavity undergoes dramatic volumetric change after surgery and continues this change during RT. The rate of change is inversely proportional to the duration from surgery. In this study no factors studied predicted large volumetric change.

Purpose: The a im of this study was to investigate the relative accuracy of megavoltage photon-beam dose calculations employing either 5 bulk densities or independent voxel densities determined by calibration of the CT Houndsfield number. Materials/Methods: Full -resolution CT and bulk density treatment plans were generated for 70 lung or esophageal cancer tumors (66 cases) using a commercial treatment planning system with an adaptive convolution dose calculation algorithm (Pinnacle3, Philips Medicals Systems). Bulk densities were applied to segmented regions. Individual and population average densities were compared to the full-resolution plan for each case. Monitor units were kept constant and no normalizations were employed. Dose volume histograms (DVH) and dose difference distributions were examined for all cases. Results: The average densities of the segmented air, lung, fat, soft tissue, and bone for the entire set were found to be 0.1 4 , 0. 26 , 0. 89, 1.02, and 1.1 2 g/cc, respectively. In all cases, the normal tissue DVH agreed to better than 2 % in dose. In 62 of 70 target DVHs, agreement to better than 3 % in dose was observed . Six cases demonstrated emphysema, one with bullous formations and one with a hiatus hernia having a large volume of gas. They required the additional assignment of density to the emphysemic lung and inflammatory changes to the lung, the regions of collapsed lung, the bullous formations, and the hernia gas. Conclusions : Bulk tissue density dose calculation provides an accurate method of heterogeneous dose calculation. However, patients with advanced emphysema may require high-resolution CT studies for accurate treatment planning.

Acoustic neuroma tumor size may be evaluated using several methods. Here we investigate the variations among measuring techniques. A retrospective analysis of pre- and posttreatment magnetic resonance (MR) scans was performed on 15 acoustic neuroma patients with a history of stereotactic radiosurgery who had been followed for more than 2 years. Tumor size was measured on each MR scan using three methods, where the extracanalicular (EX) and intracanalicular (IN) portions were measured separately. We collected data on the largest diameter (M1), the square root of the product of the maximum anteroposterior and mediolateral diameter (M2), and the average for the maximum anteroposterior, mediolateral, and superoinferior diameters (M3). Size differences between follow-up MR scans separated by more than 2 years were calculated for each method, and we evaluated whether the tumors progressed, remained stable, or regressed. A total of 154 follow-up pairs of EX and 115 follow-up pairs of IN showed a statistically significant difference for the number of each category among the three methods (P = 0.03, P < 0.01, respectively). The greatest category agreement was observed between the M2 and M3 methods. A significant difference between the tumor size measuring methods was observed. To strengthen specificity when evaluating tumor size difference, a measuring method using two or more parameters is recommended.

The Berg muscle-based categorization of axillary lymph node location (commonly referred to as levels I, II, and III) was used extensively by pathologists and surgeons to describe the extent of axillary node dissection in breast cancer patients. However, its reproducibility with different arm positions and utility in 3-dimensional radiation treatment planning hasn't been tested. Computed tomography scans were observed in 16 patients in 2 positions: historical position (HP), ipsilateral arm abducted 90 degrees to the body axis; standard position (SP), arms above head. The volume, contents, and location of Berg lymph node levels (LNL) and the location of lymph nodes, surgical clips, pectoral muscles, and vascular structures relative to reference points were compared. From HP to SP there was no difference in LNL volumes. However, if measured from an anatomic landmark, the third thoracic vertebra (T3), LNL position varied: level I, an average of 23.1 mm anteriorly, P < 0.01; level II, 7.5 mm medially, P = 0.04; level III, 18.8 mm medially, P = 0.05. Using T3 as a reference: pectoralis major and minor muscles displaced medially (23.9 mm, P < 0.01 and 7.5 mm, P = 0.09) and anteriorly (18.2 mm, P < 0.01 and 11.2 mm, P < 0.01); axillary (18.0 mm, P < 0.01), subscapular (25.4 mm, P < 0.01), and lateral thoracic (8.4 mm, P < 0.01) vessels displaced anteriorly; axillary vessels displaced also medially (15.1 mm, P = 0.03). Disagreements in LN coverage with changes in arm position were observed in 60% (LNs) and 66% (clips) for level II. Surgeons, radiologists, and radiation oncologists should be aware that LNL coverage based on muscle boundaries varies significantly with arm position changes, making objective comparisons of information collected in different arm positions unreliable.

Clinic physicians' awareness of the Japanese hypertension guideline (JSH 2000) and compliance with its recommendations were assessed to derive policy implications for effective blood pressure control. Data were obtained from two postal questionnaire surveys conducted in 2000 and 2004, and subjects were 896 and 1425 clinic physicians, respectively, who were engaged in general internal medicine. Recognition rates of JSH 2000 were 63.1% (n = 822) before its announcement in 2000 and 94.4% (n = 1400) in 2004. Rates of access, familiarity and utilisation of JSH 2000 were 87.0, 81.6 and 68.9%, respectively (n = 1400) in 2004. As for major management strategies for low-risk hypertension: in 2000, for patients with 140-149/90-94 mmHg, 81.5% of 812 respondents performed lifestyle modification, and 11.2% prescribed medicines, whereas for patients with 150-159/95-99 mmHg, 71.7% of 807 respondents prescribed medicines, and 24.3% conducted lifestyle modification; in 2004, 90.0% of 1384 respondents conducted lifestyle modification, 22.6% prescribed medicines, 2.5% referred patients to other facilities, and 6.4% did nothing. In 2004, 68.9% of 1388 respondents agreed with the new definition of hypertension, whereas 17.1% preferred 160/95 mmHg. Respondents' age (P0.05) and a percentage of hypertensives in daily patient load (P0.0005) significantly associated with the choice of the old criteria. In conclusion, JSH 2000 achieved a substantial improvement in clinic physicians' awareness and their compliance to its recommendations on low-risk hypertension management. One of the strategies for further enhancement in their compliance with JSH 2004 would be its dissemination to those who are old and/or do not see hypertensive patients so frequently.

We investigated the influences of mothers' dieting behaviors on their junior high school daughters. We assessed dieting behaviors and eating habits in 221 pairs of mothers and their junior high school daughters using questionnaires. The subjects were classified into an extraordinary-diet (Ex-D) group, who attempted to diet rapidly with unhealthy methods, a structured-diet (St-D) group, who attempted to diet gradually with healthy methods, and a non-diet (N-D) group, using the questionnaire scores. 1) A significant correlation was observed in the distribution of dieting behavior groups between the mothers and their daughters. 2) The scores for dieting behavior of the mothers whose daughters were classified into the Ex-D group were significantly higher in several question items compared with those of the mothers whose daughters were classified into the N-D group. 3) The scores for eating consciousness of the mothers whose daughters were classified into the Ex-D group were significantly lower for the item "Cooking is a fun pastime" compared with those of the mothers whose daughters were classified into the St-D or N-D groups. 4) The number of experiences of conversation with daughters about diet for the mothers whose daughters were in the Ex-D group was significantly higher than that for the mothers whose daughters were classified into the N-D group. The mothers' dieting behavior, eating consciousness, and number of conversations with daughters about diet influenced dieting behaviors in their junior high school daughters. Appropriate education of mothers would be useful to prevent their daughters' inappropriate diet.

Objective To determine the nature and origin of synovial inflammation in knees with osteoarthritis (OA). Method Synovial samples were obtained from 21 medial compartmental knee OAs from 19 patients. First, using 11 medial knee synovial samples from 9 patients, a quantitative estimation of synovitis was made with both ordinary and immunohistochemical staining. Second, from the other 10 knees, tissue samples were taken from both the medial and the lateral compartments to quantify cells that infiltrated into the synovium. Medial synovium was immunostained using antibodies to anti-type II collagen, CD68, CD2, CD4, CD8, CD15, CD19, CD25, HLA-DR, CD1a and LN5. The lateral synovium was immunostained with anti-type II collagen, CD68, HLA-DR and CD4 antibody as a control. Result Denatured cartilaginous detritus was found captured by synovial lining cells with a strong immunoreactivity to CD68 antibody, and whose phagocytic potential was activated. The number of anti-type II collagen-positive fragments in the medial compartment of the knee was larger than that found in the lateral compartment. Moreover, the population of CD68-positive cells in synovial tissue and HLA-DR-positive cells in the lining layer was larger in the medial compartment than in the lateral compartment. The number of CD4-positive cells (defined as helper/inducer T lymphocytes) was greater in medial synovium than in lateral synovium. Conclusion Overall, this study strongly supports the concept that the synovitis observed in patients with knee OA might be induced by an immunological mechanism involving, to some extent, a macrophage/helper T cell interaction.

We examined the association between green tea consumption and mortality due to all causes, cancer, heart disease, cerebrovascular disease, respiratory disease, injuries, and other causes of death in a large-scale population-based cohort study in Japan.We studied 90,914 Japanese (aged between 40 and 69 years) recruited between 1990 and 1994. After 18.7 years of follow-up, 12,874 deaths were reported. The association between green tea consumption and risk of all causes and major causes of mortality was assessed using the Cox proportional hazards regression model with adjustment for potential confounders.Hazard ratios for all-cause mortality among men who consumed green tea compared with those who drank less than 1 cup/day were 0.96 (0.89-1.03) for 1-2 cups/day, 0.88 (0.82-0.95) for 3-4 cups/day, and 0.87 (0.81-0.94) for more than 5 cups/day (P for trend.001). Corresponding hazard ratios for women were 0.90 (0.81-1.00), 0.87 (0.79-0.96), and 0.83 (0.75-0.91; P for trend.001). Green tea was inversely associated with mortality from heart disease in both men and women and mortality from cerebrovascular disease and respiratory disease in men. No association was found between green tea and total cancer mortality.This prospective study suggests that the consumption of green tea may reduce the risk of all-cause mortality and the three leading causes of death in Japan.

AIM: To determine the correlation between interleukin 12 (IL-12) expression and Epstein-Barr virus (EBV) in Sjögren syndrome. METHODS: Indirect immunohistochemical technique, enzyme linked immunosorbent assay (ELISA), and immunoblot analysis were used to investigate IL-12 expression by EBV activation, using 13 surgical specimens and four B cell lines. RESULTS: Marked expression of IL-12 was found in the epithelial cells and the infiltrating B cells of salivary gland tissues from patients with Sjögren syndrome (six of 10 cases), but not in those from normal individuals (none of three cases). A striking topographic correlation between IL-12 and EBV was found. In addition, levels of IL-12 production by B cell lines were clearly enhanced by EBV activation in vitro. CONCLUSIONS: IL-12 expression closely reflects the intracellular event of EBV activation in Sjögren syndrome, and may contribute to the T helper cell type 1 (Th1) cytokine overexpression seen in this disease.

To clarify whether regulatory cytokines inhibit hematopoiesis in patients with myelodysplastic syndromes (MDS), malignancies characterized by the formation of cytopenias despite the presence of cellular bone marrow, expression of TNF-alpha and IFN-gamma by bone marrow cells was investigated using specific reverse transcriptase-polymerase chain reaction assays. An enhanced expression of the mRNA for TNF-alpha was observed in most of the samples from MDS patients (11/14, 79%), whereas no enhancement was observed in bone marrow samples from AML (0/6), CML (0/2) or control cases (0/8). The expression of IFN-gamma was also enhanced in some of MDS cases (5/12, 42%) while AML (0/5), CML (0/2) and control cases (0/6) showed very low levels of IFN-gamma mRNA expression. Immunohistochemical examination confirmed the scattered presence of TNF-alpha or IFN-gamma producing cells in the bone marrow of MDS patients. The majority of these cells were CD68-positive macrophage lineage cells. These results suggested that disruption of hematopoiesis in MDS might be caused by enhanced production of inhibitory regulatory cytokines especially TNF-alpha and occasionally IFN-gamma by bone marrow macrophages.

Alveolar bone-derived polymorphonuclear leukocytes (PMNs) were characterized for their ability to produce inflammatory cytokines such as interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor alpha (TNF alpha), and IL-6 in vivo. Periapical exudates (PE) were collected from periapical lesions with chronic periapical periodontitis through root canals. Cells and noncellular supernatants were then isolated by centrifugation. The concentration of cytokines present in the noncellular supernatants were determined by ELISA. High concentrations of IL-1 alpha, IL-1 beta, and IL-6 were detected in PE, however, TNF alpha was not. PE contains predominantly PMNs ( > 95% of residing cells) with a few percent of lymphocytes and/or macrophages. These alveolar bone-derived PMNs were purified by the Ficoll-Hypaque gradient method and were analyzed for cytokine mRNA expression using the cytokine-specific reverse-transcription polymerase chain reaction. Highly purified PMNs ( > 99.5%) isolated from PE expressed significant levels of mRNA for IL-alpha, IL-1 beta, and TNF alpha. IL-6 mRNA was not detected, although a high concentration of IL-6 was detected in supernatants of PE by ELISA. The IL-6 secretion in PE could be derived from macrophages, T lymphocytes, osteoblasts, or fibroblasts around periapical lesions. These data strongly suggest that human PMNs derived from alveolar bone can spontaneously produce IL-1 alpha, IL-1 beta, and TNF alpha at sites of inflammation, and probably initiate inflammation and regulate augmentation of bone resorption in vivo.

In this study, we have identified the source of nitric oxide (NO) produced in the human inflammatory joints by analyzing expression of inducible NO synthase. In ex vivo organ cultures, both inflammatory synovium and cartilage from patients with rheumatoid arthritis produced NO. The NO production was suppressed by NG-monomethyl-L-arginine, an inhibitor of NO synthase. The amount of NO produced by the synovium correlated with the proportion of CD14+ cells in the corresponding tissue (r = 0.8, P < 0.05). Immunohistochemical analysis as well as in situ hybridization showed that inducible NO synthase was predominantly expressed in synovial lining cells, endothelial cells, chondrocytes, and to a lesser extent, in infiltrating mononuclear cells and synovial fibroblasts. The synovial lining cells and the infiltrating cells expressing inducible NO synthase were identified where CD14+ cells were located. Together with morphological features, this suggests that they are type A synoviocytes. NO production from freshly isolated synoviocytes and chondrocytes was up-regulated by in vitro stimulation with a combination of IL-TNF-beta, TNF-alpha, and LPS. In summary, the present results suggest that NO is produced primarily by CD14+ synoviocytes, chondrocytes, and endothelial cells in inflammatory joints of arthritides. NO production can be upregulated by cytokines present in inflamed joints. The increased NO production may thus contribute to the pathological features in inflammatory arthritides.

The beneficial effects of low energy laser irradiation on rheumatoid arthritis (RA) joints have been reported, but the mechanisms of action of low energy lasers in RA are unclear. The synovial membrane in cases of RA was studied histologically to observe the effects of low energy laser irradiation. Fourteen knee joints of RA cases, which had been scheduled for arthroplasty, were irradiated with a gallium-aluminium-arsenide (Ga-Al-As) laser (790 nm in wavelength and 10 mW of output power) prior to the surgical operation, at six points of the external aspect of the knee joint for 80 seconds at each points once a day for 6 days. On the day following the last irradiation, pieces of synovial membrane from the lateral irradiated area and from the median nonirradiated area as a control were resected during the arthroplasty. The histological findings of the irradiated synovial membrane showed flattening of epithelial cells, decreased villous proliferation, narrowed vascular lumen, and less infiltration of inflammatory cells compared with those of nonirradiated synovia. The evaluation of slides was done in a blinded manner, and significant differences was seen by Wilcoxon's t-test (P < 0.01). Histological findings suggested that the low energy laser irradiation induced suppression of inflammation in the synovial membrane of RA. © 1994 Wiley-Liss, Inc.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a type of hereditary stroke and dementia. More than 90% of patients with CADASIL have mutations in the Notch3 gene. All mutations either create or destroy a cysteine residue in the epidermal growth factor-like repeats. In addition, five polymorphisms, which lead to amino acid substitutions, have been identified within the Notch3 coding sequence. However, whether these polymorphisms affect Notch signalling or are involved in cerebrovascular diseases is unknown. In the present study, we investigated a possible association between a T6746C polymorphism in the Notch3 coding region and the occurrence of symptomatic ischaemic cerebrovascular disease (CVD) was investigated. Two hundred and thirty five patients with CVD, as confirmed by brain CT or MRI, and 315 age and sex matched control subjects were analyzed for genotype frequencies of the T6746C polymorphism in Notch3. The genotype distributions were: patients with CVD, C/C 14.0%, C/T 45.5%, and T/T 40.4%; controls, C/C, 14.3%; C/T, 47.9%; T/T, 37.8%. The Japanese population has a higher C allele frequency of the T6746C polymorphism than European populations. There was no significant difference between the T6746C polymorphism in patients with CVD and controls (chi(2)=0.414, p=0.813). This was confirmed by the results of multiple logistic regression analysis including established risk factors (chi(2) =4.65, p=0.311). In conclusion, the results indicate that T6746C polymorphism in the intracellular domain of the Notch3 gene is not associated with an increased risk for CVD.

Background/Objectives: There has been no study with regard to the association between dietary fibers and the incidence of stroke and coronary heart disease (CHD) in Asia. We investigated the association between dietary fiber and the risk of cardiovascular disease (CVD), which we defined as stroke or CHD, in a Japanese population. Subjects/Methods: We studied 86 387 Japanese subjects (age 45–65 years, without CVD or cancer in 1995 as Cohort I and in 1998 as Cohort II) and used a self-administered questionnaire to follow-up the participants until the end of 2004. Dietary fiber intake was estimated from food-frequency questionnaires comprising 138 food items. Results: After 899 141 person-years of follow-up, we documented the incidence of 2553 strokes and 684 cases of CHD. Multivariable-adjusted hazard ratios (95% confidence intervals (CIs)) of CVD for the third to fifth quintiles of total fiber were 0.79 (0.63–0.99), 0.70 (0.54–0.89) and 0.65 (0.48–0.87) in women, respectively, compared with the lowest quintile. Total fiber intake was inversely associated with the incidence of stroke, either cerebral infarction or intracerebral hemorrhage in women. The results for insoluble fiber in women were similar to those for total fiber, whereas those for soluble fiber were weak. An inverse association of total fiber with CVD was observed primarily in non-smokers (P for trend=0.045 and 0.001) and not in smokers (probability values for interaction between total fiber and smoking were 0.06 and 0.01 in men and women, respectively). Conclusions: Higher total dietary fiber was associated with reduced risk of CVD in Japanese non-smokers.

OBJECTIVE Using 5-bulk-density heterogeneous dose calculation, we investigated whether contrast-enhanced (CE+) computed tomography (CT) will affect dose-calculation accuracy in the thoracic area. METHODS We analyzed 17 radiation-oncology patients who underwent thoracic CE+ CTs. Full-resolution CT and 5-bulk-density plans were generated using an adaptive convolution algorithm. Bulk densities for air, lung, fat, soft tissue, and bone were applied to regions identified by an isodensity segmentation tool. The population-averaged physical density of each region was calculated and compared with the reference value calculated from 66 noncontrast-enhanced (CE-) thoracic CT images. Using the 5-bulk densities, we created a new plan in which the physical densities of each area were forced to be the same as the CE- reference value, and we compared the dose-volume histograms (DVH). RESULTS Average physical density for the segmented air, lung, fat, soft tissue, and bone for CE+ were 0.14, 0.29, 0.90, 1.03, and 1.13 g/cm(3), and the reference values for CE- were 0.14, 0.26, 0.89, 1.02, and 1.12 g/cm(3), respectively. In all the cases, the normal-tissue DVH agreed to better than 1%. In 15 cases, DVH of the planning target volume (PTV) agreed to better than 3%. In 2 patients, >3% difference in the PTV dose was observed. CONCLUSIONS Only 2 patients with a strong injection artifact in the PTV or beam showed >3% discrepancy in the target dose. When using CE+ CT for treatment planning, strong injection artifacts must be excluded.

Background \nMost previous studies about anxiety and depression in patients undergoing radiotherapy have only measured the quantity of general depression and anxiety and have not studied specific periods of involvement. The aim of this study was to assess anxiety and depression among early breast cancer patients, and the anxiety experienced immediately before and after radiotherapy. Methods \nWomen who started radiotherapy for stage I or II breast cancer (n = 172) were asked to answer two questionnaires: the Hospital Anxiety and Depression Scale (HADS) and Radiotherapy Categorical Anxiety Scale immediately before and after radiation therapy. Results \nThe results showed that the mean scores of anxiety and depression (HADS and Radiotherapy Categorical Anxiety Scale) decreased after radiotherapy. The mean score of depression (HAD-D) in the group receiving conventional radiotherapy was higher than in those receiving hypofractionated radiotherapy before and after radiotherapy. The mean scores of anxiety and depression (HADS) in the endocrine therapy group were lower than in the group without endocrine therapy before treatment. However, the scores after treatment of both groups were not significant. Conclusion \nSome intervention may be needed to decrease the temporary anxiety and depression raised during radiotherapy for early stage breast cancer patients. This is especially so for patients who do not receive concurrent endocrine therapy and choose the conventional radiotherapy course.

Purpose To determine the residual setup errors of several image guidance scenarios, using cone-beam computed tomography (CBCT) in conventionally fractionated radiotherapy for lung tumors. Methods Thirteen lung cancer patients were treated with conventionally fractionated radiotherapy, using daily image guidance with CBCT, resulting in 389 CBCT scans which were registered to the planning scan using automated soft-tissue registration. Using the resulting daily alignment data, 4 imaging frequency scenarios were analyzed: (A) no imaging; (B) weekly imaging with a 3-mm threshold; (C) first 5 fractions imaged, then weekly imaging with a patient-specific threshold; and (D) imaging every other day. Results The systematic setup error (Sigma) was reduced with increasing frequency of imaging from 3.4 mm for no imaging to 1.0 mm for imaging every other day. Random setup error (sigma), however, varied little regardless of the frequency of imaging: 2.9, 3.0, 3.4, and 3.2 mm for scenarios A, B, C, and D, respectively. The setup margins required to account for the residual error of each imaging scenario were 1 to 1.6 cm for scenario A, 4 to 6 mm for scenarios B and C, and 4 to 5 mm for scenario D. As the residual error of daily CBCT was not included in this analysis, these margins compare with a margin of zero for daily CBCT. Conclusions Daily image guidance is ideal as the setup margin can be reduced by about 5 mm versus a nondaily imaging scenario. However, if daily image guidance is not possible, there is little benefit in imaging more often than once a week.

Objective: To investigate axillary 2-dimensional treatment planning accuracy. Methods: Computed tomography (CT) simulation data for 16 breast cancer cases taken after level I-II axillary dissection were analyzed. An additional 6 patients underwent CT simulation using the historical 90-degree position (HP), and the standard-bore CT position (CT-P). Two physicians identified the lateral and medial borders of the coracoid process (CCP) on digitally reconstructed radiography (DRR). The DRR-identified x coordinates were compared with the CT-measured x coordinates. x coordinates differences between the most medial surgical clip and the borders of the CCP as dentified on CT were analyzed. Fields were designed to cover various amounts of the axilla, and treatment plans were generated to compare doses to the most medial surgical clip. Results: In 11 and 6 cases for each physician, respectively (lateral border), and in all cases for both physicians (medial border), the DRR identification of the CCP was medial to that on CT. In 9 and 8 cases, the most medial surgical clip was lateral to the medial and lateral borders of the CCP, respectively. In all data sets, the average difference was larger in the HP compared with CT position. The number of patients who received more than 90% of the prescribed dose when using the plans with the mid humeral head border, lateral border of the CCP, and medial border of the CCP were as follows: 6, 1, and 0, respectively. Conclusions: When using 2-dimensional treatment planning, the dose to the undissected axilla can vary depending on the anatomic landmark used to define the lateral border of the axillary field. This may account for outcome differences found in older radiotherapy studies.

PURPOSE To identify differences in regional node irradiation using historical treatment planning techniques between 2 arm positions. MATERIALS AND METHODS Sixteen breast cancer patients were scanned using a wide-bore computed tomography (CT) scanner. The patients were scanned in 2 arm positions: historical position (HP), in which the ipsilateral arm is at 90 degrees to the body axis; and standard-bore position (CT-P), in which the arms are above the head. The locations of the axillary lymph nodes were compared between the 2 positions. The dose distribution to the axillary lymph nodes was compared between the HP and the CT-P using fields designed based on bony landmarks. RESULTS When the arm position changed from the HP to the CT-P, level I lymph nodes moved anteriorly and medially. Level II and III axillary nodes moved posteriorly and medially. If historical treatment planning techniques are used to treat the axillary lymph nodes with the patient in the CT-P, level I nodes could receive a higher dose of radiation and levels II and III could be significantly underdosed as compared with treatment in the HP. The dose distribution for the CT-P was more homogeneous compared with that of the HP. CONCLUSION Coverage of the axillary lymph nodes varies significantly with arm position when using historical treatment planning techniques. Physicians should accurately contour the lymph node levels on the treatment planning CT and not rely on bony landmarks to design the axillary fields. CT-based treatment planning should be used to ensure adequate coverage of these nodes.

Direct detection of these viruses was made by using the PCR for amplifying viral DNA. In virtually all adults low levels of the herpesvirus can be detected. Therefore it is necessary to quantitate the amount of viral DNA, and a method to compare the plasmid containing the cloned target gene was used here. After 35 cycles of amplification, 10 copies of the viral DNA per 100 microliters saliva were detected. The PCR was used to detect increased levels of EBV and HHV-6 in saliva from patients with lymphoproliferative diseases, suggesting that these viruses may play a part in their pathogenesis. Viral detection by such highly sensitive methods as PCR may allow better monitoring of medication, as well as early detection of EBV- and HHV-6 related diseases that may arise in these patients. The great sensitivity of PCR and its ability to analyse very small samples make this technique most suitable for clinical diagnosis.

Intraosseous ameloblastoma (IA) is the quintessence of epithelial odontogenic tumor and histologically and behaviorally defined as an undoubted neoplastic process. Current information must lead to the consensus that IA arises from the embryologic inclusions of odontogenic epithelium within the jawbone. Nevertheless, clinically oriented evidence is limited to this day.The clinical and radiographic features, behavior, and pathology of 14 cases of small IA confined to the alveolar region were systematically examined.Six cases were a chance finding. There was no gender predilection and half of the lesions clustered in middle age (40 years). The posterior region of the mandible (n = 7) and the anterior segment of the maxilla (n = 4) were favored. Five radiographic characteristics were recognized: interradicular (n = 5) and periradicular (n = 3), and periapical, residual and pericoronal (n = 2 each). They showed solid (n = 12) or unicystic (n = 2) growth pattern and 12 lesions were divided into seven follicular, three desmoplastic, and two plexiform subtypes. The main location of tumor was microscopically traceable in six cases; three interradicular type outside the periodontal ligament space and two periradicular and one periapical variants inside.By in-depth evaluation of the spatial relationship between tumor and its surrounding structure, the alveolar process, periodontal ligament space, and pericoronal area are all the likely starting points of IA. This report re-awakens the oral pathologist to the histogenetic significance of incipient IA as the only available human specimen for reappraisal of their origin.

Nevic corpuscle (NC), a stacked lamellar structure reminiscent of Meissner corpuscle, is frequently observed in dermal melanocytic nevi. Although the heading 'neurotized' is classically used for these nevi, the exact neural nature of NC has been a topic of considerable debate. Neurotized nevi have received little attention in the dental literature, and there was no information on NC in oral melanocytic nevi.Six cases of oral intramucosal nevi with a significant number of NC (two completely and four partially neurotized nevi) were examined immunohistochemically and ultrastructurally.NC was composed of closely piled laminar cells devoid of visible melanin. NC and associated spindle nevus cells were immunopositive for S-100 protein but negative for HMB-45, myelin basic protein and epithelial membrane antigen. Within NC, no reactivity for neurofilament protein, protein gene product 9.5 or peripherin was evident. Numerous CD34-positive dendritic cells were located between nevus cells and often encircled NC. Ultrastructurally, NC consisted of concentrically layered elongated cells with a slender lamellated cytoplasm rich in thin filaments and pinocytotic vesicles. Their cytoplasmic processes were focally covered by external basal lamina and continuous to spindle nevus cells. Occasional NC cells contained a few melanosomes. There was no interposed axon in NC.Despite the close resemblance to Meissner corpuscle, NC showed no axonal supply. NC cells lacked terminal Schwannian differentiation and appeared to be modified melanocytes with some perineurial ultrastructural characteristics. The presence of CD34-positive cells, presumably corresponding to endoneurial fibroblasts, further supports an organizational relationship of NC and peripheral nerve sheath elements.

The jawbone is replete with a vestige of odontogenesis. The overall consensus is that intraosseous remnants of the enamel organ and dental lamina are the only histogenetic option for central epithelial odontogenic tumors. Curiously, incipient tumors or possible precursor conditions of residual odontogenic epithelium have rarely been reported in the literature.We microscopically evaluated 39,660 biopsy samples to determine the presence of a tumor-like odontogenic epithelial nodule in the maxilla and mandible.Seven intraosseous specimens that associated with a focal proliferation of odontogenic epithelium were retrieved. Six hamartomatous processes showed four different morphologic patterns comparable with the tumor nests comprising ameloblastoma (n = 1), squamous odontogenic tumor (n=1), calcifying epithelial odontogenic tumor (n=2) and calcifying cystic odontogenic tumor (n=2). Among six lesions, four were the intrafollicular development. The remaining case of interest was multiple hyperplastic clear rests of Malassez in association with an impacted tooth.Although it is impossible to predict the fate of these microscopic structures of hamartomatous character, the present case series indicates that any of the dormant embryonic residues of odontogenic epithelium can return to an active state, capable of non-reactive, probably neoplastic proliferation of pathological significance.

Mortality statistics have recorded an increased number of deaths from ischemic heart disease (IHD) since death certificates were revised to reflect the International Classification of Diseases, tenth revision (ICD-10) in Japan, in 1995. However, it remains unclear whether the validity of IHD diagnosis improved after this revision.We conducted the Oita Cardiac Death Survey to validate IHD certified deaths that occurred among residents aged 25-74 in Oita City, Japan (mean population = 273,000). Of the eligible 342 fatalities, 328 cases (95.0%) were examined by a review of the medical records and/or interviews with physicians. The MONICA criteria were applied and provided a reference standard against which to assess the validity of certified fatal IHD. Sensitivity (Se), positive predictive value (PPV), specificity (Sp) and negative predictive value (NPV) for IHD as the cause of death were analyzed, assuming that all validated IHD deaths were true. Multivariate logistic models were used to determine associations of false positive and false negative cases with sex, age at time of death and place of death.Vital statistics revealed 273 fatalities to be due to cardiac disease, including 143 from acute myocardial infarctions (AMI), 27 from other IHD, 52 from heart failure and 51 from other heart diseases. After validation, 25 'definite fatal AMI' and 71 'possible fatal AMI or IHD death' were identified among all subjects according to the MONICA criteria. In all, Se, PPV, Sp and NPV for IHD certified as the cause of death were 86.5% (95% Cl: 77.6-92.3), 50.3% (42.5-58.1), 64.7% (58.1-70.7), and 92.0% (86.5-95.5), respectively. PPV among persons aged 25-54 years was remarkably decreased. PPV and Sp among out-of-hospital deaths were significantly lower than for in-hospital deaths. Multivariate logistic models revealed out-of-hospital deaths and being aged 25-54 years to be significant predictors of false positive cases (odds ratio (OR) = 2.03, P0.001 versus in-hospital deaths and OR = 2.79, P0.05 versus ages of 65-74 years, respectively).Because false positive cases increased among certified IHD deaths after the revision, PPV and Sp percentages decreased. Out-of-hospital deaths and being aged 25-54 years were associated with increased possibility of false positive. Given our findings, IHD deaths in vital statistics may increase due to the tendency of physicians to certify IHD as the cause of death in cases without clear sign suggestive of other causes.

The purpose of this study is to evaluate pulmonary involvement in rapidly progressive glomerulonephritis (RPGN). Of 71 patients in whom RPGN was diagnosed, 32 (45.1%) had pulmonary involvement: 12, alveolar hemorrhage (AH) (16.9%); 10, interstitial pneumonia (IP) (14.1%); four, chronic bronchial lesions (5.6%); two, consolidation (2.8%), and four, old inflammatory lesions (5.6%). Investigation of which organ of the twelve AH patients, the kidney or the lung, was the first to be involved, showed that the lung preceded in one patient, the kidney was first in three, and the lung and kidney occurred at the same time in the other eight. Of the ten IP patients, the lung preceded in eight, the kidney was ahead in two, and lung and kidney were simultaneous in one. Three patients had a history of pneumoconiosis, and two had acute progressive IP. Seventeen (45.9%) of 37 patients who tested positive for antineutrophil cytoplasmic autoantibodies (MPO-ANCA) had lung involvement, and three (30.0%) of the ten patients who tested negative for MPO-ANCA, PR 3-ANCA and anti-GBM antibody also had lung involvement.

In order to select the optimal neurointensive treatment for patients with severe head injury and intracranial hypertension, the effects of hypothermia (HT), barbiturates (BT), and osmotic agents (OT) on focal and diffuse cerebral oxygen metabolism were evaluated by means of continuous monitoring of bifrontal regional oxygen saturation (rSO2), jugular bulb oxygen saturation (SjO2), jugular bulb temperature (Tjb), intracranial pressure (ICP), and cerebral perfusion pressure (CPP).Cerebral oxygen metabolism in SjO2 and rSO2, ICP, CPP, and Tjb were continuously monitored in severe head injury patients with Glasgow Coma Scale8, ages 10-62: 13 with focal and 10 with diffuse injuries. The effects of BT (n = 6), HT (n = 9), and OT (n = 8) on these parameters (ICP/CPP, SjO2, and rSO2) were compared. Evaluations were performed in terms of: a) Percentage of abnormal values based on normal control values; ICP20 mm Hg, CPP60 mm Hg, SjO2 55-75%, and rSO2 60-80% were calculated, b) Effects of pentobarbital dose (mg/kg/h) for the parameters compared among1.0, 1.1-2.0, 2.1-3.0, and3.1. c) Effects of Tjb (degree C) on parameters compared among hyperthermia (38 degrees C), normothermia (36-37.9 degrees C), mild hypothermia (34-35.9 degrees C) and moderate hypothermia (33.9 degrees C).a) Abnormal data differed significantly among the three treatment groups. rSO2 showing ischemia on the affected side was more marked in BT than in HT or OT. b) ICP decreases and CPP increases correlated significantly with the pentobarbital dose. c) ICP decreases and CPP increases correlated significantly with decreased Tjb.The therapeutic effects of hypothermia, barbiturates, and osmotherapy on cerebral oxygen metabolism and ICP/CPP are different according to the underlying pathological lesions of patients with severe head injury.

The following conditions of 17 patients with severe head injury (ages 9-76; mean 37:12 focal and 5 diffuse injuries) were evaluated during acute phase (1-14 days after injury, mean 5) by transcranial power Doppler imaging (PDI), a new color Doppler ultrasound technique: a) morphological changes via temporal window, b) hemodynamic changes in major intracranial/cervical arteries based on measured angle-corrected time-averaged mean (TAM)/ peak velocities and vessel diameter (Va), and calculated pulsatility indices (PI), vessel area (Va), and flow volume (Vf = TAM x Va). a) 1) Major trunks of intracranial vessels and circle of Willis and pathological changes in frontal/temporal lobes and midbrain were finely visualized. 2) Contusional hemorrhage and cerebral contusion demonstrated irregular hyper- and hypo-echoic lesions, respectively. 3) Delayed epidural hematoma showed a hyper-echoic band. b) 1) Decreased velocities, significant PI increase, and Va increase tendency were observed in intracranial arteries. 2) Increased velocities with Vf increase but no Va decrease indicated hyperemia rather than vasospasm. 3) Va in the intracranial vessels, however, tended to increase PDI appears useful in evaluating real-time and simultaneous morphological and hemodynamic information in pathogenesis and neurointensive care of patients with severe head injury.

227 of subjects with a 2-hour plasma glucose concentration of 120-199 mg/dl were selected from 413 participants who had two or more 75 g OGTT in health examinations from 1987-1995. From these subjects we established 8 groups according to initial 2-hour plasma glucose concentration 120-199 mg/dl stratified by 10 mg/dl, and calculated the total percentages of participants whose 2-hour plasma glucose concentration reached 200 mg/dl or greater over a 1-8 years (2.7 +/- 1.7 years, mean +/- SD) observation period. In 36 subjects who were tested annually over a four year period (4 times), the mean values of their 4 values were analyzed for relationships to coefficients of variation of the 2-hour plasma glucose.By stratified groups (from lowest to highest) of those with an initial plasma glucose concentration of 120-159 mg/dl, 7.4%, 12.1%, 16.1%, and 15.0% attained values of 200 mg/dl and higher, respectively in 1-8 years. On the other hand, 29.6%, 29.6%, 39.1%, and 47.4% of those with an initial plasma glucose concentration of 160-199 mg/dl moved to a diabetic type after 1-8 years, respectively. The percentages of those who ended up with levels of 200 mg/dl and greater at 2-hours tended to increase in subjects whose initial 2-hour plasma glucose concentration was over 160 mg/dl in comparison with patients below that initial level.From these results, it appears that subjects with 160-199 mg/dl 2-hour glucose concentration, which is considered a borderline status, are at high risk for future abnormal levels (200 mg/dl at 2-hours) and should be managed as a high risk level group for prevention of diabetes.

A P4 segment aneurysm of the posterior cerebral artery has rarely been described. A case of ruptured P4 segment aneurysm, which re-ruptured after clipping procedure for unruptured internal carotid artery aneurysm, was reported. A 57-old-man had sudden onset of severe headache and vomiting and was transferred to our hospital. CT scan on admission showed diffuse subarachnoid hemorrhage dominantly extending to the tentorial surface and the occipital interhemispheric tissue. Four-vessel angiography demonstrated a right internal carotid-posterior communicating artery junction aneurysm, and its neck clipping was performed on day 5. Intraoperative inspection of the whole appearance of the aneurysm was difficult because of the aneurysm existing on the ventral portion of the internal carotid artery and definite diagnosis of the bleeding source was not obtained. On day 23, he complained of severe headache and restricted vision and CT scan showed intracerebral hematoma in the left occipital lobe with intraventricular hemorrhage. The angiograms and CT scan on admission were reexamined, and another aneurysm on the left parieto-occipital artery (P4 segment) was retrospectively identified. The ruptured P4 segment aneurysm was obliterated via the interhemispheric approach and the patient enjoyed an uneventful postoperative course. When a thick subarachnoid hemorrhage distributed in the occipital interhemispheric fissure, quadrigeminal cistern, and ambient cistern is encountered, the existence of a possible P4 segment aneurysm should be suspected. Correct initial diagnosis and definite treatment of the ruptured lesion in the acute stage is essential in dealing with SAH-patient with multiple aneurysms. When they are unruptured lesions at a common aneurysm site, the existence of an unusually located aneurysm should not be overlooked as the possible source responsible for symptoms.

Association of p53 gene abnormalities with tumor progression and prognosis of many neoplasms has been demonstrated, but little is known about the clinical significance of p53 abnormalities in meningiomas. The significance of p53 protein expression in recurrent meningiomas and its relationships with MDM2 protein and proliferation activity were investigated by analyzing 39 meningiomas immunohistochemically. p53 protein was expressed in 11 (35%) of 31 non-recurrent and 7 (88%) of 8 recurrent meningiomas. A high frequency of p53 expression was observed in recurrent meningiomas, which tended to have a high p53 positive index (p53 PI), indicating that p53 immunoreactivity may be a marker for predicting tumor recurrence. Four recurrent meningiomas with high p53 PIs were analyzed by the polymerase chain reaction-single strand conformation polymorphism method to detect p53 gene mutations, but none were found in exons 4-8 of this gene. Fifteen (71%) of 21 MDM2-positive and 3 (17%) of 18 MDM2-negative tumors expressed p53 protein, showing that MDM2 expression was more common in meningiomas with p53 expression. p53 immunoreactivity in the absence of mutation may indicate stabilization of the wild type through interaction with the MDM2 protein. The Ki-67/MIB-1 proliferation index (MIB-1 PI) correlated well with recurrence. The p53-positive tumors had a significantly higher mean MIB-1 PI than p53-negative tumors, suggesting that wild-type p53 inactivation by the MDM2 protein may be involved in controlling the proliferative activity in meningiomas. In conclusion, immunohistochemical examination for p53 protein as well as proliferative activity may help predict the malignant potential of tumor recurrence.

The effect of ebselen, a seleno-organic compound with antioxidant activity through a glutathione peroxidase-like action, on the outcome of acute ischemic stroke was evaluated in a multicenter, placebo-controlled, double-blind clinical trial.Patients diagnosed as having acute ischemic stroke who could receive drug treatment within 48 hours of stroke onset were enrolled. Oral administration of ebselen granules suspended in water (150 mg BID) or placebo was started immediately after admission and was continued for 2 weeks. The major end points were the Glasgow Outcome Scale scores at 1 month and 3 months after the start of treatment. The modified Mathew Scale and modified Barthel Index scores at 1 month and 3 months were also studied as secondary outcome measures.Three hundred two patients were enrolled in the trial. Intent-to-treat analysis of 300 patients (151 given ebselen and 149 given placebo) revealed that ebselen treatment achieved a significantly better outcome than placebo at 1 month (P = .023, Wilcoxon rank sum test) but not at 3 months (P = .056, Wilcoxon rank sum test). The improvement was significant in patients who started ebselen within 24 hours of stroke onset but not in those who started treatment after 24 hours. There was a corresponding improvement in the modified Mathew Scale and modified Barthel Index scores.Early treatment with ebselen improved the outcome of acute ischemic stroke. Ebselen may be a promising neuroprotective agent.

Recent studies have suggested that the nervous system may participate in inflammatory processes. Substance P (SP) acts as a chemical mediator as well as a neurotransmitter.In order to clarify the pathogenesis of ocular allergic diseases, we assessed the concentration of SP in tears.Using a highly sensitive and specific double-antibody enzyme immunoassay (EIA), we determined the SP concentration in tears of 10 patients with seasonal allergic conjunctivitis, 10 with atopic dermatitis without keratoconjunctivitis (AD), 13 with vernal keratoconjunctivitis (VKC) and 65 normal controls. Giemsa's staining for brush cytology samples and histocytological study by immunocytochemical staining of giant papillary conjunctival cells from VKC and normal controls was conducted.The mean SP level was low in the normal controls and AD, whereas patients with seasonal allergic conjunctivitis and VKC showed significant elevation of SP (P0.01). Brush cytology samples showed conjunctival epithelial cells with lymphocytes, neutrophils and eosinophils that were not seen in normal subjects. Histocytological examination demonstrated SP positive cells in the conjunctiva of patients with VKC, but not in normal controls.This study suggests that the increased level of SP in tears may contribute to the pathogenesis and severity of ocular allergic diseases.

A 47-year-old woman with branch retinal arterial occlusion treated with sodium ozagrel is described. The patient presented with acute visual field loss in her right eye. Blood tests demonstrated the elevation of β-thromboglobulin and platelet factor 4. Sodium ozagrel, a thromboxane A2 synthetase inhibitor, 160 mg daily was administered for 14 days. This treatment prevented exacerbation of retinal arterial thrombosis and produced a marked improvement in the visual field loss. Sodium ozagrel may be a useful drug in the treatment of acute retinal arterial occlusion thought to be caused by thrombosis.

The introduction of low-osmolality contrast media has improved patient tolerance to angiographic procedures. However, nonionic contrast media may be associated with an increase in the risk of clot formation. The objective of this study was to test whether there is more clotting with nonionic agents than with ionic agents.Ninety-eight patients undergoing transfemoral cerebral angiography were randomly assigned to receive ionic (ioxaglate) (n = 62) or nonionic (iopamidol or iohexol) (n = 36) contrast material. Incidence of clot formation was examined by observation of catheters.Clot formation was found in 4.8% of patients in the ionic contrast material group and 22.2% of patients in the nonionic contrast material group (P.05).Nonionic contrast media resulted in a statistically significantly higher incidence of clot formation than ionic media during cerebral catheter angiography. These results suggest that ionic contrast media are preferable in patients with risk of thrombosis.

We discussed the risk factors for stroke and ischemic heart disease (IHD) as a main atherosclerotic disease. We showed that hypertension was the most principal risk factor for both cerebral hemorrhage and cerebral infarction, and the increase of total cholesterol (TCH) was inversely related with the incidence of cerebral hemorrhage. Many of the cerebral infarctions occurred where a large number of the cerebral hemorrhages did. We indicated that the mechanism of occurrence was different between stroke and IHD. In Japan, TCH has been recognized as a risk factor for IHD as same as western countries, but there are not many IHD. The mean of TCH was lower before one or two decade. But, it has increased in the last decade, and recently is nearing the level of American people in the thirties and forties. Death statistics of IHD became more accurate in Japan by reason for revision of the death certificate form from ICD-9 to ICD-10. The recognition of IHD death statistics will be changed. Incidence of stroke has been decreasing because of the decrease of hypertension. However, we will have to reconsider a preventive measure of IHD.

We investigated the role of arginine vasopressin (AVP) in the development of diabetic nephropathy and the effect of specific vasopressin V1 receptor antagonist of 1-(1-[4-(3-acetylaminopropoxy)-benzoyl]-4-piperidyl)-3, 4-dihydro-2(1H)-quinolinone (CAS 131631-89-5, OPC-21268) on albuminuria in patients with non-insulin dependent diabetes mellitus. Basal levels of AVP in diabetic patients showing microalbuminuria were significantly high compared to diabetics without any complications, suggesting that in those patients abnormally high amounts of AVP seem to be secreted. Three-week treatment with OPC-21268 demonstrated that albuminuria significantly decreased without affecting renal function. Increased secretion of AVP may induce proliferation of renal mesangial cells and modify blood flows in the glomerular capillaries. The present data suggest that OPC-21268 may be useful for preventing the development of diabetic nephropathy, although its long-term effects should be examined. In conclusion, AVP may play a crucial role in the pathophysiology of diabetic nephropathy and that OPC-21268 seems to prevent further progression of nephropathy in non-insulin dependent diabetes mellitus.