Strontium-89 plus zoledronic acid versus zoledronic acid for patients with painful bone metastatic breast cancer.

INTRODUCTION: ß-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases. MATERIALS AND METHODS: A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13 weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates. RESULTS: Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89. CONCLUSION: This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated.

Abundant tumor infiltrating lymphocytes after primary systemic chemotherapy predicts poor prognosis in estrogen receptor-positive/HER2-negative breast cancers.

PURPOSE: The therapeutic effect of systemic treatment for breast cancer (BC) generally depends on its intrinsic subtypes. In addition, tumor infiltrating lymphocytes (TILs) are considered to be an independent factor for tumor shrinkage and disease prognosis. High TILs at baseline or after primary systemic chemotherapy are reported to be associated with better survival in triple-negative or human epithelial growth factor receptor 2 (HER2)-positive BCs. However, the prognostic value of TILs in estrogen receptor (ER)-positive and HER2-negative (ER+/HER2-) BC is still controversial. METHODS: We assessed TIL score (low, intermediate, and high) before and after primary systemic chemotherapy in every subtype of BC, and compared the clinical outcomes. Biopsy specimens of 47 triple-negative, 58 HER2+ and 91 ER+/HER2- BCs were used to assess TILs before treatment. To assess TILs after treatment, we examined residual invasive carcinoma in surgically resected samples of 28 triple-negative, 30 HER2+ and 80 ER+/HER2- BCs. RESULTS: A high TIL score in triple-negative BC before treatment resulted in a significantly higher proportion of pathological complete response (pCR). In contrast, ER+/HER2- BC exhibited fewer instances of pCR than other subtypes. Although not statistically significant, ER+/HER2- cases with a high TIL score also tended to achieve pCR (p = 0.088). Moreover, we revealed that low TIL BCs after chemotherapy, but not at baseline, had significantly better relapse-free survival in ER+/HER2- BC (p = 0.034). CONCLUSION: Pathological examination of TILs after treatment may be a surrogate marker for prognosis in ER+/HER2- BC.

Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung.

BACKGROUND: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. METHODS: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. RESULTS: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). CONCLUSIONS: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.

Independent prognostic impact of preoperative serum carcinoembryonic antigen and cancer antigen 15-3 levels for early breast cancer subtypes.

BACKGROUND: Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. METHODS: A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. RESULTS: The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p < 0.0001) than that of CEA-low patients (n = 885, 5-year DFS 87.2%). There was a significant difference in DFS (p < 0.0001) between CA15-3-high and CA15-3-low patients (n = 314 and n = 762, respectively; 5-year DFS 71.8 vs. 89.3%). Significant associations between DFS and CA15-3 levels were observed irrespective of the subtypes. Multivariable analysis indicated that tumor size, lymph node metastasis, tumor grade, and CEA (p = 0.0474) and CA15-3 (p < 0.0001) levels were independent prognostic factors (hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.005-2.245 for CEA; HR 2.088, 95% CI 1.457-2.901 for CA15-3). CONCLUSIONS: These findings suggest that CEA and CA15-3 levels might be useful for predicting the prognosis of patients with operable early breast cancer irrespective of the subtype. Serum levels at baseline may reflect tumor characteristics for metastatic potential even when these levels are within the normal ranges.

Survival outcomes of neoadjuvant chemotherapy with zoledronic acid for HER2-negative breast cancer.

BACKGROUND: A randomized phase 2 trial in women with HER2-negative breast cancer has shown that adding zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) has potential anticancer benefits in postmenopausal and triple-negative (TN) breast cancer patients. We report the data for the secondary end point of disease-free survival (DFS). METHODS: Patients were randomly assigned to receive CT or CT + ZOL (CT-Z). All patients received four cycles of FEC100 followed by 12 cycles of paclitaxel weekly. ZOL (4 mg) was administered 3-4 times weekly for 7 wk to the CT-Z group patients. The primary end point was pathologic complete response (pCR). The secondary end points were the clinical response rates, rate of breast-conserving surgery, safety, and DFS. RESULTS: Of the 188 patients enrolled, 95 were assigned to the CT group and 93 to the CT-Z group. DFS and overall survival were analyzed in 92 and 88 patients with the mean times of 5.15 y and 5.38 y, respectively. The 3-y DFS rate was 84.6% in the CT group and 90.8% in the CT-Z group (P = 0.188). The particular benefit from ZOL for the neoadjuvant CT seen as improvement of the pCR rate was indicated in the 3-y DFS period for TN cancer cases (CT versus CT-Z: 70.6% versus 94.1%) but not for postmenopausal cases. CONCLUSIONS: ZOL did not improve DFS when combined with CT. However, the improvement of the pCR rate translated to survival outcomes in TN breast cancer. The short-term application of ZOL may not be sufficient to improve the outcome in postmenopausal patients.

Erratum to: Impact of intra-abdominal absorbable sutures on surgical site infection in gastrointestinal and hepato-biliary-pancreatic surgery: results of a multicenter, randomized, prospective, phase II clinical trial.

In the original publication, the article category was published as "Review Article". The correct category should read as "Original Article".

Impact of intra-abdominal absorbable sutures on surgical site infection in gastrointestinal and hepato-biliary-pancreatic surgery: results of a multicenter, randomized, prospective, phase II clinical trial.

BACKGROUND: The use of absorbable sutures in wound closure has been shown to reduce the incidence of surgical site infection (SSI); however, there is no evidence that the intra-abdominal use of absorbable rather than silk sutures reduces the incidence of SSI after gastrointestinal surgery. We report the findings of a phase II trial, designed to evaluate the impact of the intra-abdominal use of absorbable sutures on the incidence of SSI. METHODS: At 19 Japanese hospitals, 1147 patients undergoing elective gastrectomy, colorectal surgery, hepatectomy, or pancreaticoduodenectomy (PD) were randomly assigned to absorbable or silk intra-abdominal suture groups. The primary efficacy endpoint was the incidence of SSI. The secondary efficacy endpoints were the locations of SSI, time to resolution of SSI, length of hospital stay, and the incidence of bile leakage in hepatectomy and pancreatic fistula. RESULTS: The incidence of SSI was 11.3%, 15.5%, 11.3%, and 36.9% after gastrectomy, colorectal surgery, hepatectomy, and PD, respectively. The incidence of SSI was higher in the absorbable suture group than in the silk suture group for all the surgical procedures, but the difference was not significant. CONCLUSION: The intra-abdominal use of absorbable sutures did not have enough of an effect on the reduction of SSI in this phase II trial to justify the planning of a large-scale phase III trial.

Effects of an educational intervention on oral hygiene and self-care among people with mental illness in Japan: a longitudinal study.

BACKGROUND: The oral hygiene of patients with a mental illness is an important concern in psychiatric care, and it is necessary to increase the level of self-care among these patients. In this study, we administered an oral care questionnaire to people with mental illness in Japan and compared their answers before (baseline) and at 1 week and 1, 3 and 6 months after they participated in an educational program. METHODS: The questionnaire was distributed to 390 patients. It included questions about age, education, income, between-meal snacks, number of teeth, frequency of tooth brushing, and other items. The educational program was developed for the purposes of improving self-care. RESULTS: Before the program, the proportion of male patients who had had a mental illness for ≥ 10 years was significantly higher among those patients who did not brush their teeth before bed. In addition, such patients did not have primary care dentists, and a significantly higher proportion of male patients, compared with female patients, did not undergo routine dental checkups more than once per year. The educational program resulted in an improvement in the use of fluoride toothpaste from baseline to 6 months after the intervention (p = 0.001). The daily use of interdental brushes or floss was significantly different 6 months after the intervention. CONCLUSIONS: Male and long-term inpatients need oral hygiene instructions. Our educational program showed the effects of using oral hygiene tools. Future studies should include a control group to measure the impact of the educational program.

Comparison of Number Versus Ratio of Positive Lymph Nodes in the Assessment of Lymph Node Status in Extrahepatic Cholangiocarcinoma.

BACKGROUND: This study aimed to compare the utility of the number of positive lymph nodes with the lymph node ratio (LNR) in predicting survival after resection of extrahepatic cholangiocarcinoma. METHODS: A retrospective analysis of 142 consecutive patients who underwent radical resection of extrahepatic cholangiocarcinoma was performed. A total of 3066 regional lymph nodes were resected. The median number of nodes per patient was 21. The optimal cutoff values for the number of positive nodes and the LNR were determined using the Chi square scores calculated by the Cox proportional hazards regression model. RESULTS: Nodal disease was found in 59 patients (42 %). In the subsequent analysis of the impact that nodal status has on survival, 18 patients with R1/2 resection and 6 patients with paraaortic nodal disease who did not survive for more than 5 years after resection were excluded. The optimal cutoff value for the number of positive nodes was 1, and the optimal cutoff value for the LNR was 5 %. Univariate analysis identified both the number of positive nodes (0, 1, or ≥2; P = 0.005) and the LNR (0, 0-5, or >5 %; P = 0.007) as significant prognostic factors. Multivariate analysis identified the number of positive nodes but not the LNR as an independent prognostic factor (P = 0.012). The 5-year survival rates were 64 % for the patients with no positive nodes, 46 % for the patients with one positive node, and 28 % for the patients with two or more positive nodes. CONCLUSIONS: The number of positive lymph nodes predicts survival better than the LNR after resection of extrahepatic cholangiocarcinoma, provided that nodal evaluation is sufficient.

Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

Dialysis patients' utilization of health care services covered by long-term care insurance in Japan.

Hemodialysis patients in Japan are aging and thus more patients need support for attending hemodialysis facilities. This study aimed to clarify how dialysis patients utilize the services covered by Japan's public long-term care insurance (LTCI) system. This cross-sectional study was based on LTCI data of March 31, 2009, the latest available data provided by Niigata City, located on the northwest coast of Honshu. Among 30,349 LTCI users in Niigata City, there were 234 dialysis patients. To clarify the characteristics of the dialysis patients, we compared the utilization of LTCI services between the dialysis patients (234 users) and randomly selected 765 non-dialysis users. We also calculated the annual transportation service costs per patient for dialysis patients who continued home care (home care group) and those who switched to long-term hospital care at LTCI care levels 4 and 5 (hospital admission group). These care levels indicate difficulty in walking or maintaining a sitting posture without assistance. The dialysis group more frequently utilized home care and equipment services, such as renting or purchasing care-support products and support for home equipment repair, and utilized facility services and short-stay services (respite care) less frequently (both p < 0.001). Cost per patient was higher in the home care group than in the hospital admission group, because the transportation services for dialysis patients at care levels 4 and 5 involve higher costs. These findings indicate that LTCI services usable for dialysis patients were limited. Therefore, instead of merely subsidizing transportation expenses, transportation services must be improved.

Characteristics linked to the reduction of stigma towards schizophrenia: a pre-and-post study of parents of adolescents attending an educational program.

BACKGROUND: The stigma of schizophrenia constitutes a major barrier to early detection and treatment of this illness. Anti-stigma education has been welcomed to reduce stigma among the general public. This study examined the factors associated with the effectiveness of a web-based educational program designed to reduce the stigma associated with schizophrenia. METHODS: Using Link's Devaluation-Discrimination Scale to measure stigma, the effect of the program was measured by the difference in pre- and post-program tests. In the present study, we focused on program participants whose stigma towards schizophrenia had considerably improved (a reduction of three points or more between pre- and post-program tests) or considerably worsened (an increase of three points or more). The study participants were 1,058 parents of middle or high school students across Japan, including 508 whose stigma had significantly decreased after the program and 550 whose stigma had significantly increased. We used multiple logistic regression analysis to predict a considerable reduction in stigma (by three or more points) using independent variables measured before exposure to the program. In these models, we assessed the effects of demographic characteristics of the participants and four measures of knowledge and views on schizophrenia (basic knowledge, Link's Devaluation-Discrimination Scale, ability to distinguish schizophrenia from other conditions, and social distance). RESULTS: Participants' employment status, occupation, basic knowledge of schizophrenia, pre-program Link's Devaluation-Discrimination Scale score, and social distance were significant factors associated with a considerable decrease in the stigma attached to schizophrenia following the educational program. Specifically, full-time and part-time employees were more likely to experience reduced stigma than parents who were self-employed, unemployed, or had other employment status. Considerable decreases in stigma were more likely among parents working in transportation and communication or as homemakers than among other occupational groups. In addition, parents with higher pre-program levels of stigma, lower basic knowledge, or lower social distance were more likely to have reduced levels of stigma. CONCLUSIONS: Based on the regression analysis results presented here, several possible methods of reducing stigma were suggested, including increasing personal contact with people with schizophrenia and the improvement of law and insurance systems in primary and secondary industries.

Phase I/II trial of irinotecan and S-1 combination chemotherapy as a second-line treatment for advanced colorectal cancer.

BACKGROUND: This study attempted to determine the therapeutic dosage of irinotecan and S-1 (IRIS) as a second-line treatment for colorectal cancer (CRC). METHODS: S-1 was administered on days 1-14 of a 28-day cycle. Irinotecan was administered on days 1 and 15. The irinotecan dose was then escalated to determine the maximum-tolerated dose and the recommended dose at a fixed dosage of S-1 (80 or 65 mg·m(-2)·day(-1)). The S-1 dose was reduced to 65 mg·m(-2)·day(-1) when dose-limiting toxicities were observed at 80 mg·m(-2)· day(-1) and the irinotecan dose was increased. RESULTS: The recommended dose was 65 mg/m(2) for S-1 and 75 mg/m(2) for irinotecan. Twenty-one patients were treated at the recommended dose. The overall response rate was 28.6%. CONCLUSION: This modified IRIS regimen is considered effective with acceptable toxicities for advanced CRC resistant to treatment with 5-fluorouracil/leucovorin or uracil and tegafur/leucovorin.

Assessment of the nodal status in ampullary carcinoma: the number of positive lymph nodes versus the lymph node ratio.

BACKGROUND: This study was intended to compare the prognostic power of the number of positive lymph nodes with that of the lymph node ratio in patients with ampullary carcinoma. METHODS: A retrospective analysis was conducted of the medical records of 71 consecutive patients with ampullary carcinoma who underwent pancreaticoduodenectomy with regional lymph node dissection. A total of 2151 lymph nodes were dissected (median: 28 nodes per patient) and examined histologically. Cutoff points were determined for both the number of positive nodes and the lymph node ratio using χ(2) scores calculated with the Cox proportional hazards regression model. RESULTS: Lymph node metastasis was found in 34 patients. The best cutoff point for the number of positive nodes was identified as three nodes, and that for the lymph node ratio was identified as 10%. Univariate analysis revealed both the number of positive nodes (0, 1-3, or ≥ 4; P < 0.0001) and the lymph node ratio (0%, 0-10%, or >10%; P < 0.0001) as significant prognostic factors. Multivariate analysis identified the number of positive nodes as an independent prognostic factor (P < 0.001), whereas the lymph node ratio failed to remain as an independent variable. The cumulative 5-year survival rates were 85% for patients with 0 positive nodes, 63% for patients with 1-3 positive nodes, and 0% for patients with ≥ 4 positive nodes (P < 0.0001). CONCLUSIONS: The number of positive lymph nodes better predicts the outcome after resection than the lymph node ratio in patients with ampullary carcinoma.

Effect of an education program on improving knowledge of schizophrenia among parents of junior and senior high school students in Japan.

BACKGROUND: Early detection and intervention in schizophrenia are important in improving quality of life after treatment and are major issues in psychiatric care. Therefore, it is necessary to increase knowledge of schizophrenia among the general public. Among parents of junior and senior high school students in Japan, we compared rates of correct answers for items on knowledge of schizophrenia and ability to discriminate this psychosis from other disorders on questionnaires given before and after viewing a web-based education program. METHODS: Questionnaires were distributed to 2,690 parents. The program was developed to help parents obtain a basic understanding of schizophrenia and to emphasize the necessity of early detection. RESULTS: Before the program, the rate of correct answers was 77% for items concerning basic knowledge of schizophrenia, 47% for "discrimination of schizophrenia symptoms," and 30% for "discrimination of prodromal symptoms." The program resulted in an improvement in basic knowledge of schizophrenia, discrimination of schizophrenia symptoms, and discrimination of prodromal symptoms (P < 0.001 for all). CONCLUSIONS: Our web-based education program was useful in helping parents acquire a basic knowledge of schizophrenia and discriminate correctly the symptoms of schizophrenia.

Alcohol consumption as a risk factor for esophageal adenocarcinoma in North China.

The incidence of esophageal adenocarcinoma has been rising in many countries, while esophageal squamous cell carcinoma has remained stable or even declined in the same populations over the identical periods. These differences in trends indicate that these cancer subtypes may have a different etiology, which may be caused by lifestyle factors such as alcohol consumption and cigarette smoking. Therefore, a matched case-control study to clarify the risk factors of alcohol and tobacco intake on the development of esophageal adenocarcinoma was collected in Hebei Province of China. The life expectancy of the study area was around 70 years old. In the present study, 98 patients younger than 65 years who were diagnosed with esophageal adenocarcinoma and had initial surgeries (cases) were matched with 294 healthy adults (controls) at a ratio of 1:3 according to sex and age. We found the proportions of drinkers and smokers among cases were 48.0% and 60.2%, respectively, versus 21.2% and 43.5% among controls. Univariate conditional logistic regression analyses revealed that the odds ratios (ORs) showed a nearly monotonic increase for the duration of alcohol consumption and duration of tobacco smoking. Multivariate conditional logistic regression analysis indicated that only alcohol consumption was a significant risk factor for esophageal adenocarcinoma. Additional analysis of the combination of amount and duration of alcohol consumption indicated that heavy drinkers (> 30 ml/day) had significantly higher ORs, irrespective of the duration of alcohol consumption. In conclusion, heavy alcohol consumption increases the risk for esophageal adenocarcinoma independent of the duration of such consumption.

Programs for calculating the statistical powers of detecting susceptibility genes in case-control studies based on multistage designs.

MOTIVATION: A two-stage association study is the most commonly used method among multistage designs to efficiently identify disease susceptibility genes. Recently, some SNP studies have utilized more than two stages to detect disease genes. However, there are few available programs for calculating statistical powers and positive predictive values (PPVs) of arbitrary n-stage designs. RESULTS: We developed programs for a multistage case-control association study using R language. In our programs, input parameters include numbers of samples and candidate loci, genome-wide false positive rate and proportions of samples and loci to be selected at the k-th stage (k=1,..., n). The programs output statistical powers, PPVs and numbers of typings in arbitrary n-stage designs. The programs can contribute to prior simulations under various conditions in planning a genome-wide association study.

A stochastic model of neuronal growth cone guidance regulated by multiple sensors.

Neuronal growth cones migrate directionally under the control of axon guidance molecules, thereby forming synapses in the developing brain. The signal transduction system by which a growth cone detects surrounding guidance molecules, analyzes the detected signals, and then determines the overall behavior remains undetermined. In this study, we describe a novel stochastic model of this behavior that utilizes multiple sensors on filopodia to respond to guidance molecules. Overall growth cone behavior is determined by using only the concentration gradients of guidance molecules in the immediate vicinity of each sensor. The detected signal at each sensor, which is treated as a vector quantity, is sent to the growth cone center and then integrated to determine axonal growth in the next step by means of a simple vector operation. We compared the results of computer simulations of axonal growth with observations of actual axonal growth from co-culture experiments using olfactory bulb and septum. The probabilistic distributions of axonal growth generated by the computer simulation were consistent with those obtained from the culture experiments, indicating that our model accurately simulates growth cone behavior. We believe that this model will be useful for elucidating the as yet unknown mechanisms responsible for axonal growth in vivo.

[Relationship between asthma severity and age at onset in Japanese adults].

BACKGROUND: The relationship between age at onset of adult asthma and asthma severity has not been comprehensively investigated. METHODS: A total of 4161 patients with asthma (1578 men) aged 16 years or older were classified into 4 groups according to their age at asthma onset: group A (16-19 years), group B (20-39 years), group C (40-59 years), and group D (>60 years). We examined the relationship between the age at onset and severity of asthma among the 4 groups and analyzed factors associated with asthma severity. RESULTS: The severity of asthma rose with increasing age at onset, and vice-versa. Factors associated with severity of adult onset asthma were analyzed using multiple regression analysis. Asthma duration, total serum IgE level, smoking status, and age at onset were strongly associated with asthma severity. Age at onset was independently associated with the severity of adult-onset asthma. CONCLUSION: Our findings indicate that asthma severity is positively associated with age at onset in patients with adult-onset asthma.

[Total and specific IgE levels in adolescents and adults with bronchial asthma].

BACKGROUND: The prevalence of elevated total and specific IgE antibody levels among Japanese adults with bronchial asthma has not been comprehensively investigated. We examined the prevalence of IgE levels in patients with asthma, and analyzed factors that are associated with elevated levels of IgE. METHODS: A total of 5067 patients with asthma (2047 were men) aged 16 or older and who had visited our clinic during a recent 9-year period (1997 through 2005) were classified into 4 birth period (groups, G) according to their year of birth: G1 (before 1926), G2 (1926 to 1945), G3 (1946 to 1965), and G4 (after 1965). First, we investigated the prevalence of elevated total IgE level (> or = 300 IU/mL) and the prevalence rates of specific IgE antibodies to house dust mites (mite), cedar pollen (cedar), and Candida albicans (Candida). Then, we investigated trends in the prevalence of antibodies among the 4 age groups during a 9-year period. RESULTS: 1. The prevalence of elevated levels of total IgE and specific IgE antibodies to mites and cedar pollen significantly increased in ascending order from G1 to G4. 2. Compared with women, men had a significantly higher prevalence of elevated levels of total IgE and specific IgE antibodies to mites, cedar pollen, and Candida. 3. Compared with never smokers, current smokers had a significantly higher prevalence of elevated levels of total IgE and specific IgE antibodies to mites, cedar pollen, and Candida. 4. During the 9-year period, the prevalence of elevated levels of total IgE and specific IgE antibodies to mites and Candida significantly decreased in the G2, G3, and G4 groups. 5. Multiple logistic regression analysis revealed that elevated levels of total IgE and specific IgE antibodies to Candida were significantly associated with younger age, male gender, and smoking. Elevated levels of mite-specific IgE were associated with age and gender, and elevated levels of cedar-specific IgE were associated with gender, age, and generation. CONCLUSION: Gender, age, generation, and smoking status were associated with elevated levels of total and specific IgE antibodies to mites, cedar pollen, and Candida in patients with asthma; however, the degree of association varied.