Potential curing and beneficial effects of Ooitabi (Ficus pumila L.) on hypertension and dyslipidaemia in Okinawa.

BACKGROUND: Over 30% of the population of Okinawa Prefecture have a high body mass index. The incidence of hypertension and dyslipidaemia has also increased in recent years. We found that Ooitabi (Ficus pumila L.), a plant native to Okinawa, was useful for hypertension. During ancient times, the extracts of Ooitabi leaves were used for making Ishimaki tea in some areas of Okinawa Prefecture. The plants in Okinawa are rich in antioxidants, and four flavonoid glycosides, including rutin, have been identified in Ooitabi. METHODS: In the present study, we conducted clinical verification tests on the effects of drinking Ishimaki tea on outpatients with hypertension and dyslipidaemia. Of 3814 Japanese patients who underwent medical check-ups in Okinawa, 38 individuals with high blood pressure, dyslipidaemia, liver dysfunction and gout visited our hospital as outpatients and were asked to drink Ishimaki tea. RESULTS: After 3 months, there were significant reductions in body mass index, systolic and diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, γ-glutamyltrans peptidase, uric acid and ratio of blood vessel insulin resistance. CONCLUSIONS: Ooitabi extract can lower blood pressure and improve lipid abnormalities and has likely contributed to the well-known health and longevity of the population in Okinawa.

Validation of the Japanese version of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities.

BACKGROUND: Dementia in people with intellectual disabilities (IDs) is difficult to detect because of preexisting cognitive deficits. An effective screening method is required. The Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) was developed as an observer rating tool to screen dementia in people with ID. The aim of this study was to verify the screening accuracy of the DSQIID for Japanese people with ID. METHODS: Four-hundred ninety-three subjects with ID participated in this study. Caregivers who had observed the participants for more than 2 years scored the Japanese version of the DSQIID (DSQIID-J) of the participants. Three doctors examined participants directly and diagnosed dementia using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. To identify the key screening items that predict dementia, the specificities of a single and pairs of items with 100% sensitivity were evaluated relative to the dementia diagnosis. RESULTS: Of 493 participants, 34 were people with Down syndrome (DS), and 459 were people without DS. Seventeen participants were diagnosed with dementia. The suitable cut-off score of the DSQIID-J was 10/11 (sensitivity 100% and specificity 96.8%) for screening dementia. The inter-rater reliability, test-retest reliability and internal consistency of the DSQIID-J were excellent. Regarding key items, there was no single item with 100% sensitivity, and the best two-item combination was the pair of 'Cannot dress without help' and 'Walks slower' (sensitivity 100% and specificity 93.5%). CONCLUSIONS: We identified several important question items of the DSQIID-J related to the diagnosis of dementia in people with ID. The DSQIID-J is a useful screening tool for dementia in adults with ID.

The Relationship between Psychotropic Drug Use and Suicidal Behavior in Japan: Japanese Adverse Drug Event Report.

Introduction: Very few studies have explored the adverse effect of psychotropic drugs worldwide. Methods: This study analyzed 1 813 suicide-related drug reports involving 553 patients collected from the Japanese National Adverse Drug Report Database between October 2001 and January 2012 to investigate psychotropic drugs associated with completed suicide vs. other suicide-related behaviors, including ideation and self-injury. The drugs investigated included antidepressants, antipsychotics, benzodiazepines, non-benzodiazepine hypnotic agents, noradrenergic and specific serotonergic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and other drugs. Results: These reports referenced 300 (54.2%) individuals who completed suicide. Adjusting for age, sex, and drugs used, the multivariate model revealed that participants who took antipsychotics were 1.70 times (95% CI, 1.11-2.61) more likely to complete suicide compared with those who did not. All other drugs became non-significant. Compared with those who took only one medication, those prescribed more than 4 drugs were more likely to complete suicide (OR 4.44, 95% CI, 2.40-8.20). Discussion: Antipsychotic drugs and polypharmacy may be regarded as predictors of completed suicide.

Self-awareness of fast eating and its impact on diagnostic components of metabolic syndrome among middle-aged Japanese males and females.

OBJECTIVE: The aim of the present study was to examine the association between subjects with self-awareness of fast eating and diagnostic components of metabolic syndrome in Japanese middle-aged male and female. PATIENTS AND METHODS: Subjects consisted of 3208 males (average age 50.6 years) and 2055 females (average age 50.0 years). Associations between subjects with self-awareness of fast eating and multiple components of metabolic syndrome (waist circumference, body mass index [BMI], blood pressure, and related blood sample tests) were evaluated. RESULTS: Significantly more males (57.7%) acknowledged themselves as "fast eater" than females (46.5%). Self-reported fast eaters showed significantly elevated body weight, BMI, and waist circumference in both genders. However, only male self-reported fast eaters showed high levels of blood pressure, fasting blood glucose, uric acid, and low-density lipoprotein (LDL)-cholesterol. CONCLUSION: Fast eating is associated with diagnostic components of metabolic syndrome. The effect of acknowledging themselves as fast eater presents a higher impact on males than on females in the middle-aged Japanese population. The present study indicates that finding subjects with self-awareness of fast eating may lead to the prevention of developing metabolic syndrome.

Expression and mutation of SMAD4 in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum.

Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.

Mutational analysis of TGF-beta type II receptor, Smad2, Smad3, Smad4, Smad6 and Smad7 genes in colorectal cancer.

Transforming growth factor-beta(TGF-beta) is known to play an important role in controlling embryonal development, cell proliferation and homeostasis. The purpose of this study is to elucidate the involvement of the TGF-beta pathway in colorectal carcinogenesis. DNA was extracted from 100 patients with colorectal cancer. Then, all coding regions of the TGF-beta type II receptor (TRII) and the genes for Smad2, Smad3, Smad4, Smad6, and Smad7 were analyzed by PCR-SSCP and direct sequencing. Also, a LOH analysis of 18q21, where the Smad2 and Smad4 genes are located, was performed. We detected 11 cases of frameshift mutation in the TRII gene (11%) and 5 cases of point mutations in the Smad4 gene (5.0%); LOH at 18q21 was detected with 33% frequency. No abnormalities were found in the genes for Smad2, Smad3, Smad6, and Smad7. These results suggest that the abnormalities of TRII and Smad4 play an important role inhibiting TGF-beta signaling in colorectal carcinogenesis.

Video-assisted parathyroidectomy.

A parathyroid tumor is not larger than other tumors, so minimally invasive surgery has long been a major focus of parathyroid surgeons. Improving endoscopic instruments has facilitated the recent changes in approaches to parathyroid surgery. Endoscopic parathyroidectomy is developed in a totally closed space with CO2 gas insufflation. This method has a risk of complications, such as extensive emphysema or hypercarbia. Minimally invasive video-assisted parathyroidectomy (MIVAP) has greater safety, low cost, easy procedure and flexibility in changing the working space including conversion to open method when compared with endoscopic parathyroidectomy. MIVAP can be performed with only a 1-1.5-cm small incision on the neck. MIVAP is indicated in the patient with parathyroid adenoma or renal hyperplasia that is defined preoperatively using ultrasonography and 99mTc-methoxyisobutylisonitrile (MIBI) scan. Furthermore, the radio-guided technique using nuclear navigation after preoperative administered MIBI is being developed. This method is so useful during MIVAP that we combined MIVAP and radio-guided surgery to develop minimally invasive radio-guided and video-assisted parathyroidectomy (MIRVAP). After injection of 600 MBq of MIBI, intraoperative nuclear mapping was performed using a hand-held gamma probe. Then we expected to find swollen parathyroid tumor at surgery when radioactivity at a level relatively higher than background was found. Following this mapping result, MIVAP was started and succeeded. The radio-guided technique is also indicated for open parathyroidectomy (radio-guided open parathyroidectomy, RGOP) in multiglandular disease (MGD) when it was not possible to identify those lesions completely, for instance in asymmetric hyperplasia, such as multiple endocrine neoplasia (MEN) 1. In conclusion, MIVAP is beneficial for minimal invasiveness and cosmesis. Furthermore, radio-guided parathyroidectomy (MIRVAP and RGOP) is more useful and feasible. Improvement of endoscopic instruments and modification of the dose of MIBI administered might facilitate treating more cases by MIRVAP instead of RGOP.

Microsatellite instability in thyroid cancer: hot spots, clinicopathological implications, and prognostic significance.

PURPOSE: To determine whether microsatellite instability (MSI) in particular loci has clinicopathological significance in thyroid cancer. EXPERIMENTAL DESIGN: Seventy-six cases of surgically resected thyroid cancer were screened for MSI at nine microsatellites: THRA1, TSHR, D2S123, D11S912, D2S115, D2S399, p53, RET, or BAT-26. Multivariate analysis was performed to test for links between MSI and the clinical parameters of gender, age, histology, stage, nodal involvement, and prognosis. RESULTS: THRA1, residing in the thyroid hormone receptor alpha gene, displayed the highest levels of MSI at 36.5%. MSI in TSHR, located within the thyroid-stimulating hormone receptor gene, was found to be linked to cancer in the elderly (>70 years of age) and with high-grade (N 3, 4) nodal involvement. In follicular cancer, MSI in D2S123 occurred at a frequency of 100% (7/7) with no (0%) occurrence of MSI at the nearby D2S115, D2S399, or BAT-26 loci. Regarding prognosis, patients with MSI-positive cancer showed better long-term survival. BAT-26, which is an important marker in colorectal cancer, displayed the lowest frequency of MSI in our panel of thyroid tumors. CONCLUSION: Whereas patients with MSI-positive cancer showed better long-term survival, as is the case for colorectal cancer, our finding of the low frequency of MSI in BAT-26 suggests that the biochemical defects governing the spectrum of MSI in thyroid and colorectal cancer are different. MSI in THRA1, TSHR, and D2S123 appears to be an integral part of thyroid carcinogenesis, as evidenced by the high frequency of MSI and significant correlation to clinical data.

[Intermittent administration of 5-FU and isovorin to patients with advanced and recurrent colon cancer].

We attempted a new regimen of intermittent administration of 5-FU and low-dose Isovorin (F.I) to four patients with advanced and recurrent colon cancer. A partial response (PR) was achieved in two of four patients who had evaluable lesions for this treatment. We observed few side effects among these patients. Only one patient among four showed grade 1 neuropathy after two administrations of this chemotherapy. However, after a two-week pause in administration, the neuropathy disappeared and we could continue the therapy. This patient with multiple liver metastases achieved a partial response. Other patients had no side effects such as bone marrow suppression or digestive symptoms. This intermittent F.I treatment might be an effective and promising therapy with few side effects even for patients with poorer conditions.

[Clinical experience of intermittent administration of 5-FU and CDDP to patients with advanced and recurrent gastric cancer].

We administered 5-FU and CDDP (FP) intermittently to four patients with advanced and recurrent gastric cancer. A minor response (MR) and partial response (PR) were achieved in two of four patients who had evaluable lesions for this treatment, and few side effects were observed. Only one patient among six showed grade 2 leucocytopenia after 15 administrations of this chemotherapy, when she had attained a partial response in a lung metastasis. The other patients had no side effects such as bone marrow suppression or digestive symptoms. This intermittent FP treatment may be an effective and promising therapy with few side effects even for the patients with serious conditions.

Mutational analysis of the Smad6 and Smad7 genes in hepatocellular carcinoma.

Resistance to the transforming growth factor-beta (TGF-beta) is a frequently found phenotype in human malignancies. The recent identification of Smad6 and Smad7, both anti-Smads which inhibit TGF-beta signaling, raises a possibility that constitutive activation of the anti-Smads by a somatic mutation may impair the TGF-beta signaling pathway. We tested this hypothesis by screening the entire coding sequences of these anti-Smads for mutations in 52 hepatocellular carcinoma (HCC) samples using polymerase chain reaction - single strand conformation polymorphism analysis. We detected no mutations, but found 3 single nucleotide polymorphisms (SNPs) in the Smad6 gene and 2 SNPs in the Smad7 gene. These results suggest that mutations of the Smad6 and Smad7 genes are not the main cause of the TGF-beta resistance in human HCC.

Computer-assisted complete three-dimensional reconstruction of the mammary ductal/lobular systems: implications of ductal anastomoses for breast-conserving surgery.

BACKGROUND: The intraductal spread of breast carcinoma can occur along the mammary ductal/lobular systems (MDLS) with no invasion of tissues. Because ductal anastomoses in the MDLS are considered to be a possible risk factor for extensive intraductal spread of breast carcinoma, the architecture of the MDLS has important therapeutic implications for patients treated with breast-conserving surgery. METHODS: An entire breast resected by subcutaneous mastectomy from a 69-year-old woman with ductal carcinoma in situ (DCIS) was examined in submacroscopic sections by stereomicroscopic and histologic techniques. Serial 2-mm sections underwent computer-assisted complete three-dimensional reconstruction of all MDLS. RESULTS: The entire breast that was studied contained 16 MDLS that were arranged radially, with the nipple at the center. Of these 16 MDLS, 4 (25.0%) had ductal anastomoses whereas the remaining 12 MDLS had no ductal anastomoses and completely independent regional anatomy. Ductal anastomoses were observed at 11 sites in the 4 MDLS. The 2 of 11 ductal anastomoses that connected different MDLS (18.2%) were situated > 4 cm from the nipple. The remaining nine ductal anastomoses connected ducts within the same MDLS; their location varied from near the nipple to the peripheral region. In the specimen examined, DCIS extended only within a single MDLS and did not spread between different MDLS via ductal anastomoses. CONCLUSIONS: To the authors' knowledge, the current study is the first time the complete architecture of all MDLS in an entire breast has been studied three-dimensionally. The risk of promoting the intraductal spread of disease during surgery may be greater when intraductal lesions extend more peripherally than centrally. The features of ductal anastomoses may provide a significant anatomic clue regarding negative surgical margins in breast-conserving surgery.

Heterogeneity of the signal transduction pathways for VEGF-induced MAPKs activation in human vascular endothelial cells.

Vascular endothelial growth factor (VEGF) activates ERK and p38 MAPK in endothelial cells (ECs). The present study was aimed to compare its intracellular signal transduction pathways between three primary cultures of human ECs including human aortic ECs (HAECs), human umbilical vein ECs (HUVECs), and human microvascular ECs (HMVECs). VEGF activated ERK and p38 MAPK in all of three ECs. Isoforms of p38 MAPK that were activated by VEGF in HUVECs were p38-alpha and p38-delta. GF109203X, a specific inhibitor of PKC, markedly inhibited VEGF-induced activation of ERK and p38 MAPK in HAECs and HUVECs, whereas it exhibited little effect in HMVECs. In contrast, dominant negative mutant of Ha-Ras almost completely abrogated VEGF-induced activation of ERK and p38 MAPK in HMVECs. Although dominant negative mutant of Ha-Ras substantially inhibited the basal activities of ERK and p38 MAPK, it exhibited marginal effect on VEGF-induced activation of ERK and p38 MAPK in HUVECs and HAECs. The activation of Ras by VEGF appeared to be most prominent in HMVECs. These results indicate that intracellular signal transduction pathways for VEGF-induced activation of MAPKs are heterogeneous and vary depending on the origin of ECs.

Increased expression of UDP-galactose transporter messenger RNA in human colon cancer tissues and its implication in synthesis of Thomsen-Friedenreich antigen and sialyl Lewis A/X determinants.

A series of human nucleotide sugar transporters of the Golgi apparatus was recently cloned, including the transporters for UDP-galactose (UDP-Gal), UDP-N-acetylglucosamine (UDP-GlcNAc) and CMP-sialic acid (CMP-SA). We have examined the mRNA expression of these three transporters in human colon cancer tissues by reverse transcription-PCR analysis and compared it with that in nonmalignant colonic mucosa prepared from the same patients. The amount of mRNA for UDP-Gal transporter was significantly increased in colon cancer tissues compared with nonmalignant mucosa tissues (P = 0.035; n = 20). The increase was more prominent in patients with advanced colorectal cancer of Dukes' stages C and D, in which the amount of UDP-Gal transporter mRNA in cancer tissues showed on average about a 3.6-fold increase over the paired nonmalignant mucosa (statistically significant at P = 0.004; n = 14). The mRNA content of the other two transporters showed no significant difference between the paired cancer and normal tissues. When UDP-Gal transporter cDNA was stably transfected to cultured human colon cancer cells, the expression of Thomsen-Friedenreich (TF) antigen and of sialyl Lewis A (NeuAcalpha2-->3Galbeta1-->3[Fucalpha1-->4]GlcNAcbeta1-->R) and sialyl Lewis X (NeuAcalpha2-->3Galbeta1-->4[Fucalpha1-->3]GlcNAcbeta1-->R) determinants was significantly induced on transfectant cells, which resulted in markedly enhanced cell adhesion to vascular E-selectin. These findings suggest that the increase of UDP-Gal transporter mRNA is involved in the enhanced expression of cancer-associated carbohydrate determinants such as TF and sialyl Lewis A/X antigens in colon cancers.

Sentinel node biopsy with technetium-99m colloidal rhenium sulphide in patients with breast cancer.

BACKGROUND: Sentinel node biopsy is emerging as a technique to replace routine axillary lymph node dissection. The lymphatic mapping technique is still at a developmental stage and no standard technique exists. This study used technetium-99m colloidal rhenium sulphide with a mean particle size of 100 (range 50-200) nm for sentinel node mapping. METHODS: Eighty-seven patients with breast cancer, but no clinical evidence of axillary metastasis, were studied. One day before operation technetium-99m colloidal rhenium sulphide was injected at four points into breast tissue surrounding the tumour. Lymphoscintigraphy was performed 2 h after injection, and surgery was usually performed after 20 h. A hand-held gamma probe guided sentinel node biopsy. RESULTS: Lymphoscintigraphy revealed axillary hot spots in all patients. During operation, the sentinel node was identified in all 87 patients (100 per cent). The number of sentinel nodes per patient ranged from 1 to 5 (mean 2). Metastatic sentinel nodes were identified in 37 of 87 patients. There were no false negatives. CONCLUSION: This study suggests that technetium-99m rhenium sulphide is a suitable agent for sentinel node mapping in patients with breast cancer.

Giant mammary hamartoma diagnosed by stereomicroscopic analysis of the mammary glandular tree in an adolescent girl: report of a case.

This report describes a rare case of a giant hamartoma that developed in the right breast of a 17-year-old girl. No abnormalities were found by endocrinological studies and a well-circumscribed tumor, approximately 20 cm in diameter, was easily enucleated without bleeding during surgery, following which the bilateral breasts became nearly symmetrical. Histologic features revealed predominant fibrous stroma and scattered normal or occasionally dysplastic mammary glands without neoplastic properties. No distorted lobular structures indicating fibroadenoma characteristics were observed. Subgross and stereomicroscopic analysis of serial 2-mm-thick sections revealed mature normal lobules and predominant fibrous interstitial components. Therefore, the tumor was diagnosed as a giant hamartoma of the breast, according to the histologically non-neoplastic features and the delimited macroscopic appearance. This is a rare mammary gland disease characterized by the fact that although each of the histological components seemed to be normal, their constitution was abnormal. It appears that not only histological features but also clinical details are indispensable for the diagnosis of this disease.

Colorectal carcinogenesis.

Colorectal carcinogenesis is a multi-step process during which genetic and epigenetic events determine the transition from a normal cell to a malignant cell. In the past decade, intensive research led to the identification of two types of colorectal cancers that are distinct by their carcinogenesis process. The first group, named LOH (Loss of Heterozygosity) type, is characterized by allelic losses of tumor suppressor genes. The second group, called MSI (Microsatellite Instability) type, is characterized by genetic instability at microsatellite loci. In addition, recent studies suggest the four different signaling pathways, Wnt/Wingless pathway, K-ras pathway, TGF-beta pathway and p53 pathway, could be implicated in tumor progression. In this review we discuss the development of colorectal cancer on the basis of molecular biology and recent advances in research of the colorectal cancer.

[The evaluation of pamidronate therapy for bone metastases from breast cancer].

We devised a method to evaluate comprehensively the therapy to alleviate the pain of bone metastases from breast cancer according to the three items of bone pain and effects of analgesia and radiology. In 12 patients, we evaluated the therapeutic effect of pamidronate as an alleviative treatment for the pain of bone metastases from breast cancer. Bone pain was evaluated on a 6-grade scale, as was use of analgesics. Improvement in bone pain, in addition to improvement in use of analgesia, was evaluated as markedly improved, improved, unchanged, aggravated, no pain or undeterminable. Radiological improvement in bone lesions was evaluated as markedly improved, improved, unchanged, aggravated or undeterminable. An overall evaluation was made by combining the above two. In this evaluation method, pamidronate therapy resulted in an evaluation of markedly improved in 2 patients, improved in 5, unchanged in 4 and aggravated in 1, demonstrating that the therapy was very useful as an alleviative treatment for the pain of bone metastases from breast cancer. The evaluation method, in which pain, a subjective complaint, is combined with use of analgesics, an objective factor, and to which radiological evaluation is added for further objectively, may in the future to be applicable for evaluation of various alleviative treatments of pain of bone metastases.

Double cystic duct detected by endoscopic retrograde cholangiopancreatography and confirmed by intraoperative cholangiography in laparoscopic cholecystectomy: a case report.

A case of double cystic duct with cholecystolithiasis detected by preoperative endoscopic retrograde cholangiopancreatography and confirmed by intraoperative cholangiography which was treated successfully by laparoscopic surgery is reported. The patient was a 74-year-old woman who complained of abdominal pain in the right upper quadrant. On admission, ultrasonography revealed hyperechoic areas accompanied by obscure acoustic shadows in the gallbladder. Preoperative endoscopic retrograde cholangiopancreatography showed 2 cystic ducts; 1 branched from the common bile duct and the other from the right hepatic duct. After a diagnosis of double cystic ducts, we chose laparoscopic cholecystectomy. Intraoperative cholangiography via 1 of the cystic ducts revealed the presence of the other. We were able to perform laparoscopic cholecystectomy without any complications and the postoperative course was uneventful. This case suggests that preoperative endoscopic retrograde cholangiopancreatography and intraoperative cholangiography is required to avoid complications during laparoscopic cholecystectomy.