The relationship between anagliptin concentration showing over 80% inhibition of plasma dipeptidyl peptidase-4 activity and its protective effect against glucagon-like peptide-1 degradation.

In dipeptidyl peptidase-4 (DPP-4) inhibitors, the inhibition of plasma DPP-4 activity by 80% is considered sufficient to have an effect on glycemic control improvement through the elevation of intact glucagon-like peptide-1 (GLP-1). To clarify whether or not the 80% inhibition is sufficient to protect against GLP-1 degradation, we investigated rats with a continuous infusion of exogenous GLP-1. When GLP-1 was infused into the femoral or portal vein, the steady state active GLP-1 levels in plasma significantly increased (P<0.05) at the 80% inhibitory concentration (IC80) of anagliptin (a highly selective DPP-4 inhibitor) against plasma DPP-4 activity, compared with control. In addition, the peptide levels increased in a concentration-dependent manner at drug concentrations from IC80 to 10-fold IC80, and the levels at the 10-fold IC80 were significantly higher (P<0.05) than those at IC80. The concentration dependency on GLP-1 increment was also confirmed based on the experiment in which the endogenous active GLP-1 levels were measured after an oral carbohydrate load. These findings suggest that an almost complete inhibition (80%) of plasma DPP-4 activity was insufficient to protect GLP-1 degradation, and much higher drug concentrations such as 10-fold IC80 are necessary to potently protect GLP-1 from degradation by DPP-4 commonly present in blood and tissues.

Clinical biopsychosocial risk factors for depression in lung cancer patients: a comprehensive analysis using data from the Lung Cancer Database Project.

BACKGROUND: Various risk factors for depression in lung cancer patients have been suggested but have been examined separately in studies with relatively small sample sizes. The present study examined the biopsychosocial risk factors of depression in lung cancer patients, focusing on psychological factors in the largest patient sample reported to date. PATIENTS AND METHODS: A total of 1334 consecutively recruited lung cancer patients were selected, and data on cancer-related variables, personal characteristics, health behaviors, physical symptoms, and psychological factors were obtained. The participants were divided into groups with or without depression using the Hospital Anxiety and Depression Scale. RESULTS: Among the recruited patients, 165 (12.4%) manifested depression. The results of a binary logistic regression analysis were significant (overall R2, 36.5%), and a greater risk for depression was strongly associated with psychological factors, such as personality characteristics (neuroticism) and coping style (low fighting spirit, helplessness/hopelessness, and anxious preoccupation). Although the contributions of cancer-related variables, personal characteristics, health behaviors, and clinical state were relatively low, cancer stage, cancer type, sex, and age correlated significantly with depression. CONCLUSION: Depression was most strongly linked with personality traits and coping style, and using screening instruments to identify these factors may be useful for preventive interventions.

Adiposity in female B6C3F1 mice continuously irradiated with low-dose-rate gamma rays.

Abstract We previously reported significant increases in body weight in B6C3F1 mice continuously exposed to low-dose-rate (21 mGy/day) gamma rays compared to that of nonirradiated control mice (Tanaka et al., Radiat. Res. 167, 417-437, 2007). To further study the underlying cause of the increase in body weight, feed consumption, adipose tissue weight, liver and serum lipid contents, and selected factors related to glucose and lipid metabolism such as serum levels of insulin and adipocytokines were examined in female B6C3F1 mice irradiated continuously with gamma rays at 20 mGy/day in group-housed or individually housed rearing conditions. Increased body weight, adipose tissue weight, serum levels of leptin, and lipid contents of the liver and serum were observed in both group-housed (accumulated dose = 6 Gy, 43 weeks from start of irradiation) and individually housed (accumulated dose = 4.4 Gy, 31 weeks from start of irradiation) irradiated mice compared to nonirradiated controls. Feed consumption measurements, however, revealed no significant difference between irradiated mice and nonirradiated controls when mice were housed individually. Our results show for the first time that the increase in the body weight of mice continuously irradiated with low-dose-rate gamma rays is due to adiposity with no corresponding increase in feed consumption.

Risk factors for regrowth of intracranial meningiomas after gamma knife radiosurgery: importance of the histopathological grade and MIB-1 index.

INTRODUCTION: The influence of histopathological grade and MIB-1 index of intracranial meningioma on the results of its radiosurgical management is not clear. The objective of the present retrospective study was to make an evaluation of these factors along with an analysis of other variables associated with progression-free survival after gamma knife radiosurgery (GKR). PATIENTS AND METHODS: Thirty-four intracranial meningiomas with known detailed histopathological diagnosis were analyzed. Tumors of WHO histopathological grades I, II, and III were diagnosed in 24, 3, and 7 cases, respectively. The median MIB-1 index was 1.3% (range: 0-31.9%). In 14 cases the MIB-1 index was 3.0% and more. In 26 cases the treatment was done at the time of tumor recurrence. Median volume of the neoplasm at the time of GKR was 4.1 mL (range: 0.4-43.1 mL). Median marginal dose was 12 Gy (range: 8-19 Gy). Median length of follow-up constituted 63 months (range: 19-132 months). RESULTS: Actuarial progression-free survival at 1, 3, 5, and 10 years constituted 100, 94, 83, and 58%, respectively. Histopathological grade II or III (p<0.0001), MIB-1 index 3% and more (p=0.0004), and non-skull base location (p=0.0026) of the tumor showed negative associations with progression-free survival in multivariate analyses. Actuarial progression-free survival at 5 years after GKR for benign and non-benign meningiomas constituted 100 and 45%, respectively (p<0.0001). CONCLUSION: Radiosurgery is a highly effective management option for benign intracranial meningiomas, but growth control of non-benign ones is significantly worse. It requires close neuroradiological follow-up and necessitates the search for modified treatment strategies.

Dynamics of metabolic changes in intracranial metastases and distant normal-appearing brain tissue after stereotactic radiosurgery: a serial proton magnetic resonance spectroscopy study.

The present study evaluated the dynamics of metabolic changes in intracranial metastases and distant normal-appearing brain after stereotactic radiosurgery (SRS). Forty neoplasms were evaluated with single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) both before and after treatment. From one to six examinations (median, 3) were done in each individual case during follow-up. At the time of each investigation additional (1)H-MRS was obtained from the normal-appearing brain distant from the radiosurgical target. Investigated metabolites included N-acetylaspartate (NAA), choline-containing compounds (Cho), creatine (Cr), and mobile lipids (Lip). Within the first month after SRS responded tumors showed a statistically significant increase in NAA/Cho ratio, and decrease of Cho content and Lip-to-normal brain Cr (nCr) ratio. By contrast, statistically significant metabolic alterations were not detected in stabilized tumors. Statistically significant volumetric and metabolic changes were not marked between three and 12 months after treatment in non-progressing lesions. Alternatively, decrease of NAA/Cho ratio, NAA content and Cr content, and increase in Lip/nCr ratio and Cho content were evident in progressive neoplasms, and subtle metabolic alterations could be revealed even before the increase in the lesion volume. Metabolic characteristics of normal-appearing brain distant from the radiosurgical target did not show statistically significant changes within the first year after treatment. In conclusion, additional use of serial (1)H-MRS during follow-up after SRS for intracranial metastases permits detailed evaluation of the metabolic tumor response and may be potentially helpful for early prediction of recurrence.

Corticotropin-releasing hormone receptor 1 antagonist blocks colonic hypersensitivity induced by a combination of inflammation and repetitive colorectal distension.

Gastroenteritis is one of the risk factors for developing irritable bowel syndrome (IBS). However, the precise mechanism of postinfectious IBS is still unknown. We tested the hypothesis that a combination of previous inflammation and repetitive colorectal distention (CRD) makes the colon hypersensitive and that treatment with a corticotropin-releasing hormone receptor 1 (CRH-R1) antagonist blocks this colonic hypersensitivity. Rats were pretreated with vehicle or 2,4,6-trinitrobenzene sulphonic acid (TNBS) 6 weeks before CRD. For the CRD experiment, the colorectum was distended once a day for six consecutive days. The CRH-R1 antagonist (CP-154,526, 20 mg kg(-1)) or vehicle was injected subcutaneously 30 min before CRD. Visceral perception was quantified as visceromotor response (VMR) using an electromyograph. For histological examination, the rats were killed on the last day of CRD experiment, and haematoxylin and eosin-staining of colon segments was performed. Although from the first to the third day of CRD, VMRs increased in both the vehicle-treated rats and TNBS-treated rats, they were significantly higher in TNBS-treated rats than those in vehicle-treated controls. On the fifth day of CRD, however, VMRs in the vehicle-treated rats were significantly greater than those in TNBS-treated rats. Pretreatment of rats with CP-154,526 significantly attenuated the increase in VMR induced by repetitive CRD with previous inflammation. Finally, we found that repetitive CRD and repetitive CRD after colitis induced visceral inflammation. These results indicate that a combination of previous inflammation and repetitive CRD induces visceral hypersensitivity and that a CRH-R1 antagonist attenuates this response in rats.

Low-dose gamma knife radiosurgery for cavernous sinus hemangioma: report of 3 cases and literature review.

Optimal management of cavernous sinus hemangiomas remains unclear. Total microsurgical removal of these neoplasms may be extremely difficult due to their rich vascularization. Three cases of cavernous sinus hemangioma treated with low-dose Gamma Knife radiosurgery are presented. Marginal dose varied from 10 to 13 Gy. Treatment planning and radiation dosimetry were done with a goal of conformal and selective coverage of the lesion with 50% prescription isodose line using multiisocenter technique. In all cases significant shrinkage of the neoplasm was marked at 3 months after treatment. Mean volume reduction at 12 months after radiosurgery was 60% (range: 45-75%). In all patients the shrinkage of the neoplasm was accompanied by notable improvement of the preexistent oculomotor nerve palsy. No radiosurgery-related complications were met during follow-up. In conclusion, low-dose Gamma Knife radiosurgery seems to be very effective for management of cavernous sinus hemangiomas, and can be considered as a treatment modality of choice for these lesions.

Metabolic characteristics of intracranial metastases, detected by single-voxel proton magnetic resonance spectroscopy, are seemingly not predictive for tumor response to gamma knife radiosurgery.

Metabolic characteristics of intracranial metastases, detected with proton magnetic resonance spectroscopy (1H-MRS) have known associations with clinical predictors of tumor response to radiosurgery. Therefore, it can be suspected that the metabolic profile of the neoplasm by itself might have some prognostic significance for the outcome after irradiation. Twenty-six intracranial metastases, which underwent metabolic evaluation with single-voxel 1H-MRS before gamma knife radiosurgery (GKR) and were followed for at least 3 months after treatment, were selected for retrospective analysis. The tumors most frequently originated from the lungs (9 cases), breast (7 cases), colon and rectum (5 cases). The average volume of the investigated intracranial neoplasm was 5.4+/-2.0 mL. The average marginal irradiation dose was 18.6+/-2.3 Gy. The mean follow-up after GKR constituted 8.0+/-5.5 months. Tumor response to GKR was identified in 13 cases on average 2.2+/-1.8 months after treatment. Local recurrence was marked in 10 cases on average 8.7+/-4.1 months after treatment. None of the investigated 1H-MRS metabolic parameters of intracranial metastases showed a statistically significant association with the outcome after GKR. The negative results of the present study make doubtful the predictive value of metabolic characteristics of intracranial metastases, detected with single-voxel 1H-MRS, for the outcome after radiosurgery.

Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array.

Homozygous deletions (HD) provide an important resource for identifying the location of candidate tumor suppressor genes. To identify the tumor suppressor gene in oral cancer, we employed high-resolution comparative genomic hybridization (CGH)-array analysis. We identified a homozygous loss of FAT (4q35), a new member of the human cadherin superfamily, from genome-wide screening of copy number alterations in one primary oral cancer. This result was evaluated by genomic polymerase chain reaction in 13 oral cancer cell lines and 20 primary oral cancers and Southern blot in the cell lines. We found frequent exonic HD of FAT in the cell lines (3/13, 23%) and in primary oral cancers (16/20, 80%). FAT expression was absent in these cell lines. Homozygous deletion hot spots were observed in exon 1 (9/20, 45%) and exon 4 (7/20, 35%). Moreover, loss of gene expression was identified in other types of squamous cell carcinoma. The methylation status of the FAT CpG island in squamous cell carcinomas correlated negatively with its expression. Our results identify mutations in FAT as an important factor in the development of oral cancer and indicate the importance of FATs function in some squamous cell carcinomas.

Personality traits and cancer survival: a Danish cohort study.

We conducted a population-based prospective cohort study in Denmark to investigate associations between the personality traits and cancer survival. Between 1976 and 1977, 1020 residents of the Copenhagen County completed a questionnaire eliciting information on personality traits and various health habits. The personality traits extraversion and neuroticism were measured using the short form of the Eysenck Personality Inventory. Follow-up in the Danish Cancer Registry for 1976-2002 revealed 189 incidents of primary cancer and follow-up for death from the date of the cancer diagnosis until 2005 revealed 82 deaths from all-cause in this group. A Cox proportional-hazards model was used to estimate the hazard ratios (HRs) of death from all-cause according to extraversion and neuroticism adjusting for potential confounding factors. A significant association was found between neuroticism and risk of death (HR, 2.3 (95% CI=1.1-4.7); Linear trend P=0.04) but not between extraversion and risk of death (HR, 0.9 (0.4-1.7); Linear trend P=0.34). Similar results were found when using cancer-related death. Stratification by gender revealed a strong positive association between neuroticism and the risk of death among women (Linear trend P=0.03). This study showed that neuroticism is negatively [corrected] associated with cancer survival. Further research on neuroticism and cancer survival is needed.

Sensitivity to radiation-induced apoptosis and neuron loss declines rapidly in the postnatal mouse neocortex.

Therapeutic brain irradiation can cause progressive decline in cognitive function, particularly in children, but the reason for this effect is unclear. The study explored whether age-related differences in apoptotic sensitivity might contribute to the increased vulnerability of the young brain to radiation. Postnatal day 1 (P1) to P30 mice were treated with 0-16 Gy whole-body X-irradiation. Apoptotic cells were identified and quantified up to 48 h later using the TdT-UTP nick end-labelling method (TUNEL) and immunohistochemistry for activated caspase-3. The number of neuron-specific nuclear protein (NeuN)-positive and -negative cells were also counted to measure neuronal and non-neuronal cell loss. Significantly greater TUNEL labelling occurred in the cortex of irradiated P1 animals relative to the other age groups, but there was no difference among the P7, P14 and P30 groups. Irradiation decreased the %NeuN-positive cells in the mice irradiated on P1, whereas in P14 animals, irradiation led to an increase in the %NeuN-positive cells. These data demonstrate that neocortical neurons of very young mice are more susceptible to radiation-induced apoptosis. However, this sensitivity decreases rapidly after birth. By P14, acute cell loss due to radiation occurs primarily in non-neuronal populations.

Evaluation of clinical and serological data from Taenia solium cysticercosis patients in eastern Inner Mongolia Autonomous Region, China.

Neurocysticercosis (NCC) is one of the major causes of neurological disease in China. ELISA and immunoblotting using glycoproteins purified by preparative isoelectric focusing were used to detect human cysticercosis in Tongliao area, Inner Mongolia, China in 1998. Approximately 89% (39 of 44 inpatients and outpatients with suspected NCC at Tongliao City Hospital) were residents of Inner Mongolia. About 53% were male and 77% were of working age (18-59 years), and 32% were farmers. Immunoblotting and ELISA showed a high correlation. Of the 44 patients, 31 positive by cerebral computed tomography (CT) scan were confirmed serologically to have cysticercosis. In the ELISA, patients with no lesions by CT scan had lower OD values, similar to those of normal serum. These findings confirm that both ELISA and immunoblotting assays are sufficiently sensitive to detect asymptomatic or symptomatic cysticercosis patients.

Kinetic pathway to double-gyroid structure.

We have investigated the structural development during order-order transitions to the double-gyroid (DG) phase of nonionic surfactant/water systems based on two-dimensional small-angle x-ray scattering patterns from highly oriented ordered mesophases. The lamellar (L) to DG transition proceeds through two intermediate structures, a fluctuating perforated layer structure having ABAB stacking and a hexagonal perforated lamellar structure with ABCABC stacking (HPLABC). For a hexagonally packed cylinder (H) to DG transition, we also observed the HPLABC structure as the intermediate phase, thus the HPLABC is an entrance structure for the DG phase. The hexagonal perforated lamellar (HPL) structure consists of hexagonally packed holes surrounded by the planar tripods, and the transition from HPL structure to the DG phase proceeds by rotation of the dihedral angle of connected tripods. A geometrical consideration shows that large deformations of HPL planes are necessary to form the DG structure from the HPLABC structure, whereas the transition from a HPL structure with ABAB stacking (HPLAB) to the DG structure is straightforward. In spite of the topological constraints, the HPLABC structure is observed in the kinetic pathway to the DG structure.

Personality and cancer survival: the Miyagi cohort study.

We tested the hypothesis that personality plays a role in cancer outcome in a population-based prospective cohort study in Japan. In July 1990, 41 442 residents of Japan completed a short form of the Eysenck Personality Questionnaire-Revised and a questionnaire on various health habits, and between January 1993 and December 1997, 890 incident cases of cancer were identified among them. These 890 cases were followed up until March 2001, and a total of 356 deaths from all causes was identified among them. Cox proportional-hazards regression was used to estimate the hazard ratio (HR) of death according to four score levels on each of four personality subscales (extraversion, neuroticism, psychoticism, and lie), with adjustment for potential confounding factors. Multivariable HRs of deaths from all causes for individuals in the highest score level on each personality subscale compared with those at the lowest level were 1.0 for extraversion (95% CI=0.8-1.4; Trend P=0.73), 1.1 for neuroticism (0.8-1.6; Trend P=0.24), 1.2 for psychoticism (0.9-1.6; Trend P=0.29), and 1.0 for lie (0.7-1.5; Trend P=0.90). The data obtained in this population-based prospective cohort study in Japan do not support the hypothesis that personality is associated with cancer survival.

Static and dynamic structures of spherical nonionic surfactant micelles during the disorder-order transition.

We have investigated the static and dynamic structures of nonionic surfactant micelles, a C(12)E(8)/water binary system, during the disorder-order transition using small angle x-ray scattering, static light scattering, and dynamic light scattering techniques. In the disordered phase, the micelles have spherical shape and intermicellar interactions are governed by the hard core and weak long ranged attractive potentials. With increase of the micellar concentration, the disordered micelles transform to the three characteristic ordered micellar phases, a hexagonally close packed lattice, a body centered cubic lattice, and an A15 lattice having area-minimizing structure. The stability of these phases is well explained by balance of a close packing rule and a minimal-area rule proposed by Ziherl and Kamien [Phys. Rev. Lett. 85, 3528 (2000)]. The role of hydrodynamic interactions in surfactant micellar solutions was compared with that in hard sphere colloidal particle suspensions.

Inter-lamellar interactions modulated by addition of guest components.

We have investigated the effects of a guest component (polymer or spherical colloidal particle) confined between flexible lamellar slits on the inter-lamellar interaction by means of a small-angle X-ray scattering technique and a neutron spin echo technique. The dominant interaction between flexible lamellar membranes without guest components is the Helfrich mechanism. The addition of a neutral polymer into the lamellar phase induces an attractive inter-lamellar interaction and finally destabilizes the lamellar phase. On the other hand, spherical colloidal particles confined between flexible lamellar membranes reduce the undulational fluctuations of lamellae and bring a repulsive inter-lamellar interaction. The behavior of the layer compression modulus of the lamellar membrane containing colloidal particles is well described by the entropical repulsive inter-lamellar interaction driven by steric hindrance.

Hymenolepis microstoma: direct life cycle in immunodeficient mice.

The mouse bile duct tapeworm Hymenolepis microstoma requires beetles as the obligatory intermediate host. However, when congenitally athymic NMRI-nu mice were infected with the mature tapeworm and allowed to eat their own faeces with tapeworm eggs, the oncospheres penetrated the intestinal tissue and developed to cysticercoids. After excysting, growth to adult worms occurs in the lumen of the small intestine and bile duct. Furthermore, the same happened when NMRI-nu mice, non-obese diabetic severe combined immunodeficiency (NOD/Shi-scid) mice and NOD/Shi-scid, IL-2 Rgamma(null) (NOG) mice were orally inoculated with shell-free eggs of this parasite. Differences between the cysticercoids of H. microstoma and H. nana developed in the mouse intestinal tissues were: (i) the time course for the development of fully matured cysticercoids of H. microstoma in mice was about 11 days but only 4 days for H. nana; and (ii) cysticercoids of H. microstoma developed in mice had a tail while those of H. nana had none.

Taenia solium taeniasis/cysticercosis in Papua, Indonesia in 2001: detection of human worm carriers.

A preliminary study to detect human worm carriers of Taenia solium in Papua (Irian Jaya), Indonesia was carried out using stool examinations for the detection of copro-antigens and adult proglottids after chemotherapy, and confirmation by mitochondrial DNA analysis using expelled proglottids and metacestodes developed in NOD/Shi-scid mice from eggs of expelled proglottids. Approximately 8.6% of the local population in Kama (5/58), 1 km from the local capital city centre, Wamena, were confirmed to harbour adult T. solium using these techniques.

Evaluation of tongue inspection and serology for diagnosis of Taenia solium cysticercosis in swine: usefulness of ELISA using purified glycoproteins and recombinant antigen.

Evaluation of serology using glycoproteins (GPs) purified by preparative isoelectric focusing (pH 8.8) and recombinant chimeric antigen (RecTs) of Taenia solium was carried out using (1) blood samples on filter papers from pigs infected with different doses of eggs of T. solium in Mexico, (2) serum samples from pigs found infected naturally in Vietnam and Ecuador and (3) serum samples from pigs suspected to be infected with T. solium by tongue inspection in Tanzania. Antibody responses (IgG) were detectable in experimentally infected pigs confirmed harbouring 16 or more cysts at necropsy from 30 days after egg inoculation. One of three pigs naturally infected and harbouring 2.5 cysts/kg muscle and most of pigs harbouring=5.0 cysts/kg were also seropositive by ELISA. Although pigs may be infected with other taeniid species such as Taenia hydatigena, pigs harbouring this parasite were negative in ELISA. Approximately, 76 and 78% of sera from pigs having nodule(s) in the tongue (positive tongue inspection) were serologically positive by both ELISA and immunoblot, respectively. Furthermore, approximately 34 and 18% of sera from pigs having no nodules in the tongue (negative tongue inspection) were also seropositive by ELISA and immunoblot, respectively. ELISA using the two antigens was more sensitive than immunoblot and reliable for differentiation of pigs infected with cysticerci of T. solium from those either uninfected or infected with other taeniid species. Pigs without nodule by tongue inspection should be checked serologically in endemic areas.

Cysticercosis/taeniasis: recent advances in serological and molecular diagnoses.

Serodiagnosis by immunoblot, using recombinant chimeric T. solium antigen and native glycoprotein antigens, has been applied for neurocysticercosis cases. Specific antibodies against both antigens were detected in serum samples from NCC patients involving multiple cysts in the brain, whereas it was not always easy to detect specific antibodies in NCC cases with a solitary cyst or calcified lesion(s). On the other hand, the diagnosis for human taeniasis or worm carriers has been routinely performed by stool examination. In this study, multiplex PCR has been established to differentiate taeniasis using Taenia mitochondrial DNA in fecal samples from worm carriers. Furthermore, the molecular identification of human taeniid cestodes by base excision sequence scanning thymine-base analysis has also been introduced. This method provides four thymine-base peak profiles unique for Asian and American/African genotypes of T. solium, T. saginata and T. asiatica. By comparing thymine base peak profiles, it is possible to differentiate human taeniid cestodes without DNA sequencing. The approaches are powerful tools for the routine diagnosis of taeniasis and the molecular identification of taeniid cestodes.