Postcomparison of [(18) F]-fluorodeoxyglucose uptake in the brain after short-term bright light exposure and no intervention.

OBJECTIVE: Bright light therapy is widely used as the treatment of choice for seasonal affective disorder. Nonetheless, our understanding of the mechanisms of bright light is limited and it is important to investigate the mechanisms. The purpose of this study is to examine the hypothesis that bright light exposure may increase [(18) F]-fluorodeoxyglucose (FDG) uptake in olfactory bulb and/or hippocampus which may be associated neurogenesis in the human brain. METHOD: A randomized controlled trial comparing 5-day bright light exposure + environmental light (bright light exposure group) with environmental light alone (no intervention group) was performed for 55 participants in a university hospital. The uptake of [(18) F]FDG in olfactory bulb and hippocampus using FDG positron emission tomography was compared between two groups. RESULTS: There was a significant increase of uptake in both right and left olfactory bulb for bright light exposure group vs. no intervention group. After adjustment of log-transformed illuminance, there remained a significant increase of uptake in the right olfactory bulb. CONCLUSION: The present findings suggest a possibility that 5-day bright light exposure may increase [(18) F]FDG in the right olfactory bulb of the human brain, suggesting a possibility of neurogenesis. Further studies are warranted to directly confirm this possibility.

A Predictive Model of Plasma Lamotrigine Levels.

Introduction: Lamotrigine is one of several mood stabilizers and its effects for the treatment and prevention of depressive episodes, particularly in bipolar disorder, are generally accepted. Although the findings about a therapeutic window of lamotrigine are yet to be determined, it seems important to obtain information on individual pharmacokinetic peculiarities. This study was conducted to formulate the predictive model of plasma lamotrigine levels. Methods: Using the data of 47 patients whose lamotrigine levels, liver function, and renal function were measured, predictive models of lamotrigine levels were formulated by stepwise multiple regression analyses. The predictive power of the models was compared using another dataset of 25 patients. Results: Two models were created using stepwise multiple regression. The first model was: plasma lamotrigine level (µg/mL)=2.308+0.019×lamotrigine dose (mg/day). The second model was: plasma lamotrigine level (µg/mL)=0.08+0.024×lamotrigine dose (mg/day)+4.088×valproate combination (no=0, yes=1). The predictive power of the second model was better than that of the first model. Discussion: The present study proposes a prompt and relatively accurate equation to predict lamotrigine levels.

Therapeutic window of lamotrigine for mood disorders: a naturalistic retrospective study.

INTRODUCTION: Lamotrigine is widely used for mood disorders including bipolar disorder and major depression, but its therapeutic levels have yet to be determined. This study was conducted to investigate the hypothesis that lamotrigine may have a therapeutic window for mood disorders. METHODS: 25 patients with mood disorders received lamotrigine for more than one year during which time plasma lamotrigine levels were measured at least once. Their mental state was retrospectively and regularly but blindly assessed using the Clinical Global Impression-Severity (CGI-S) scale. In order to investigate our hypothesis, we depicted the relationship between the last lamotrigine levels and the last CGI scores in 25 patients. If any, the potential therapeutic window was further investigated. RESULTS: The relationship between the last lamotrigine levels and the last CGI scores in the 25 patients indicated the presence of a therapeutic window of lamotrigine from 5 to 11 µg/mL. The repeated measures of ANOVA reached a significant tendency of the effects of lamotrigine levels within 5-11 µg/mL on better CGI-S scores, and the CGI-S scores at the last observation of the 15 patients whose lamotrigine levels were within 5-11 µg/mL were significantly better than those of 10 patients whose lamotrigine levels were not within 5-11 µg/mL. CONCLUSION: These findings suggest that lamotrigine may have a therapeutic window for patients with mood disorder from 5 to 11 µg/mL.

Phylogenetic study of the species within the family Streptomycetaceae.

Species of the genus Streptomyces, which constitute the vast majority of taxa within the family Streptomycetaceae, are a predominant component of the microbial population in soils throughout the world and have been the subject of extensive isolation and screening efforts over the years because they are a major source of commercially and medically important secondary metabolites. Taxonomic characterization of Streptomyces strains has been a challenge due to the large number of described species, greater than any other microbial genus, resulting from academic and industrial activities. The methods used for characterization have evolved through several phases over the years from those based largely on morphological observations, to subsequent classifications based on numerical taxonomic analyses of standardized sets of phenotypic characters and, most recently, to the use of molecular phylogenetic analyses of gene sequences. The present phylogenetic study examines almost all described species (615 taxa) within the family Streptomycetaceae based on 16S rRNA gene sequences and illustrates the species diversity within this family, which is observed to contain 130 statistically supported clades, as well as many unsupported and single member clusters. Many of the observed clades are consistent with earlier morphological and numerical taxonomic studies, but it is apparent that insufficient variation is present in the 16S rRNA gene sequence within the species of this family to permit bootstrap-supported resolution of relationships between many of the individual clusters.

Coherence between oscillations in the cardiorespiratory system and tissue oxygen index in muscle recovering from intensive exercise in humans.

It has been shown that the tissue oxygen index (TOI) measured by near-infrared spectroscopy oscillates at very low frequencies during recovery after exercise and that this oscillation is derived from interactions among biochemical substances involved in oxidative metabolism in skeletal muscle. As a further step, we examined whether TOI in muscle interacts through oscillation with factors related to oxygen in the cardiorespiratory system. For this examination, coherence and phase difference between the TOI in the vastus lateralis and heart rate (HR) and between TOI and arterial oxygen saturation (SpO2) were sequentially determined during recovery (2-60 min) after severe cycle exercise with a workload of 7.5% of body weight for 20 s. Significant coherence between TOI and HR was obtained in the very low-frequency band (approximate range: 0.002-0.03 Hz) and in the low-frequency band (approximate range: 0.06-0.12 Hz). The phase difference was negative in the low-frequency band and positive in the very low-frequency band. The coherence between TOI and SpO2 was significant in the very low-frequency band. The phase difference was negative. There were no sequential changes in these coherences and phase differences. The results suggest that TOI in skeletal muscle interrelates with factors related to the heart and lungs.

Transport of storage proteins to protein storage vacuoles is mediated by large precursor-accumulating vesicles

Novel vesicles that accumulate large amounts of proprotein precursors of storage proteins were purified from maturing pumpkin seeds. These vesicles were designated precursor-accumulating (PAC) vesicles and had diameters of 200 to 400 nm. They contained an electron-dense core of storage proteins surrounded by an electron-translucent layer, and some vesicles also contained small vesicle-like structures. Immunocytochemical analysis revealed numerous electron-dense aggregates of storage proteins within the endoplasmic reticulum. It is likely that these aggregates develop into the electron-dense cores of the PAC vesicles and then leave the endoplasmic reticulum. Immunocytochemical analysis also showed that complex glycans are associated with the peripheral region of PAC vesicles but not the electron-dense cores, indicating that Golgi-derived glycoproteins are incorporated into the PAC vesicles. These results suggest that the unique PAC vesicles might mediate a transport pathway for insoluble aggregates of storage proteins directly to protein storage vacuoles.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.

Catalytic activities of hammerhead ribozymes with a triterpenoid linker instead of stem/loop II.

A minizyme is a hammerhead ribozyme with short oligonucleotide linkers instead of stem/loop II. In a previous study we demonstrated that a minizyme with high-level activity forms a dimeric structure with a common stem II (Amontov and Taira, J. Am. Chem. Soc., 118 (1996) 1624-1628). As a continuation of this study, we recently examined whether a short oligonucleotide linker at stem/loop II could be replaced by a triterpenoid linker and whether the resulting minizymes with bulky hydrophobic groups would form dimeric structures. In contrast to the minizyme with high-level activity that we characterized in the previous study, minizymes that contained a triterpenoid group had low cleavage activities. The nature of the dependence of the activity on the concentration of ribozyme revealed that these minizymes with a triterpenoid group do not form dimeric structures. Thus, the low activities of these structures can be attributed to their failure to form dimers.

Effect of surface roughness on proliferation and alkaline phosphatase expression of rat calvarial cells cultured on polystyrene.

Rough-surfaced substrates made by a variety of methods have been shown to influence osteoblast proliferation and differentiation. The purpose of this study is to confirm the role of surface roughness in promoting osteoblastic differentiation using tissue culture polystyrene as substrate, by excluding factors other than roughness. Immature osteogenic cells derived from fetal rat calvariae were cultured on the plastic cover strips having varied degrees of roughness created by treatment with four kinds of grinding paper of different particle sizes. The proliferation and gene expression of alkaline phosphatase (ALP) and osteocalcin of the calvarial cells increased on the rough-surfaced cover strips. These levels increased in response to the increase in the degree of surface roughness up to 0.8 microm of average roughness and then decreased to the level observed for the smooth surface. These results demonstrate that the surface roughness itself caused increases in osteoblastic proliferation and differentiation in cell cultures.

Neural substrates for recognition of familiar voices: a PET study.

Identification of familiar people is essential in our social life. We can identify familiar people by hearing their voices as well as by viewing their faces. By measuring regional cerebral blood flow (rCBF) by positron emission tomography (PET), we identified neural substrates for the recognition of familiar voices. The brain activity during discrimination of voices of the subjects' associates and friends from those of unfamiliar people was compared with that during an analogous discrimination of their own voice from unfamiliar voices as well as during vowel discrimination. The left frontal pole, right temporal pole, right entorhinal cortex, and left precuneus were activated to a greater extent during discrimination of familiar voice than during control discriminations, suggesting that these brain regions are involved in the recognition of familiar voices. Furthermore, the adjusted values of rCBF in the left frontal pole and right temporal pole correlated with the number of subjects' correct identification of familiar voices. The present results suggest that these two regions are coactively associated with matching the currently heard voice to familiar voices in one's memory.

Entire hemithorax irradiation following complete resection in patients with stage II-III invasive thymoma.

PURPOSE: To evaluate the feasibility and efficacy of prophylactic entire hemithorax irradiation (EH) in addition to mediastinal irradiation (MRT) following a complete resection in Stage II-III invasive thymoma. METHODS AND MATERIALS: Forty-three patients with invasive thymoma treated with surgery and radiation therapy between 1978 and 1993 were analyzed retrospectively. All 43 patients underwent a complete surgical resection and were judged to have Masaoka's Stage II-III invasive thymoma. Of these, 23 patients received EH and MRT (EH-MRT) and the remaining 20 received MRT. Of the 23 patients with EH-MRT, 11 were Stage II and 12 Stage III. Of the 20 with MRT, 11 were Stage II and 9 Stage III. In most cases, EH was 15 Gy per 15 fractions over 3 weeks (without lung compensation calculation). In both the EH-MRT and MRT group, the total radiation doses to the mediastinum were similar with a median of 40 Gy. The median follow-up time after surgery was 63 months and no patients were lost to follow-up. RESULTS: Only one of the 23 patients with EH-MRT relapsed. On the other hand, eight of the 20 with MRT relapsed, six of whom died of disease. The pleura was the most common site of failure. At 5 years, the relapse-free rate was 100% for those receiving EH-MRT and 66% for those with MRT (p = 0.03); the overall survival rate was 96% for those with EH-MRT, and 74% for those with MRT (p: not significant). The only significant treatment-related complication was radiation pneumonitis requiring treatment, in one patient who received MRT and three who received EH-MRT, including one death of a 72-year-old man and one 68-year-old woman with severe lung fibrosis. CONCLUSION: Except for elderly patients, EH-MRT following a macroscopically complete resection appears to be safe and feasible, and can reduce intrathoracic relapses.

Evaluation of the therapeutic effect of radiotherapy on cervical cancer using magnetic resonance imaging.

PURPOSE: This study was performed to evaluate magnetic resonance imaging (MRI) in determining the therapeutic effect of radiotherapy (RT) on cervical cancer. METHODS AND MATERIALS: Serial MRI studies were performed in 42 patients with predominantly advanced cervical cancer before, during, and after radiotherapy. Patients underwent external irradiation combined with high-dose-rate intracavitary (HDR) brachytherapy. T-2 weighted spin-echo pulse sequences with long repetition and echo times were used at a field strength of 1.5 T. Multiple punch biopsies of the cervix were obtained from the high-signal intensity area in all patients at the same time as the MRI. RESULT: In biopsies performed immediately after RT, no residual tumors were found in 36 patients (86%); in 6 patients, residual tumors were observed. The simultaneous MRI study demonstrated no high-signal intensity on T2-weighted images in 28 patients. A high-signal area was observed in 14 patients, and this disappeared 3 months after RT in 8 patients with a negative histological study. The sensitivity, specificity, and accuracy of MRI studies at 3 months after RT were 100%. When the relationship between reduction of tumor volume at 30 Gy and local tumor control was analyzed, every patient with a reduction under 30% gained local control. Also, patients with no residual tumors 3 months after RT gained local control. CONCLUSION: MRI studies performed at 30 Gy of external irradiation and 3 months after RT were predictive factors of local control.

D2-dopamine receptor specific brain uptake of carbon-11-labeled YM-09151-2.

The in vivo D2-receptor specific brain uptake of N-[(2RS,3RS)-1-benzyl-2- methyl-3-pyrrolidinyl]-5-chloro-2-methoxy-4-[11C]methylaminobenzamide ([11C]YM-09151-2), was investigated. In rat brain the high uptake of [11C]YM-09151-2 in striatum was displaced with sulpiride, spiroperidol, and YM-09151-2. SCH-23390 and ritanserin, D1-dopamine and S2-serotonin antagonists, showed no effect on the distribution of [11C]YM-09151-2. In the striatum at 60 min, 95% of the radioactivity was detected as [11C]YM-09151-2 by high performance liquid chromatography. On the other hand, 41% of 11C in the plasma at 60 min was observed as metabolites. In vivo autoradiography showed a high uptake of [11C]YM-09151-2 in the striatum and in the nucleus accumbens of rat brain. A high uptake of radioactivity was also found in the canine basal ganglia with positron emission tomography. The uptake was reduced by pretreatment with spiroperidol. The present results demonstrate that [11C]YM-09151-2 is a D2 receptor specific compound and is a potential in vivo tracer for measuring D2 receptors.

Measurement of D2 dopamine receptor-specific carbon-11-YM-09151-2 binding in the canine brain by PET: importance of partial volume correction.

Carbon-11-YM-09151-2 binds highly selectively to D2 dopamine receptors in the brain. Using this ligand, D2 dopamine receptor density (Bmax) and affinity (Kd) in canine striatum were measured. After administering various doses of the ligand in nine experiments, regional uptake was followed by repeated PET scanning for up to 80 min. D2 dopamine receptor specific binding at equilibrium was defined as striatal minus occipital activity after partial volume correction. Bmax and Kd were estimated by Scatchard analysis to be 40.3 pmole/ml of tissue and 22.9 nM, respectively. When a low mass dose of the ligand was administered, the bound-to-free ligand ratio in the striatum at equilibrium was consistent with the Bmax/Kd value obtained from the Scatchard analysis. The present study demonstrates the importance of partial volume correction and the Bmax/Kd measurement in a single PET study with carbon-11-YM-09151-2.

Localization of coronary artery narrowings by applying R-wave amplitude correction to exercise-induced ST depression in angina pectoris and single-vessel coronary artery narrowing.

This study investigated whether coronary artery narrowings can be localized by applying R-wave amplitude correction to exercise-induced ST depression in multiple unipolar precordial lead electrocardiography using 20 electrodes covering the left chest wall. Ten normal subjects and 29 patients with stable angina pectoris and single-vessel coronary artery narrowing (greater than or equal to 75% luminal diameter stenosis in only 1-vessel) participated. Of the 29 patients, 5 had left main coronary artery disease (CAD), 14 had left anterior descending CAD, 4 had right CAD and 6 had left circumflex CAD. The exercise-induced ST depression with R-wave amplitude correction was defined as the exercise-induced ST depression divided by the R-wave amplitude. The 20 points of the lead system were divided into 4 areas: the left main, left anterior descending, right and left circumflex coronary arteries. Coronary artery narrowing was supposed to be in an artery corresponding to the area where the maximal value of the exercise-induced ST depression with and without R-wave amplitude correction was situated. By applying R-wave amplitude correction, the diagnostic ability of localization of coronary artery narrowings was improved significantly from 52% to 86% (p less than 0.005). In particular, localization of the left main coronary artery narrowing was correctly diagnosed in 100% (5 of 5) of angina pectoris patients with left main CAD.

Evaluation by exercise Doppler echocardiography of maintenance of cardiac output during ventricular pacing with or without chronotropic response.

To examine the effectiveness of activity-initiated rate-responsive pacing, this study assessed the increases in stroke volume and cardiac output during randomized treadmill exercise in rate-responsive and fixed-rate ventricular (VVI) pacing in 10 patients. Stroke volume index and cardiac index were determined by suprasternal Doppler measurements. Compared with the findings during VVI pacing, the rate-responsive pacing was associated with (1) prolongation of exercise duration (8.0 +/- 4.0 vs 7.3 +/- 3.6 minutes, p less than 0.05); (2) greater exercise-induced positive chronotropic response (mean maximal heart rate 127 +/- 12 vs 78 +/- 15 beats/min, p less than 0.001); (3) smaller increase in stroke volume index (38 +/- 10 vs 50 +/- 11 ml/m2, p less than 0.001), and (4) greater increase in cardiac index (4.7 +/- 1.1 vs 3.9 +/- 1.0 liters/min/m2, p less than 0.001). A significant correlation was observed between age and percent increase in stroke volume index during VVI pacing (p less than 0.05). These findings indicate that VVI pacing increased stroke volume more than did rate-responsive pacing, especially in younger patients, but the increase in cardiac output was less than that seen with rate-responsive pacing due to the absence of chronotropic response. Accordingly, an activity-sensing, rate-responsive pacemaker can effectively increase the heart rate, significantly augment cardiac output and extend the duration of exercise.

Prognostic factors for local control in nasopharyngeal cancer (NPC): analysis by multivariate proportional hazard models.

Despite the development of meticulous radiation therapy techniques, the local control of the nasopharyngeal cancer (NPC) remains unsatisfactory. We examined retrospectively the clinicopathologic factors which have impact upon local recurrence-free survival (LRFS) of the 67 patients with NPC who had been irradiated greater than or equal to 40 Gy with curative intent from 1975 through 1988. Three-year LRFS rate was 63%. T stage, histology, the presence of accompanying lymphocytic infiltration, and the properness of radiation therapy had influence upon LRFS with a statistical significance. Multivariate proportional hazard models showed that T stage and pathology retained significance. Radiation therapy properness emerged as a third factor when only the patients irradiated greater than or equal to 60 Gy were included in the analysis. From these results, three groups with low, moderate, and high risk of shortened LRFS could be separated. This risk classification could contribute to the stratification criteria of future study for the improvement of local control by new modalities.

Prognostic impact of cathepsin B and matrix metalloproteinase-9 in pulmonary adenocarcinomas by immunohistochemical study.

The expression of Cathepsin B (CB) and matrix metalloproteinase-9 (MMP-9) in extirpated tissues of adenocarcinomas in non-small cell lung cancer from 90 cases was investigated immunohistologically, and the correlations between the extent of the expression and the clinicopathological features were assessed for investigating the process of tumor metastasis. It is important to reveal the mechanisms of destruction of the basal membrane and infiltration of tumor cells at the primary lesion. Sections were obtained from 10%-formalin-fixed and paraffin-embedded tissues. They were reacted with an anti-human CB polyclonal antibody or an anti-human MMP-9 polyclonal antibody. Of 90 patients, 58 (64.4%) and 39 (48.3) cases were found to be positive for CB and MMP-9 expression, respectively. A significantly higher extent of the CB expression was observed in the tissues of patients who showed postoperative recurrence of the tumor (P = 0.013). Especially, a similar observation was obtained among early cases of T1N0 (P = 0.023). In contrast, no such tendency was demonstrated in the expression profile of MMP-9. Furthermore, the enzyme expressions were compared among different types of metastases. Patients with higher extents of CB expression tended to show significantly higher rates of hematogenous and intrapulmonary metastases (P = 0.023 and P = 0.010, respectively). However, there was no significant correlation between MMP-9 expression and the prognostic factor of the patients. Therefore, we suggested that evaluation of CB expression in the tumor tissue might be useful as a postoperative prognostic factor of pulmonary adenocarcinoma. Especially, early cancer of T1N0 cases showing higher expression of CB may need postoperative adjuvant chemotherapy.