Protocol for a phase II study to evaluate the efficacy and safety of nivolumab as a postoperative adjuvant therapy for patients with esophageal cancer treated with preoperative docetaxel, cisplatin plus 5-fluorouracil treatment (PENTAGON trial).

BACKGROUND: In Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. METHODS: This study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4-16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events. DISCUSSION: To our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.

Synchrotron µ-XRF mapping analysis of trace elements in in-situ cultured Japanese red coral, Corallium japonicum.

Precious corals belong to the family Coralliidae (Cnidaria, Octocorallia), and their axis, which consists of high magnesian calcium carbonate, has long been used in jewelry. With its low growth rate and long lifespan, precious coral is a representative taxon of the vulnerable marine ecosystem. Due to years of overfishing, coral fishery has become a controversial issue. To estimate the growth rate and clarify the uptake process of trace elements in relation to the growth of the carbonate axis, Japanese red coral (Corallium japonicum) was cultured at a depth of 135 m off Takeshima Island, Kagoshima, Japan for 98 months and analyzed by microscopic X-ray fluorescence/soft X-ray photoabsorption (µ-XRF/XAS) speciation mapping. The growth rate was estimated to be 0.37 mm/year in diameter, and 10-11 growth rings were observed in a cross section of the axis. This estimated growth-rate value is the first ever to be obtained from the in-situ culture of Japanese precious coral. The fluctuation in water temperature near the in-situ-culture site was recorded for part of the culture period and then compared with the changes in the growth ring and the distribution of trace elements in a cross section of the coral axis during the same period. When the water temperature was increasing, the growth ring was light in color, sulfur and phosphorus concentrations were low, and magnesium was high. Conversely, a dark band in the growth ring, high sulfur and phosphorus, and low magnesium concentrations were observed when the water temperature was decreasing. In a cross section of the coral axis, the distribution of sulfur and magnesium from the center to the surface corresponded, respectively, to dark and light bands in the annual growth ring. Sulfur concentration was high in the dark band and low in the light band, while magnesium was negatively correlated with sulfur.

Speciation analysis of inorganic selenium in wastewater using a highly selective cellulose-based adsorbent via liquid electrode plasma optical emission spectrometry.

Speciation of selenium (Se) is typically carried out using a sophisticated technique such as ICP-MS after preconcentration using an adsorbent; however, the separation and preconcentration of inorganic Se has not been realized in the solutions containing high concentrations of SO42-. A dithiocarbamate-modified cellulose (DMC) was used in this study for the selective extraction and preconcentration of inorganic Se in wastewater, with a portable liquid electrode plasma-optical emission spectrometry (LEP-OES) being employed for quantification. DMC was found to selectively and quantitatively adsorb selenite (SeIV) over a wide range of pH (1.0-8.0); however, less than 3.0% of selenate (SeVI) was adsorbed in a pH range of 3.0-11. Quantitative extraction of SeIV was achieved even in the presence of 3.5 mol L-1 SO42-. The maximum sample volume from which 10 mg of DMC could quantitatively extract SeIV was found to be 500 mL. KOH (0.60 mL, 1.5 mol L-1) was found to quantitatively desorb SeIV retained on the adsorbent and yielded an enrichment factor of 833. The recovery of Se species from synthetic flue-gas desulfurization wastewater containing SeIV and SeVI at concentrations of 5.0 µmol L-1 was 96.2 ± 1.8% and 105.8 ± 1.8%, respectively.

Branched-chain amino acids protect the liver from cirrhotic injury via suppression of activation of lipopolysaccharide-binding protein, toll-like receptor 4, and signal transducer and activator of transcription 3, as well as Enterococcus faecalis translocation.

OBJECTIVES: Branched-chain amino acids (BCAAs) are used as nutritional support and for improving prognosis in liver cirrhosis. Here we investigate the molecular mechanisms of BCAA treatment and liver damage focused on pathways related to lipopolysaccharide-binding protein (LBP). METHODS: Serum LBP levels were measured in cirrhotic patients and in cirrhotic rats treated with BCAA to examine the correlation between liver function and survival. In cirrhotic rats, liver damage, Enterococcus faecalis translocation, serum capsular polysaccharide, and intestinal tight junction levels were assessed. Damaged HepG2 cells were cultured with BCAA-supplemented, BCAA-deficient, or control amino acid medium, followed by examination of LBP expression. RESULTS: Serum LBP levels were significantly increased in deceased patients individuals with liver cirrhosis. The survival rate in patients with lower serum LBP (<3.48 µg/mL) was significantly improved. In BCAA-treated rat liver samples, protein expression of LBP, toll-like receptor 4 (TLR4), and phosphorylated signal transduction and activator of transcription 3 (STAT3) were significantly reduced. Also in BCAA-treated rats, intestinal zonula occludens gene expression was increased, whereas hepatic translocation of E. faecalis and serum capsular polysaccharide levels were reduced. In damaged HepG2 cells, lipopolysaccharide-induced elevation of LBP expression was rapidly and strongly repressed in BCAA-enriched medium. CONCLUSIONS: Serum LBP level is a prognostic biomarker in liver cirrhosis. BCAA treatment reduced translocation of E. faecalis through intestinal tight junction recovery and reduced LBP expression in the liver, which repressed activation of LBP, toll-like receptor 4, and signal transduction and activator of transcription 3. Our findings suggest that BCAA supplementation protects the liver from damage via multiple pathways.

Superior-Type Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Phenotype Mimicking the Slow-Fast Type.

BACKGROUND: Superior-type fast-slow (sup-F/S-) atrioventricular nodal reentrant tachycardia (AVNRT) is a rare AVNRT variant using a superior slow pathway (SP) as the retrograde limb. Its intracardiac appearance, characterized by a short atrio-His (AH) interval and the earliest site of atrial activation in the His-bundle, is an initial indicator for making a diagnosis. METHODS: Among 22 consecutive patients with sup-F/S-AVNRT, 3 (age, 68-81 years) patients had an apparent slow-fast (S/F-) AVNRT characterized by a long AH interval and the earliest site of atrial activation in or superior to the His-bundle region (tachy-long-AH). RESULTS: The diagnosis of sup-F/S-AVNRT was based on the standard criteria in 2 patients and on the occurrence of Wenckebach-type atrioventricular block during tachycardia, which was attributable to a block at the lower common pathway (LCP) below the circuit of the AVNRT, detected owing to the lower common pathway potentials, in one patient. As with the typical S/F-AVNRT, tachy-long-AH was induced after a jump in the AH interval. In contrast to typical S/F-AVNRT, fluctuation in the ventriculoatrial interval was observed during the tachy-long-AH. Ventricular overdrive pacing was unable to entrain or terminate the tachy-long-AH. Moreover, the tachy-long-AH reciprocally transited to/from sup-F/S-AVNRT spontaneously or was triggered by ventricular contractions while the atrial cycle length and earliest site of atrial activation remained unchanged. Both tachycardias were cured by ablation at a single site in the right-side para-Hisian region of 2 patients and the noncoronary aortic cusp of one patient. Collectively, the essential circuit of both tachycardias was identical, and the tachy-long-AH was diagnosed as another phenotype of sup-F/S-AVNRT accompanied by sustained antegrade conduction via another bystander slow pathway breaking through the His-bundle owing to the repetitive antegrade block at the lower common pathway, thus representing a long AH interval during the ongoing sup-F/S-AVNRT. CONCLUSIONS: An unknown sup-F/S-AVNRT phenotype exists that apparently mimics the typical S/F-AVNRT and is also an unknown subtype of apparent S/F-AVNRT.

Unique electrophysiological properties of fast-slow atrioventricular nodal reentrant tachycardia characterized by a shortening of retrograde conduction time via a slow pathway manifested during atrial induction.

INTRODUCTION: Electrophysiological properties of reentry circuits of fast-slow atrioventricular nodal reentrant tachycardia (F/S-AVNRT) may contribute to cyclic variability after atrial induction. METHODS: In 156 atrial inductions of 33 patients with F/S-AVNRT, we measured the atrio-His (AH) and His-atrial (HA) intervals in the first cycle after the induction (AH[1] and HA[1], respectively), those in the second cycle (AH [2] and HA [2], respectively), and those during tachycardia that maintained a stable cycle length AH[T] and HA[T], respectively), and calculated the value of AH(1) minus AH(T) [ΔAH] and the value of HA(1) minus HA(T) [ΔHA] in each induction. According to the sum of ΔAH and ΔHA, tachycardia variability was classified as incremental (<-20), balanced (-20 to 20), or decremental (>20). RESULTS: ΔAH and ΔHA were significantly different between the three responses: 6 ± 28 and -67 ± 39 in 55 inductions (35%) with an incremental response, 20 ± 10 and -23 ± 28 in 59 (38%) with a balanced response, and 54 ± 44 and 4 ± 50 in 42 (27%) with a decremental response, respectively. Incremental response was reproducibly and consistently observed in 33% of patients. HA(2) was similar to HA(T) in inductions with an incremental response. These results suggest that incremental response can be manifested only in the first cycle when HA(1) is excessively shortened, approximating a retrograde conduction time over a slow pathway, in contrast, and far superior to a decremental delay of AH(1). CONCLUSION: In specific patients with F/S-AVNRT, poorly recognized, electrophysiological properties of shortening a retrograde conduction time over a slow pathway was manifested during atrial induction.

Moderate intensity, exercise-induced catecholamine release in the preoptic area and anterior hypothalamus in rats is enhanced in a warm environment.

Thermoeffector responses and core body temperature (Tcore) homeostasis during exercise are affected by both ambient temperature and exercise intensity. We have previously reported that Tcore, heat loss responses, and catecholamine release in the preoptic area and anterior hypothalamus (PO/AH) increased during incremental treadmill running. However, no previous study has examined whether changes in the thermoregulatory responses at warm ambient temperature are related to catecholamine responses during moderate intensity exercise in rats. Therefore, the aim of the present study was to investigate the responsiveness of neurotransmission in the PO/AH to moderate intensity exercise at different ambient temperatures, and to relate this to changes in thermoregulation. We measured the monoamine levels in the PO/AH and the thermoregulatory responses in exercising rats simultaneously using a combination of methods, including in vivo microdialysis, biotelemetry, and animal O2/CO2 metabolism measuring system. On the day of experiments, rats ran for 60min at a speed of 18mmin-1 on a treadmill at a 5% gradient, in an ambient temperature of 23°C or 30°C. Tcore, tail skin temperature (Ttail; an index of heat loss), and oxygen consumption (V̇O2: an index of heat production) were monitored. Dopamine (DA), noradrenaline (NA), and serotonin (5-HT) levels were measured by high performance liquid chromatography (HPLC) with electrochemical detection. Exercise significantly increased the Tcore, Ttail, and V̇O2 values, as well as DA and NA release in the PO/AH at both temperatures, and the increases were more pronounced at the warm ambient temperature. The results suggest that the increase in the Tcore, heat production, and heat loss responses even during moderate intensity running in a warm environment are likely associated with an increase in DA and NA release in the PO/AH region.

Mn accumulation in a submerged plant Egeria densa (Hydrocharitaceae) is mediated by epiphytic bacteria.

Many aquatic plants act as biosorbents, removing and recovering metals from the environment. To assess the biosorbent activity of Egeria densa, a submerged freshwater macrophyte, plants were collected monthly from a circular drainage area in Lake Biwa basin and the Mn concentrations of the plants were analysed. Mn concentrations in these plants were generally above those of terrestrial hyperaccumulators, and were markedly higher in spring and summer than in autumn. Mn concentrations were much lower in plants incubated in hydroponic medium at various pH levels with and without Mn supplementation than in field-collected plants. The precipitation of Mn oxides on the leaves was determined by variable pressure scanning electron microscopy-energy dispersive X-ray analysis and Leucoberbelin blue staining. Several strains of epiphytic bacteria were isolated from the field-collected E. densa plants, with many of these strains, including those of the genera Acidovorax, Comamonas, Pseudomonas and Rhizobium, found to have Mn-oxidizing activity. High Mn concentrations in E. densa were mediated by the production of biogenic Mn oxide in biofilms on leaf surfaces. These findings provide new insights into plant epidermal bacterial flora that affect metal accumulation in plants and suggest that these aquatic plants may have use in Mn phytomining.

Endovascular parent artery occlusion of proximal posterior cerebral artery aneurysms: a report of two cases.

We report two cases of proximal posterior cerebral artery (PCA) aneurysms treated with endovascular parent artery occlusion (PAO) with coils. In both cases, selective injection from the 4 F distal access catheter clearly showed the perforating arteries arising from the PCA. Case No 1, a 49-year-old woman, was successfully treated with preservation of a paramedian artery. Case No 2, a 54-year-old woman, was treated in the same manner. The patient underwent extensive thalamic infarction after the procedure because of paramedian artery occlusion. Endovascular PAO with coils is feasible for proximal PCA aneurysms; however, preservation of perforating arteries arising from the PCA is mandatory.

[The characteristics of a comprehensive geriatric assessment in patients with mild cognitive impairment with a cerebral white matter lesion].

AIM: Vascular dementia may be referred to as "treatable dementia" because its development and progress can be inhibited by intervention in the early stage. In particular, cerebral white matter lesions are readily encountered the clinical setting. In this study, we aimed to clarify the phenomenon and symptoms of patients with mild cognitive impairment (MCI) with cerebral white matter lesions prior to the onset of dementia. METHODS: The subjects included 181 cases diagnosed with MCI among 643 consecutive new patients of the Center for Comprehensive Care on Memory Disorder at Kyorin University Hospital from January 1, 2013 to January 31, 2014. Patients with particular diseases were excluded. An interview, physical examination, comprehensive geriatric assessment, brain MRI and SPECT were performed for all subjects. The cerebral white matter lesions were evaluated using the modified Fazekas scale. We defined Grades 0 and 1 as the group without apparent cerebral white matter lesions and Grades 2 and 3 as the group with apparent cerebral white matter lesions. We compared the laboratory findings and outcomes of these two groups. RESULTS: The age of the group with apparent cerebral white matter lesions was significantly higher than the group without apparent cerebral white matter lesions (P<0.05). No significant difference was observed regarding gender, MMSE, or "vegetable" term retrieval. A significant difference was observed in the total score and the subordinate component of the 21-item fall risk index and geriatric depression scale between the groups (P<0.05). Additionally, a significant difference was observed regarding the subordinate component of the instrumental ADL, the Dementia Behavior Disturbance Scale and the Zarit Care Burden Scale between the groups (P<0.05). CONCLUSIONS: Our results suggest that the presence of white matter lesions at the stage of MCI has a significant relationship to care burden due to the deterioration of ADL, risk of falling, and the presence of depression and behavior disorders. We speculate that our results are useful for the explanation of the characteristics of MCI with white matter lesion to the patients and the care givers. Furthermore, these results may lead to improvements in the appropriate approach, intervention and appropriate nursing of such patients.

Evaluation of the metabolic chiral inversion of d-selenomethionine in rats by stable isotope dilution gas chromatography-mass spectrometry.

The stereoselective pharmacokinetics of selenomethionine enantiomers in rats has been studied to evaluate the chiral inversion of D-selenomethionine to the L-enantiomer. After bolus intravenous administration of D- or L-selenomethionine to rats, the plasma concentrations of these two enantiomers were determined by stereoselective gas chromatography-mass spectrometry with selected ion monitoring. This method involved derivatization of selenomethionine enantiomers with HCl in methanol to form methyl ester followed by N-acylation with (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form the diastereomeric amide, and separation of the diastereomer on GC with an achiral column. Plasma concentrations of administered D- and L-selenomethionine declined with terminal half-lives of 96 ± 17 min and 91 ± 6 min, respectively. L-Selenomethionine appeared rapidly in plasma after administration of D-selenomethionine, whereas D-selenomethionine was not detected in plasma after administration of L-selenomethionine. The fraction of conversion of D-selenomethionine to L-selenomethionine was estimated to be 61.3 ± 14.5%. The present method evaluates the stereoselective pharmacokinetics of selenomethionine enantiomers, including the estimation of the metabolic chiral inversion.

Usefulness of Levocarnitine and/or Branched-Chain Amino Acids during Invasive Treatment for Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) are effective treatments for hepatocellular carcinoma (HCC). However, the extent of treatment depends on hepatic functional reserve. L-Carnitine is a vitamin-like substance and several reports have described the usefulness of L-carnitine supplementation in cases of cirrhosis, with confirmed effectiveness against refractory hepatic encephalopathy. On the other hand, we have previously reported that in patients who underwent TACE or RFA, administration of branched-chain amino acids (BCAAs) pre-intervention significantly reduced inflammatory reactions. We first determined serum levels of total, free, and acyl-carnitine before and at 7 d after performing TACE in 10 HCC patients. We administered levocarnitine (L-carnitine chloride, a biologically active form of carnitine) at 900 mg/d to 69 consecutive HCC patients hospitalized to undergo TACE and/or RFA, and compared changes in blood test values with those in 119 consecutive patients not administered this drug. Sixty-seven patients had a history of using BCAAs at the time of admission. We found that after 7 d of TACE, serum levels of total and acyl-carnitine are significantly decreased. On comparing the four groups, the carnitine+BCAA, carnitine-alone, and BCAA-alone groups showed significantly higher values for changes in NH3 when compared with the non-dosed group. The decrease in albumin (Alb) was significantly suppressed in the carnitine+BCAA and BCAA-alone groups. We also conducted the same examinations in a subset of patients classified as Child-Pugh class A, and noted the same trends. Administration of levocarnitine and/or BCAAs during invasive treatments reduced blood NH3 concentrations and suppressed decreases in Alb.

Continuous monitoring of hypothalamic neurotransmitters and thermoregulatory responses in exercising rats.

The purpose of the present study was to investigate the relationship between thermoregulation and catecholamine release in the preoptic area and anterior hypothalamus (PO/AH) during incremental treadmill running in the rat. To this aim, we combined in vivo brain microdialysis, biotelemetry and metabolic measurements for continuous monitoring of core body temperature (T(core)), neurotransmitters and thermoregulatory responses. The animals were exercised for 1h at 23°C. Treadmill speed was increased every 20 min (10, 20 and 26 m min⁻¹). T(core), oxygen consumption (V˙O2, an index of heat production) and tail skin temperature (T(tail), an index of heat loss) were simultaneously measured. Brain microdialysis samples were collected every 10 min, and these samples were analyzed for noradrenaline (NA), dopamine (DA) and serotonin (5-HT). T(core) and V˙O(2)2 significantly increased during treadmill and were exercise intensity dependent. After an initial drop T(tail) increased significantly during exercise. Both NA and DA levels in the PO/AH increased significantly during exercise. There was no effect on serotonin release. T(core), V˙O2 and T(tail) were positively correlated with the levels of NA and DA. Our data suggest that thermoregulatory responses are dependent on the intensity of the exercise and that these responses are associated with changes in NA and DA release, but not in 5-HT release in the PO/AH.

Influence of aggregated particles on biodegradation activities for dimethylarsinic acid (DMA) in Lake Kahokugata.

Aquatic arsenic cycles mainly depend on microbial activities that change the arsenic chemical forms and influence human health and organism activities. The microbial aggregates degrading organic matter are significantly related to the turnover between inorganic arsenic and organoarsenic compounds. We investigated the effects of microbial aggregates on organoarsenic mineralization in Lake Kahokugata using lake water samples spiked with dimethylarsinic acid (DMA). The lake water samples converted 1 µmol L(-1) of DMA to inorganic arsenic for 28d only under anaerobic and dark conditions in the presence of microbial activities. During the DMA mineralization process, organic aggregates >5.0 µm with bacterial colonization increased the densities. When the organic aggregates >5.0 µm were eliminated from the lake water samples using filters, the degradation activities were reduced. DMA in the lake water would be mineralized by the microbial aggregates under anaerobic and dark conditions. Moreover, DMA amendment enhanced the degradation activities in the lake water samples, which mineralized 50 µmol L(-1) of DMA. The DMA-amended aggregates >5.0 µm completely degraded 1 µmol L(-1) of DMA with a shorter incubation time of 7d. The supplement of KNO(3) and NaHCO(3) to lake water samples also shortened the DMA-degradation period. Presumably, the bacterial aggregates involved in the chemical heterotrophic process would contribute to the DMA-biodegradation process in Lake Kahokugata, which is induced by the DMA amendment.

Synthesis of D- and L-selenomethionine double-labeled with deuterium and selenium-82.

The synthesis of D- and L-selenomethionine labeled with 8²Se and three deuteriums at Se-methyl group (D- and L-[²H3, 8²Se]selenomethionine) was described. D- And L-[²H3, 8²Se]selenomethionine were prepared by condensation of (R)- and (S)-2-amino-4-bromobutylic acid with lithium [²H3, 8²Se]methaneselenolate, which was prepared from metal (82)Se and [²H3]methyl iodide. The optical purities of D- and L-[²H3, 8²Se]selenomethionine were determined by HPLC with a chiral stationary phase column and were found more than 99% ee. The chemical ionization mass spectra showed that the molecular related ion for N-isobutyloxycarbonyl ethyl ester derivatives of [²H3, 8²Se]selenomethionine did not overlap with the m/z values known from that of non-labeled selenomethionine.

Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway.

The lipid kinase PIK3C3 (also called Vps34) regulates both the endosomal and autophagic pathways. However, the effect of inactivating PIK3C3 on neuronal endosomal versus autophagic processes in vivo has not been studied. We generated mice in which Pik3c3 was conditionally deleted in differentiated sensory neurons. Within a few days after Pik3c3 deletion, mutant large-diameter myelinated neurons accumulated numerous enlarged vacuoles and ubiquitin-positive aggregates and underwent rapid degeneration. By contrast, Pik3c3-deficient small-diameter unmyelinated neurons accumulated excessive numbers of lysosome-like organelles and degenerated more slowly. These differential degenerative phenotypes are unlikely caused by a disruption in the autophagy pathway, because inhibiting autophagy alone by conditional deletion of Atg7 results in a completely distinct phenotype in all sensory neurons (i.e., formation of very large intracellular inclusion bodies and slow degeneration over a period of several months). More surprisingly, a noncanonical PIK3C3-independent LC3-positive autophagosome formation pathway was activated in Pik3c3-deficient small-diameter neurons. Analyses of Pik3c3/Atg7 double mutant neurons revealed that this unconventional initiation pathway still depends on ATG7. Our studies represent in vivo characterization of PIK3C3 functions in mammals and provide insights into the complexity of neuronal endo-lysosomal and autophagic pathways.

[Localized cerebral blood flow changes in response to ADL-related vitality in elderly patients with dementia using single photon emission computed tomography].

AIM: To clarify the area in the brain related to responsible for vitality and volition. METHODS: We studied 123 outpatients (39 men, 84 women, 77.7+/-6.7 years old) who visited the Center for comprehensive care on memory disorders in Kyorin University Hospital. No patients were prescribed with anti-depressants, anti-anxiety agents, psychomimetics, acetylcholinesterase inhibitors, Chinese herbal medicines or cerebrovascular circulation modifying drugs. Patients with frontotemporal dementia or depression were excluded. ADL-related vitality and volition was measured by a vitality index. Cerebral brain blood flow was measured by single photon emission computed tomography (99mTc-ECD SPECT). Relative blood flow changes were calculated by Statistical Parametric Mapping (SPM). Absolute blood flow changes were calculated by a three-dimensional stereotaxic ROI template on anatomically standardised 99mTc-ECD SPECT (3D SRT). Statistically significant correlations between semi-quantitatively measured scores of vitality index and blood flow changes in SPM and 3D-SRT were tested and displayed on a brain map. RESULTS: Analysis of relative and absolute blood flow showed that the common responsible area in the brain related to vitality was the frontal lobe, fronto-cingulate gyrus, temporal lobe, basal ganglia (caudate nucleus) and thalamus. Blood flow changes in the orbital gyrus were strongly correlated with vitality index specially in the frontal lobe. CONCLUSION: ADL-related vitality is affected mainly by the blood flow in the frontal-subcortical circuit. However, deep white matter was also important to determine vitality and volition.

Brain neurotransmitters in fatigue and overtraining.

Since the publication of the serotonin hypothesis, numerous theories involving the accumulation or depletion of different substances in the brain have been proposed to explain central fatigue. Although the theoretical rationale for the "serotonin-fatigue hypothesis" is clear, several seemingly well-conducted studies have failed to support a significant role for 5-hydroxytryptamine in the development of fatigue. As brain function appears to be dependent upon the interaction of a number of systems, it is unlikely that a single neurotransmitter system is responsible for central fatigue. Several other mechanisms are involved, with evidence supporting a role for the brain catecholamines. Fatigue is therefore probably an integrated phenomenon, with complex interaction among central and peripheral factors. When prolonged and excessive training happens, concurrent with other stressors and insufficient recovery, performance decrements can result in chronic maladaptations that can lead to the overtraining syndrome (OTS). The mechanism of the OTS could be difficult to examine in detail, perhaps because the stress caused by excessive training load, in combination with other stressors, might trigger different "defence mechanisms" such as the immunological, neuroendocrine, and other physiological systems that all interact and probably therefore cannot be pinpointed as the "sole" cause of the OTS. It might be that, as in other syndromes, the psychoneuroimmunology (study of brain-behavior-immune interrelationships) might shed a light on the possible mechanisms of the OTS, but until there is a definite diagnostic tool, it is of utmost importance to standardize measures that are now thought to provide a good inventory of the training status of the athlete. It is very important to emphasize the need to distinguish the OTS from overreaching and other potential causes of temporary underperformance such as anemia, acute infection, muscle damage, and insufficient carbohydrate intake.

Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization.

Pretreatment with a combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) has been reported to attenuate left ventricular (LV) remodeling after acute myocardial infarction (MI). We here examined whether the cytokine treatment started after MI has also beneficial effects. Anterior MI was created in the recipient mice whose bone marrow had been replaced with that of transgenic mice expressing enhanced green fluorescent protein (GFP). We categorized mice into five groups according to the following treatment: 1) saline; 2) administration of G-CSF and SCF from 5 days before MI through 3 days after; 3) administration of G-CSF and SCF for 5 days after MI; 4) administration of G-CSF alone for 5 days after MI; 5) administration of SCF alone for 5 days after MI. All the three treatment groups with G-CSF showed less LV remodeling and improved cardiac function and survival rate after MI. The number of capillaries, which express GFP, was increased and the number of apoptotic cells was decreased in the border area of all the treatment groups with G-CSF. Even if the cytokine treatment is started after MI, it could prevent LV remodeling and dysfunction after MI--at least in part--through an increase in neovascularization and a decrease in apoptosis in the border area.

[Evaluation of reticulocyte hemoglobin content, percentage of hypochromic red blood cells, and ratio of serum transferrin receptor level/serum iron level as markers of iron-deficiency erythropoiesis in patients undergoing hemodialysis].

UNLABELLED: Reticulocyte hemoglobin content(CHr), percentage of hypochromic red blood cells(%HRC, level of serum transferrin receptor(sTfR), and sTfR/serum iron ratio(sTfR/Fe) were measured in 132 hemodialysis patients. On univariate analysis, CHr was positively correlated with serum amyloid A(SAA) and negatively correlated with Kt/V. %HRC showed a positive correlation with the recombinant human erythropoietin(rHuEPO) dosage. The dependency of each iron-status index on 5 variables, SAA, sFt, TS, KtN, and dose of rHuEPO administered, was determined by stepwise multiple regression analysis. CHr was influenced only by TS, while %HRC, sTfR and sTfR/Fe were influenced by both logrHuEPO dosage and TS. Patients whose hemoglobin concentration increased by more than 1 g/dl following iron supplementation were defined as Iron-Responders, and the remaining patients were defined as Iron-Nonresponders. Fifteen out of 20 patients responded to 10 consecutive intravenous administrations of 80 mg of saccharated ferric oxide at each dialysis session, while five did not. The baseline CHr was significantly lower in Iron-Responders than Iron-Nonresponders. The baseline %HRC, sTfR, and sTfR/Fe were significantly higher in Iron-Responders than Iron-Nonresponders. The baseline CHr, %HRC, and sTfR/Fe were correlated with the degree of change in Hb concentration at 4 weeks of iron supplementation. The absolute change in CHr at 2 weeks of iron supplementation was positively correlated with the absolute change in Hb concentration over the first 4 weeks. CONCLUSION: (1) In assessing the iron metabolic status of dialysis patients, CHr, %HRC, and sTfR/Fe were unique indices compared with the ordinary indices, particularly in diagnosing the functional iron deficiency state. (2) CHr was a valuable marker of iron deficiency anemia and could predict the degree of increase in Hb level following iron supplementation. (3) The %HRC and sTfR/Fe seemed to reflect both erythropoiesis induced by rHuEPO and the iron supply to erythropoietic cells.