Low phase angle: A predictor of functional status and discharge disposition in acute stroke older patients.

BACKGROUND & AIMS: This study aimed to investigate the effects of low phase angle (PhA) on functional status and discharge disposition during the acute phase in older patients with acute stroke. METHODS: We included consecutive patients who experienced acute stroke between October 2021 and December 2022. The exclusion criteria included: age<65 years, admission from other than home, death during hospitalization, inability to measure bioelectrical impedance analysis owing to implantation, and missing data. We defined low PhA (<5.28° for male and <4.62° for female) and categorized them into the low PhA group and normal group. The clinical outcomes were functional independence by the modified Rankin Scale (mRS) score (0-2, independence; 3-5, nonindependence) and discharge disposition (home or others). We used multivariate logistic regression analysis to examine the effect of low PhA on the mRS score at discharge and discharge disposition. RESULTS: Ultimately, a total of 205 patients were included in this analysis. More patients in the low PhA group were unable to be independent (27.7% vs. 66.7%, P < 0.001) and were unable to be discharged home (53.4% vs. 82.5%, P < 0.001) than in the normal group. Logistic regression analysis of the mRS scores showed that baseline low PhA decreased the likelihood of functional independence (odds ratio [OR] = 0.275, P = 0.003) and home discharge (OR = 0.378, P = 0.044). CONCLUSIONS: Low PhA is a risk factor for low functional status at hospital discharge; it decreases the likelihood of home discharge in older patients with acute stroke.

Individual prefrontal neurons contribute to sensory-to-motor information transformation by rotating reference frames during spatial working memory performance.

Performing working memory tasks correctly requires not only the temporary maintenance of information but also the visual-to-motor transformation of information. Although sustained delay-period activity is known to be a mechanism for temporarily maintaining information, the mechanism for information transformation is not well known. An analysis using a population of delay-period activities recorded from prefrontal neurons visualized a gradual change of maintained information from sensory to motor as the delay period progressed. However, the contributions of individual prefrontal neurons to this process are not known. In the present study, we used a version of the delayed-response task, in which monkeys needed to make a saccade 90o clockwise from a visual cue after a 3-s delay, and examined the temporal change in the preferred directions of delay-period activity during the delay period for individual neurons. One group of prefrontal neurons encoded the cue direction by a retinotopic reference frame and either maintained it throughout the delay period or rotated it 90o counterclockwise to adjust visual information to saccade information, whereas other groups of neurons encoded the cue direction by a saccade-based reference frame and rotated it 90o clockwise. The results indicate that visual-to-motor information transformation is achieved by manipulating the reference frame to adjust visual coordinates to motor coordinates.

A Histogram Analysis of the Pixel Grayscale (Luminous Intensity) of B-Mode Ultrasound Images of the Subcutaneous Layer Predicts the Grade of Leg Edema in Pregnant Women.

The technique most widely used to quantitatively measure leg edema is only a pitting edema method. It has recently become possible to digitize B-mode ultrasound images and accurately quantify their brightness using an image-analysis software program. The purpose of this study was to find new indices of the grade of leg skin, to study whether or not analyses of the subcutaneous layer of leg skin on ultrasound images using image-editing software program can be used to evaluate it and to digitize it. Images of 282 subcutaneous layers of leg skin in 141 pregnant women were obtained using a B-scan portable ultrasound device. Rectangular photographs (vertical: skin thickness; horizontal: width of probe) were obtained using an image-editing program, and the luminous intensity (pixel grayscale: 0-255) and thickness of the skin were calculated using a histogram. We investigated the correlation between these parameters and the grade of pitting edema (0-3). There was a significant positive correlation between the grade of pitting edema and the average luminous intensity value, its standard deviation, and the skin thickness (ρ = 0.36, ρ = 0.22, ρ = 0.51, p < 0.0001, respectively). In particular, there was strong positive correlation between the grade of pitting edema and both the total number of pixels in a rectangle × (multiplied by) the average luminous intensity value and the total number of pixels in a rectangle × the standard deviation of the average luminous intensity value (ρ = 0.58 and ρ = 0.59, p < 0.0001, respectively). We could quantitatively evaluate the grade of leg edema by analyzing ultrasound photographs of the subcutaneous layer of the leg skin using an image-editing software program and found new indices to digitize it.

Hippocampal-prefrontal long-term potentiation-like plasticity with transcranial direct current stimulation in rats.

Transcranial direct current stimulation (tDCS) has been explored as a new treatment method for improving cognitive and motor functions. However, the neuronal mechanisms of tDCS in modulating brain functions, especially cognitive and memory functions, are not well understood. In the present study, we assessed whether tDCS could promote neuronal plasticity between the hippocampus and prefrontal cortex in rats. This is important because the hippocampus-prefrontal pathway is a key pathway in cognitive and memory functions and is involved in various psychiatric and neurodegenerative disorders. Specifically, the effect of anodal or cathodal tDCS on the medial prefrontal cortex was investigated in rats by measuring the medial prefrontal cortex response to electrical stimulation applied to the CA1 region of the hippocampus. Following anodal tDCS, the evoked prefrontal response was potentiated compared to that in the pre-tDCS condition. However, the evoked prefrontal response did not show any significant changes following cathodal tDCS. Furthermore, the plastic change of the prefrontal response following anodal tDCS was only induced when hippocampal stimulation was continuously applied during tDCS. Anodal tDCS without hippocampal activation showed little or no changes. These results indicate that combining anodal tDCS of the prefrontal cortex with hippocampal activation induces long-term potentiation (LTP)-like plasticity in the hippocampus-prefrontal pathway. This LTP-like plasticity can facilitate smooth information transmission between the hippocampus and the prefrontal cortex and may lead to improvements in cognitive and memory function.

Endoscopic Grading of Gastric Intestinal Metaplasia Using Magnifying and Nonmagnifying Narrow-Band Imaging Endoscopy.

Several endoscopic findings obtained by magnifying image-enhanced endoscopy (IEE) are reportedly correlated with gastric intestinal metaplasia (IM); however, the differences between magnifying and nonmagnifying IEE for the diagnosis of gastric IM remain unknown. This study included 100 consecutive patients who underwent narrow-band imaging endoscopy. Four areas of the stomach were evaluated using nonmagnifying and magnifying IEE. Light-blue crest (LBC), white opaque substance (WOS), and endoscopic grading of the gastric IM (EGGIM) were assessed. The concordance rates between nonmagnifying and magnifying IEE were 80.5% for LBC and 93.3% for WOS. The strength of agreement between each observation technique showed good reproducibility, with a kappa value of 0.69 and 0.83 for LBC and WOS, respectively. The individual EGGIM score indicated a good correlation between nonmagnifying and magnifying IEE (concordance rate, 75%; kappa value, 0.67). The prevalence of a high EGGIM score in patients with and without gastric cancer (GC) showed a significant difference both with nonmagnifying IEE (odds ratio (OR), 3.3; 95% confidence interval (CI), 1.2-9.0), and magnifying IEE (OR, 3.1; 95% CI, 1.1-8.9). Nonmagnifying IEE has the potential to stratify the individual risk of GC, similar to magnifying IEE, warranting further investigation with histological assessment.

Measurement of Skin Thickness Using Ultrasonography to Test the Usefulness of Elastic Compression Stockings for Leg Edema in Pregnant Women.

Background: One of the most common treatments for leg edema during pregnancy is the use of compression stockings. The purpose of this study was to evaluate the objective effectiveness in pregnant women, by measuring the changes of skin thickness using ultrasonography. Methods: Pregnant women were diagnosed with leg edema using the pitting edema method at 36 weeks of gestation. Twenty-four pregnant women (48 legs) with leg edema spent time without wearing elastic stockings at 36−37 weeks of gestation. Then, they wore elastic stockings for one week at 37−38 weeks of gestation. We measured the grade of edema (from 0 to 3) and the skin thickness of the lower leg by portable ultrasonography at 36, 37, and 38 weeks of gestation (a before-and-after study). Results: In 24 pregnant women, thigh edema was not detected in any of the 48 legs before or after the use of elastic stockings. All 48 legs in 24 pregnant women had physiological lower leg edema, but not thigh edema. The average grade of pitting edema in each lower leg significantly decreased after using the stockings (36 weeks, 1.77 ± 0.85; 37 weeks, 1.79 ± 0.77; 38 weeks, 1.04 ± 0.74, p < 0.0001). In addition, the skin thickness of the lower legs was significantly decreased after the use of elastic stockings (36 weeks, 7.47 ± 2.45 mm; 37 weeks, 7.93 ± 2.83 mm; 38 weeks, 7.15 ± 2.35 mm, p < 0.0001). Conclusions: The wearing of elastic compression stockings on the lower legs is objectively effective for improving leg edema in pregnant women.

Prognosis after Palliative Surgery for Patients with Spinal Metastasis: Comparison of Predicted and Actual Survival.

Prediction of prognosis is a key factor in therapeutic decision making due to recent the development of therapeutic options for spinal metastases. The aim of the study was to examine predictive scoring systems and identify prognostic factors for 6-month mortality after palliative surgery. The participants were 75 patients with spinal metastases who underwent palliative surgery and had a minimum follow-up period of 1 year. Associations of actual survival with categories based on the revised Tokuhashi score and new Katagiri score were evaluated. Univariate and multivariate analyses were performed to identify prognostic factors for 6-month mortality after palliative surgery. The median actual survival period was longer than those predicted using the scoring systems. However, 21.3% of patients died of cancers within 6 months after surgery. A higher CRP/albumin ratio (odds ratio: 0.39; cut-off 0.409) and absence of postoperative adjuvant therapy (odds ratio: 7.15) were independent risk factors for 6-month mortality. There was no association of mortality with primary site, severity of sarcopenia, or other biomarkers. These results suggest that careful consideration is needed to determine whether palliative surgery is the best option for patients with a high preoperative CRP/albumin ratio and/or absence of postoperative adjuvant therapy, regardless of predictions made from scoring systems.

PET imaging of brain aromatase in humans and rhesus monkeys by 11C-labeled cetrozole analogs.

Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions. To quantify aromatase expression in the brain by positron emission tomography (PET), we had previously developed [11C]cetrozole, which showed high specificity and affinity. To develop more efficient PET tracer(s) for aromatase imaging, we synthesized three analogs of cetrozole. We synthesized meta-cetrozole, nitro-cetrozole, and iso-cetrozole, and prepared the corresponding 11C-labeled tracers. The inhibitory activities of these three analogs toward aromatase were evaluated using marmoset placenta, and PET imaging of brain aromatase was performed using the 11C-labeled tracers in monkeys. The most promising analog in the monkey study, iso-cetrozole, was evaluated in the human PET study. The highest to lowest inhibitory activity of the analogs toward aromatase in the microsomal fraction from marmoset placenta was in the following order: iso-cetrozole, nitro-cetrozole, cetrozole, and meta-cetrozole. This order showed good agreement with the order of the binding potential (BP) of each 11C-labeled analog to aromatase in the rhesus monkey brain. A human PET study using [11C]iso-analog showed a similar distribution pattern of binding as that of [11C]cetrozole. The time-activity curves showed that elimination of [11C]iso-cetrozole from brain tissue was faster than that of 11C-cetrozole, indicating more rapid metabolism of [11C]iso-cetrozole. [11C]Cetrozole has preferable metabolic stability for brain aromatase imaging in humans, although [11C]iso-cetrozole might also be useful to measure aromatase level in living human brain because of its high binding potential.

Lesions of the nucleus basalis magnocellularis (Meynert) induce enhanced somatosensory responses and tactile hypersensitivity in rats.

We used the immunotoxin 192 immunoglobulin G-saporin to produce a selective cholinergic lesion in the nucleus basalis of Meynert (NBM) of rats and investigated whether the NBM lesion led to tactile hypersensitivity in the forepaw. The paw mechanical threshold test showed that the lesioned rats had a decreased threshold compared to the control. Surprisingly, there was a significant positive correlation between mechanical threshold and survival rate of NBM cholinergic neurons. Furthermore, using local field potential (LFP) recordings and voltage-sensitive dye (VSD) imaging, we found that the forepaw-evoked response in the primary somatosensory cortex (S1) was significantly enhanced in both amplitude and spatial extent in the NBM-lesioned rats. The neurophysiological measures of S1 response, such as LFP amplitude and maximal activated cortical area depicted by VSD, were also correlated with withdrawal behavior. Additional pharmacological experiments demonstrated that forepaw-evoked responses were increased in naive rats by blocking S1 cholinergic receptors with mecamylamine and scopolamine, while the response decreased in NBM-lesioned rats with the cholinergic agonist carbachol. In addition, NBM burst stimulation, which facilitates acetylcholine release in the S1, suppressed subsequent sensory responses to forepaw stimulation. Taken together, these results suggest that neuronal loss in the NBM diminishes acetylcholine actions in the S1, thereby enhancing the cortical representation of sensory stimuli, which may in turn lead to behavioral hypersensitivity.

The Preventive Effect of Dietary Antioxidants on Cervical Cancer Development.

Cervical cancer results from a continuous process, starting from a normal cervical epithelium after human papillomavirus (HPV) infection and progressing to cervical intraepithelial neoplasia (CIN), before finally developing into invasive squamous carcinoma (ISC). In recent decades, dietary antioxidants, such as vitamins, have received much attention in relation to cancer prevention. We reviewed the relevant literature to investigate the dietary and nutrient intake on cervical cancer. The intake of vitamins A and D and carotenoids may inhibit early cervical cancer development. The intake of folate may prevent or inhibit HPV infection rom progressing to various grades of CIN. The intake of vitamins C and E may widely inhibit the process of cervical cancer development. Polyphenols are often used in cases of cervical cancer in combination chemotherapy and radiation therapy. Regarding nutrients, different antioxidants may have differing abilities to intervene in the natural history of cervical diseases associated with HPV infection. Regarding foods, the intake of both vegetables and fruits containing multiple vitamins may widely suppress cervical cancer development. Most previous papers have described epidemiological studies. Thus, further research using in vitro and in vivo approaches will be needed to clarify the effects of the dietary and nutrient intake in detail.

Development and Themes of Diagnostic and Treatment Procedures for Secondary Leg Lymphedema in Patients with Gynecologic Cancers.

Patients with leg lymphedema sometimes suffer under constraint feeling leg heaviness and pain, requiring lifelong treatment and psychosocial support after surgeries or radiation therapies for gynecologic cancers. We herein review the current issues (a review of the relevant literature) associated with recently developed diagnostic procedures and treatments for secondary leg lymphedema, and discuss how to better manage leg lymphedema. Among the currently available diagnostic tools, indocyanine green lymphography (ICG-LG) can detect dermal lymph backflow in asymptomatic legs at stage 0. Therefore, ICG-LG is considered the most sensitive and useful tool. At symptomatic stage ≥1, ultrasonography, magnetic resonance imaging-lymphography/computed tomography-lymphography (MRI-LG/CT-LG) and lymphosintiography are also useful. For the treatment of lymphedema, complex decongestive physiotherapy (CDP) including manual lymphatic drainage (MLD), compression therapy, exercise and skin care, is generally performed. In recent years, CDP has often required effective multi-layer lymph edema bandaging (MLLB) or advanced pneumatic compression devices (APCDs). If CDP is not effective, microsurgical procedures can be performed. At stage 1-2, when lymphaticovenous anastomosis (LVA) is performed, lymphaticovenous side-to-side anastomosis (LVSEA) is principally recommended. At stage 2-3, vascularized lymph node transfer (VLNT) is useful. These ingenious procedures can help maintain the patient's quality of life (QOL) but unfortunately cannot cure lymphedema. The most important concern is the prevention of secondary lymphedema, which is achieved through approaches such as skin care, weight control, gentle limb exercises, avoiding sun and heat, and elevation of the affected leg.

Change of information represented by thalamic mediodorsal neurons during the delay period.

The thalamic mediodorsal (MD) nucleus plays an important role in transforming visual information into motor information during spatial working-memory performances. To understand the neural mechanism of this transformation process, we examined whether or not the information represented in individual MD neuron's activity changes during a trial of the task. Two monkeys performed two oculomotor delayed-response tasks (an ordinary and a rotatory oculomotor delayed-response task). As MD neurons show directional delay-period activity, we compared the directional selectivity of the same MD neuron between these two tasks and determined whether the activity represented the cue direction or the saccade direction. Among the 26 MD neurons that showed directional delay-period activity, representing information of 27% of neurons gradually altered from the visual domain to the oculomotor domain, while the remaining neurons kept holding either the visual or the oculomotor information throughout the delay period. These results indicate that gradual alteration of information representing in individual MD neurons during the delay period plays an important role in spatial working-memory performance. This alteration could be performed by interactions among MD neurons representing different information during the delay period.

Methylene-Bridged Bisphosphine Monoxide Ligands for Palladium-Catalyzed Copolymerization of Ethylene and Polar Monomers.

A series of palladium complexes bearing a bisphosphine monoxide with a methylene linker, that is, [κ2-P,O-(R12P)CH2P(O)R22]PdMe(2,6-lutidine)][BArF4] (Pd/BPMO), were synthesized and evaluated as catalysts for the homopolymerization of ethylene and the copolymerization of ethylene and polar monomers. X-ray crystallographic analyses revealed that these Pd/BPMO complexes exhibit significantly narrower bite angles and longer Pd-O bonds than Pd/BPMO complexes bearing a phenylene linker, while maintaining almost constant Pd-P bond lengths. Among the complexes synthesized, menthyl-substituted complex 3f (R1 = (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-yl; R2 = Me) showed the best catalytic performance in the homo- and copolymerization in terms of molecular weight and polymerization activity. Meanwhile, complex 3e (R1 = t-Bu; R2 = Me) exhibited a markedly higher incorporation of comonomers in the copolymerization of ethylene and allyl acetate (≤12.0 mol %) or methyl methacrylate (≤0.6 mol %). The catalytic system represents one of the first examples of late-transition-metal complexes bearing an alkylene-bridged bidentate ligand that afford high-molecular-weight copolymers from the copolymerization of ethylene and polar monomers.

Topographical projections from the nucleus basalis magnocellularis (Meynert) to the frontal cortex: A voltage-sensitive dye imaging study in rats.

BACKGROUND: The nucleus basalis magnocellularis/Meynert (NBM) has been explored as a new target for deep brain stimulation for neurological disorders. Although anatomical studies suggest the existence of cholinergic topographical projections of the NBM, it is still unknown whether NBM subregions differentially activate the frontal cortex. OBJECTIVE: To investigate the topography between the NBM and frontal cortex. METHODS: Electrical stimulation was applied to the anterior and posterior sites of the NBM in rats, and the evoked frontal activity was investigated using voltage-sensitive dye (VSD) imaging. RESULTS: VSD imaging revealed the functional topography of the NBM and frontal cortex: the anteroposterior axis of the NBM corresponded to the mediolateral axis of the dorsal frontal cortex. CONCLUSION: The present results suggest site-specific control of frontal neuronal activity by the NBM. These findings have practical implications, as the anterior and posterior parts of the NBM could be targeted to improve cognitive and motor function, respectively.

Root Fungal Endophytes Enhance Heavy-Metal Stress Tolerance of Clethra barbinervis Growing Naturally at Mining Sites via Growth Enhancement, Promotion of Nutrient Uptake and Decrease of Heavy-Metal Concentration.

Clethra barbinervis Sieb. et Zucc. is a tree species that grows naturally at several mine sites and seems to be tolerant of high concentrations of heavy metals, such as Cu, Zn, and Pb. The purpose of this study is to clarify the mechanism(s) underlying this species' ability to tolerate the sites' severe heavy-metal pollution by considering C. barbinervis interaction with root fungal endophytes. We measured the heavy metal concentrations of root-zone soil, leaves, branches, and fine roots collected from mature C. barbinervis at Hitachi mine. We isolated fungal endophytes from surface-sterilized root segments, and we examined the growth, and heavy metal and nutrient absorption of C. barbinervis seedlings growing in sterilized mine soil with or without root fungal endophytes. Field analyses showed that C. barbinervis contained considerably high amounts of Cu, Zn, and Pb in fine roots and Zn in leaves. The fungi, Phialocephala fortinii, Rhizodermea veluwensis, and Rhizoscyphus sp. were frequently isolated as dominant fungal endophyte species. Inoculation of these root fungal endophytes to C. barbinervis seedlings growing in sterilized mine soil indicated that these fungi significantly enhanced the growth of C. barbinervis seedlings, increased K uptake in shoots and reduced the concentrations of Cu, Ni, Zn, Cd, and Pb in roots. Without root fungal endophytes, C. barbinervis could hardly grow under the heavy-metal contaminated condition, showing chlorosis, a symptom of heavy-metal toxicity. Our results indicate that the tree C. barbinervis can tolerate high heavy-metal concentrations due to the support of root fungal endophytes including P. fortinii, R. veluwensis, and Rhizoscyphus sp. via growth enhancement, K uptake promotion and decrease of heavy metal concentrations.

11C-cetrozole: an improved C-11C-methylated PET probe for aromatase imaging in the brain.

UNLABELLED: Aromatase (an enzyme that converts androgens to estrogens) in the brain is involved in neuroprotection, synaptic plasticity, and regulation of sexual and emotional behaviors. To investigate the physiologic and pathologic importance of aromatase in the brain, including in humans, we here report the development of a novel PET probe for aromatase, (11)C-cetrozole, which allows noninvasive quantification of aromatase expression. METHODS: (11)C-cetrozole was synthesized by the C-(11)C-methylation method developed by our group. In vitro autoradiography of frozen sections and a binding study with rat brain homogenates were conducted to demonstrate the specific binding and the dissociation constant. PET studies with anesthetized rhesus monkeys were performed to analyze the dynamics in the brain. RESULTS: In vitro and in vivo studies using (11)C-cetrozole showed its superiority in brain aromatase imaging in terms of specificity and selectivity, compared with previously developed (11)C-vorozole. PET studies showed that (11)C-cetrozole had a higher signal-to-noise ratio, providing a sharper image than (11)C-vorozole, because the radioactive metabolite of (11)C-vorozole was taken up into the brain. High specific binding of (11)C-cetrozole was observed in the amygdala and hypothalamus, and we also noted binding in the nucleus accumbens of rhesus monkeys for the first time. CONCLUSION: These results suggest that PET imaging with newly developed (11)C-cetrozole is suitable for quantifying the expression of brain aromatase in vivo, possibly providing critical information regarding the functional roles of aromatase in human neurologic and emotional disorders.

Numbness in the tip of the tongue and lower lip caused by thalamic hemorrhage.

Although patients with isolated oral syndrome or facial sensory loss following stroke of thalamic ventroposteromedial (VPM) nucleus have been reported, there have been no reports of numbness in the tip of the tongue and lower lip. Furthermore, symptoms in the tip of the tongue caused by stroke are typically characterized as gustatory sensory disturbances. A 62-year-old hypertensive man experienced an acute onset of severe numbness in the left tip of the tongue and ipsilateral lower lip. Neurological examination revealed no other abnormalities except for the aforementioned numbness. Head computed tomography showed a small hematoma in the medial part of the right thalamus, most likely within the VPM nucleus. The somatosensory impulse of the tongue is conveyed via the lingual nerve, and it reaches the contralateral medial VPM proper via the trigeminal spinal nucleus. Therefore, thalamic stroke mainly involving the medial VPM proper has the potential to elicit numbness in the tip of the tongue. A major portion of the VPM nucleus is vascularized by the inferolateral arteries. The inferolateral arteries vary greatly in the number and position of the arteries and their tributaries, and small-vessel disease in this territory can present with diverse symptoms because of this complexity. These findings indicate that central neurological involvement should not be overlooked in the case of sensory disturbance restricted to the tip of the tongue and lip.

[Brain abscess due to Fusobacterium necrophorum in a patient with convulsion and no signs of meningitis].

Here, we report brain abscess due to Fusobacterium necrophorum (F. necrophorum) in a 78-year-old healthy man. He developed convulsion and did not have any signs of meningitis. Although the brain magnetic resonance imaging findings of the left occipital lobe were typical of a brain abscess, his cerebrospinal fluid examination revealed only slight pleocytosis and mild increase in protein levels. Thus, it was difficult to rule out the possibility of metastatic brain tumor; the patient's condition was provisionally diagnosed as symptomatic epilepsy secondary to brain abscess. His convulsion disappeared soon after administration of antiepileptic, antibacterial, and steroid agents. A craniotomy was performed to evacuate the abscess, and F. necrophorum was identified by culturing the abscess contents. After the operation, he was treated with appropriate antibacterial agents, which resulted in resolution of the brain abscess. Although Fusobacterium species are gram-negative anaerobic bacilli commensal of the human oropharynx, we need to recognize that Fusobacterium species can be a primary pathogen causing brain abscesses and may leave residual neurological sequelae without early appropriate treatment.

PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me.

UNLABELLED: It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of (11)C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-(11)C-TIC-Me)] in healthy subjects. METHODS: Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-(11)C-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively. RESULTS: After rapid hydrolysis in blood, the acid form-(11)C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-(11)C-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-(11)C-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R)-(11)C-TIC-associated radioactivity is excreted into the bile by organic anion transport systems. CONCLUSION: We demonstrated that PET image analysis with (15R)-(11)C-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system.

Thalamic mediodorsal nucleus and working memory.

Working memory is a dynamic neural system for temporarily maintaining and processing information. The prefrontal cortex (PFC) plays an important role in working memory. However, several evidences indicate that the thalamic mediodorsal nucleus (MD) also participates in working memory. Neurophysiological studies revealed that MD neurons exhibit sustained delay activity, which is considered to be a neural correlate of the temporary maintenance of information. Most MD neurons with delay activity represented information regarding motor responses, whereas some represented information regarding visual cues, suggesting that the MD participates more in prospective aspects of working memory, in contrast to the PFC, in which a minority participates in prospective aspects of working memory. A population vector analysis revealed that the transformation of sensory-to-motor information occurred during the earlier phase of the delay period in the MD compared with the PFC. These results indicate that reverberating neural circuits constructed by reciprocal connections between the MD and the PFC could be an important component for constructing prospective information in the PFC.