Oral supplementation with branched-chain amino acid granules prevents hepatocarcinogenesis in patients with hepatitis C-related cirrhosis: A propensity score analysis.

AIM: It has been reported that branched-chain amino acids (BCAA) supplementation can improve nutritional status and reduce liver-related complications in patients with decompensated cirrhosis. BCAA supplementation reportedly reduces the incidence of hepatocellular carcinoma (HCC) in obese cirrhotic patients infected with hepatitis C virus (HCV). We investigated the effects of oral supplementation with BCAA granules on hepatocarcinogenesis in patients with HCV-related cirrhosis using propensity score matching. METHODS: A total of 60 patients with HCV-related cirrhosis and without history of HCC who were selected by one-to-one matching of propensity scores: 30 patients receiving 12 g/day of BCAA granules for 3 months or more (BCAA group) and 30 being observed without BCAA supplementation (control group). The impact of BCAA supplementation was analyzed on the incidence of HCC. RESULTS: The 3- and 5-year rates of HCC development were 13.7% and 13.7% in the BCAA group and 35.1% and 44.5% in the control group, respectively. The BCAA group had a significantly lower rate of HCC than the control group (P = 0.032). Multivariate analysis for factors that were associated with hepatocarcinogenesis indicated that BCAA supplementation was independently associated with a reduced incidence of HCC (hazard ratio 0.131; 95% confidence interval, 0.032-0.530; P = 0.004) along with sex and serum α-fetoprotein. Obesity (body mass index, ≥25 kg/m(2) ) was not significantly associated with an increased incidence of HCC. CONCLUSION: Oral supplementation with BCAA granules is associated with a reduced incidence of HCC in patients with HCV-related cirrhosis regardless of the presence of obesity based on the propensity score analysis.

Inhibition in superior colliculus neurons in a brightness discrimination task?

Simultaneous recordings were collected from between two and four buildup neurons from the left and right superior colliculi in rhesus monkeys in a simple two-choice brightness discrimination task. The monkeys were required to move their eyes to one of two response targets to indicate their decision. Neurons were identified whose receptive fields were centered on the response targets. The functional role of inhibition was examined by conditionalizing firing rate on a high versus low rate in target neurons 90 ms to 30 ms before the saccade and examining the firing rate in both contralateral and ipsilateral neurons. Two models with racing diffusion processes were fit to the behavioral data, and the same analysis was performed on simulated paths in the diffusion processes that have been found to represent firing rate. The results produce converging evidence for the lack of a functional role for inhibition between neural populations corresponding to the two decisions.

Prefrontal neurons coding suppression of specific saccades.

The prefrontal cortex has been implicated in the suppression of unwanted behavior, based upon observations of humans and monkeys with prefrontal lesions. Despite this, there has been little direct neurophysiological evidence for a mechanism that suppresses specific behavior. In this study, we used an oculomotor delayed match/nonmatch-to-sample task in which monkeys had to remember a stimulus location either as a marker of where to look or as a marker of where not to look. We found a group of neurons in both the frontal eye field and the caudal prefrontal cortex that carried signals selective for the forbidden stimulus. The activity of these "don't look" neurons correlated with the monkeys' success or failure on the task. These results demonstrate a frontal signal that is related to the active suppression of one action while the subject performs another.

Single trial-based prediction of a go/no-go decision in monkey superior colliculus.

While some decision-making processes often result in the generation of an observable action, for example eye or limb movements, others may prevent actions and occur without an overt behavioral response. To understand how these decisions are made, one must look directly at their neuronal substrates. We trained two monkeys on a go/no-go task which requires a saccade to a peripheral cue stimulus (go) or maintenance of fixation (no-go). We performed binary regressions on the activity of single neurons in the superior colliculus (SC), with the go/no-go decision as a predictor variable, and constructed a virtual decision function (VDF) designed to provide a good estimation of decision content and its timing in a single trial decision process. Post hoc analyses by VDF correctly predicted the monkey's choice in more than 80% of trials. These results suggest that monitoring of SC activity has sufficient capacity to predict go/no-go decisions on a trial-by-trial basis.

Accurate and rapid identification of feeding arteries with multidetector-row angiography-assisted computed tomography for transarterial chemoembolization for hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) is an important treatment modality for hepatocellular carcinoma (HCC). Accurate identification of feeding arteries and catheterization are necessary for achieving treatment efficacy, especially with selective TACE. However, this often requires multiple imaging studies. We evaluated the utility of a newly developed apparatus that combines multidetector-row computed tomography (MDCT) and angiography (angio-MDCT) to facilitate TACE for treatment of HCC. METHODS: A total of 73 patients who underwent selective TACE with angio-MDCT were compared with 57 patients who had undergone selective TACE with single-row computed tomography assisted by angiography (angio-CT) in terms of the number of imaging studies needed to complete TACE. RESULTS: The mean number of digital subtraction arteriography (DSA) and CT studies required for characterization of feeding arteries before embolization was 3.53 (range 1-8) and 5.16 (range 2-11), respectively, with single-row angio-CT, and 1.67 (range 1-5) and 2.90 (range 1-5), respectively, with angio-MDCT. Fewer studies were needed in patients who underwent TACE with angio-MDCT (p < 0.0001 for both DSA and CT). Whereas single-row angio-CT failed to identify extrahepatic feeders in three patients (37.5%), all extrahepatic feeders could be identified with angio-MDCT. CONCLUSIONS: Angio-MDCT facilitates rapid and accurate identification of feeding arteries in patients undergoing TACE through the three-dimensional image analyses by the reconstruction with the workstation.

Sequential observation of pathomorphologic alterations in preneoplastic lesions during the promoting stage of hepatocarcinogenesis and the development of short-term test system for hepatopromoters and hepatocarcinogens.

The aims of this study were 1) to observe the sequential development of hepatocellular carcinomas from preneoplastic lesions and to investigate hyperplastic (neoplastic) foci or nodules (HN) as an indicator of a preneoplastic population, and 2) to test the promoting effect of various agents and to study the dose-dependent effect of promoting agents in the induction of preneoplastic lesions in the rat liver. 1) F344 rats were injected with N-nitrosodiethylamine (DEN) and then given basal diet containing 2-acetylaminofluorene (2-AAF) or α-hexachlorocyclohexane (α-HCH). Two-thirds partial hepatectomy (PH) was performed at the end of week 3. Animals were killed periodically for quantitative analysis of HN and for study of changes in blood supply to the lesions by method using a resin. In the liver of rats treated with 2-AAF after DEN, the number and area of HN were maximal in week 10, and then the number gradually decreased to week 50 (P < 0.001), whereas the area remained almost constant. In the group given α-HCH after DEN, the number of HN decreased temporarily in week 20 and then gradually increased, whereas the area of HN increased slowly throughout the experiment. Histological examination suggested that the decrease of HN after week 10 was due to degeneration of HN with their change to a spongy or cystic appearance, and that the degeneration resulted from circulatory disturbance. The number and area of these degenerating hyperplastic nodules (DHN) increased reciprocally to the decrease of HN with time until week 30. The number of hepatocellular carcinomas was maximal at week 40. The blood supply to the early hyperplastic nodules was mainly through the portal vein as with normal or surrounding liver tissue, but at a later stage HN and hepatocellular carcinomas were supplied with a blood mainly from the hepatic artery. Therefore, arterial blood supply seemed important for the persistence of HN and development of hepatocellular carcinoma. Most of the HN which appeared within the first 10 weeks were histochemically positive for γ-glutamyl-transpeptidase (γ-GT) activity. This experiment showed that detectable preneoplastic lesions measured as γ-GT positive foci or HN were induced by exposure to promoting agents for 6 to 10 weeks after initiation with DEN. 2) In tests of the promoting activity and dose-dependent effect of various compounds, rats were injected intraperitoneally with DEN and given the test compounds for 6 to 10 weeks and then killed. PH was performed as in experiment 1. Potent hepatocarcinogens, such as 2-AAF, 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB), ethionine and N-nitrosodimethylamine (DMN), induced a large number and area of HN or γ-GT positive foci whereas weak ones, such as α-HCH, dieldrin, hormones and bile acids evoked less response. Both potent and weak carcinogens showed a clear dose-dependent effect. A similar dose-dependent effect was also shown in the induction of hepatocellular carcinoma in a long-term experiment by continuous feeding of DMN. Non-hepatocarcinogens, such as N-ethylnitrosourea (ENU) and 3-methylcholanthrene (3-MC) induced them only in small numbers.

Development of a neural circuit in the superior colliculus: analysis of the propagation of neuronal excitation from intermediate to superficial layers.

The superior colliculus is important for orientation behaviors, in which visuomotor transformation is performed by the pathway from the superficial layer (SGS) to the intermediate layers (SGI). The opposite pathway (from the SGI to the SGS) also exists, raising the possibility of a feedback circuit, although it could be either negative (inhibitory) or positive (excitatory). In this study, we focused on the development of the feedback circuit. We used optical imaging methods that can measure neuronal population responses directly, as the orientation behaviors are determined by large population activities of superior colliculus neurons. We examined the postnatal development of the propagation pattern of neuronal excitation from the SGI to the SGS using a GABAA receptor antagonist. The optical response propagated within the SGI, but not to the SGS in infant mice that have not opened their eyes. In contrast, in young mice after eye opening, the optical response propagated initially in the SGI and then to the SGS. The GABAA receptor antagonist increased the optical response in the SGS in young mice, as well as that in the SGI in infant mice. Together, these results suggest that axons of SGI neurons terminate to the SGS during development after eye opening.

[Development of a cognitive BMI "neurocommunicator" as a communication aid of patients with severe motor deficits].

A cognitive brain-machine interface (BMI), "neurocommunicator" has been developed by the author's research group in AIST in order to support communication of patients with severer motor deficits. The system can identify candidate messages (pictograms) in real time from electroencephalography (EEG) data, combining three core technologies; 1) a portable/wireless EEG recorder; 2) a high-speed and high-accuracy decoding algorithm; and 3) a hierarchical message generation system. The accuracy of the model at single predictions of the target was generally over 95%, corresponding to about 32 bits per minute for normal subjects. Monitor experiments have been also started for patients at their home, in which further technical improvements are required.

Neural mind reading of multi-dimensional decisions by monkey mid-brain activity.

Brain-machine interfaces (BMIs) have the potential to improve the quality of life for individuals with disabilities. We engaged in the development of neural mind-reading techniques for cognitive BMIs to provide a readout of decision processes. We trained 2 monkeys on go/no-go tasks, and monitored the activity of groups of neurons in their mid-brain superior colliculus (SC). We designed a virtual decision function (VDF) reflecting the continuous progress of binary decisions on a single-trial basis, and applied it to the ensemble activity of SC neurons. Post hoc analyses using the VDF predicted the cue location as well as the monkey's motor choice (go or no-go) soon after the presentation of the cue. These results suggest that our neural mind-reading techniques have the potential to provide rapid real-time control of communication support devices.

Dual diffusion model for single-cell recording data from the superior colliculus in a brightness-discrimination task.

Monkeys made saccades to one of two peripheral targets based on the brightness of a central stimulus. Task difficulty was manipulated by varying the ratio of stimulus black-and-white pixels. Correct response probability for two monkeys varied directly with difficulty. Deep layer SC neurons exhibited robust presaccadic activity the magnitude of which was unaffected by task difficulty when the stimulus specified a saccade toward a target within the neuron's response field. Activity after stimuli specifying saccades to targets outside the response field was affected by task difficulty, increasing as the task became more difficult. A quantitative model derived from studies of human decision-making was fit to the behavioral data. The model assumes that information from the stimulus drives two independent diffusion processes. Simulated paths from the model were compared with neuron activity, assuming that firing rate is linearly related to position in the accumulation process. The firing rate data show delayed availability of discriminative information for fast, intermediate, and slow decisions when activity is aligned on the stimulus and very small differences in discriminative information when aligned on the saccade. The model produces exactly these patterns of results. The accumulation process is highly variable, allowing the process both to make errors, as is the case for the behavioral performance, and also to account for the firing rate results. Thus the dual diffusion model provides a quantitative account for both the behavior in a simple decision-making task as well as the patterns of activity in competing populations of neurons.

Neurons in monkey prefrontal cortex whose activity tracks the progress of a three-step self-ordered task.

The self-ordered task is a powerful tool for the analysis of dorsal prefrontal deficits. Each trial consists of a number of steps, and subjects must remember their choices in previous steps. The task becomes more difficult as the number of objects to be remembered increases. We recorded the activity of 156 neurons in the mid-dorsal prefrontal cortex of two rhesus monkeys performing an oculomotor version of the task. Although the task requires working memory, there was no convincing evidence for activity selective for the working memory of the objects that the monkey had to remember. Instead, nearly one-half of neurons (47%, 74/156) showed activity that was modulated according to the step of the task in any one or more task periods. Although the monkey's reward also increased with step, the neurons exhibited little or no step modulation in a reward control task in which reward increased without a concurrent increase in task difficulty. The activity of some neurons was also selective for the location of saccade target that the monkey voluntarily chose. Neurons showed less step modulation in error trials, and there was no increase between the second and third step responses on trials in which the error was on the third step. These results suggest that the mid-dorsal prefrontal cortex contributes to the self-ordered task, not by providing an object working memory signal, but by regulating some general aspect of the performance in the difficult task.