Insular neural system controls decision-making in healthy and methamphetamine-treated rats

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.Decision-making is a key activity of everyday life. Consequently, disturbances in the ability to make appropriate decisions or anticipate their possible consequences can result in massive social, medical, and financial problems. Decision-making depends on three temporally and partially functionally distinct sets of processes: (i) assessment and formation of preferences among possible options, (ii) selection and execution of an action, and (iii) experience or evaluation of the outcome (1). These processes are thought to require an extended neural network, mainly comprising glutamatergic, serotonergic, noradrenergic, and dopaminergic pathways in the frontostriatal and limbic loops, including the cingulate cortex, orbitofrontal cortex (OFC), insular cortex (INS), striatum (St), basal ganglia, and amygdala (2). Analysis of these processes helps to distinguish which aspects of decision-making are differentially affected in various neuropsychiatric disorders (1).Poor decision-making is a symptom of several neuropsychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and drug dependence (1, 3–5). Pathological decision-making in neuropsychiatric disorders is associated with an inability to make profitable long-term decisions that incorporate expectations of future outcomes (6). Thus, pathological decision-making is recognized as a core problem in neuropsychiatric disorders, and a better understanding of the mechanisms underlying altered decision-making should provide insights that could lead to successful treatments for these diseases.A hallmark of addiction is continuous use of substances despite negative consequences or the absence of positive consequences (7). Addicts are less able to flexibly adapt their behavior to changes in reward contingencies, and they have difficulties in integrating reinforcers to guide future behavior (8). Several altered decision-making patterns have been observed in patients with drug dependence: in particular, they tend to preferentially select actions associated with larger short-term gains but long-term losses over actions associated with smaller short-term gains and overall long-term gains (1, 4). Moreover, brain imaging studies have demonstrated that cocaine-dependent patients exhibit reduced cortical thickness in the INS and dorsolateral prefrontal cortex in association with abnormal judgment and decision-making (9), and patients with methamphetamine (METH) dependence exhibit dysfunction in the OFC (1, 4) and activation in the INS (1, 10, 11). In animal studies, dopamine signaling in prefrontal cortex, including the INS and OFC, has been implicated in impulsive choice (12) and risky decision-making (13). However, the specific contributions of these regions to impaired decision-making remain unclear, and it is not known whether the dysfunctions in decision-making and the underlying neural substrates are preexisting conditions that contribute to the initiation of drug use or are instead a consequence of repeated use of drugs.To address this issue, we tested the effect of chronic METH treatment on decision-making in rats, using a developed gambling test for rodents. Furthermore, we examined the effects of pharmacogenetic manipulations of neuronal activity in the INS on decision-making by using the designer receptor exclusively activated by designer drug (DREADD) technology.     

Transient nonketotic hyperglycinemia in an asphyxiated patient with pyridoxine-dependent seizures

An asphyxiated neonate with pyridoxine-dependent seizures and associated transient nonketotic hyperglycinemia is reported. Frequent seizures and their resultant hypoxic-ischemic insult may have led to the elevation of the cerebrospinal fluid glycine level in this patient. Early diagnosis and treatment of pyridoxine-dependent seizures is essential for an improved neurologic outcome.     

Aerobic interval exercise with an eccentric contraction induces muscular hypertrophy and augmentation of muscular strength in rats

[Purpose] The purpose of this study was to examine whether an aerobic interval exercise using an eccentric contraction would result in skeletal muscular hypertrophy and augmentation of muscular strength in rats. [Subjects and Methods] Twenty-one female Wistar rats were used in this study. The rats were randomly divided into three groups. The control group performed no exercise. The aerobic endurance exercise group ran for 90 min. The aerobic interval exercise group ran for a total of 90 minutes in 5 minute bouts separated by 2 minute rest periods. The exercise groups ran on a downhill treadmill incline, once every three days, for a total of twenty sessions. [Results] The muscle wet weights, the muscle fiber cross-section minor axes, and the tetanus tension results of the aerobic endurance and aerobic interval exercise groups were significantly larger than those of the control group. [Conclusion] These results indicate that aerobic interval exercise may be an effective method of inducing hypertrophy and augmenting muscular strength in skeletal muscle.Key words: Aerobic interval exercise, Muscular hypertrophy, Augmentation of muscular strength     

Platelet adhesion to human umbilical vein endothelial cells cultured on anionic hydrogel scaffolds

In this work we describe experiments designed to understand the human platelet adhesion to human umbilical vein endothelial cells (HUVECs) cultured on various kinds of chemically cross-linked anionic hydrogels, which were synthesized by radical polymerization. HUVECs could proliferate to sub-confluent or confluent on poly(acrylic acid) (PAA), poly(2-acrylamido-2-methyl-propane sulfonic acid sodium salt) (PNaAMPS), and poly(sodium p-styrene sulfonate) (PNaSS) gels. The proliferation behavior was not sensitive to the cross-linker concentration of the gels. However, the platelet adhesion on the HUVECs cultured on these gels showed different behavior, as revealed by human platelet adhesion test in static conditions. Only a few platelets adhered on the HUVEC sheets cultured on PNaAMPS gels with 4 and 10mol% cross-linker concentrations, and completely no platelet adhered on the HUVEC sheets cultured on PNaSS gels with 4 and 10mol% cross-linker concentrations. On the other hand, a large number of platelets adhered on the HUVECs cultured on PAA gels with 1, 2mol% cross-linker concentrations and PNaAMPS gel with 2mol% cross-linker concentration. Furthermore, the study showed that promote of the glycocalyx of HUVECs with transforming growth factor-beta(1) (TGF-beta(1)) decreased platelet adhesion, and degrade the glycocalyx with heparinase I increased platelet adhesion. The results suggested that the glycocalyx of cultured HUVECs modulates platelet compatibility, and the amount of glycocalyx secreted by HUVECs dependents on the chemical structure and cross-linker concentration of gel scaffolds. This result should be applied to make the hybrid artificial blood vessel composes of gels and endothelial cells with high platelet compatibility.     

Experimental evidence for the efficacy of combined therapy of CPT-11 and hyperthermia for squamous cell carcinoma of the esophagus

BACKGROUND/AIMS: The aim of the current study was to show an anti-tumor effect for esophageal squamous carcinoma cells derived from a combination of hyperthermia and CPT-11, which would ultimately lead to the clinical usage of this therapeutic modality for patients with squamous cell carcinoma of the esophagus. METHODOLOGY: Survival fraction of esophageal squamous carcinoma cells after administrating SN-38, active metabolite of CPT-11, and combination of hyperthermia and SN-38 was compared using data measured by MTT assay. RESULTS: Reduction of cell survival fraction derived by simultaneous induction of hyperthermia and SN-38, in many combinations of the temperature and charging period, was significantly greater than that acquired by SN-38 alone. CONCLUSIONS: Combination of hyperthermia and CPT-11 can exert a synergic anti-tumor efficacy for SCC of the esophagus.     

Bisphosphonates and adhesion molecules

Bisphosphonates are highly effective inhibitors of osteoclastic bone resorption. They can be divided into two groups with distinct mechanisms of action. The nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate, incadronate etc) can inhibit the mevalonate pathway in osteoclasts and inhibit protein prenylation of small G proteins including Rho, which might lead to alter cytoskeletal organization and cell motility. Others, like etidronate and clodronate, do not inhibit protein prenylation and can be incorporated into ATP-containing compounds that may be cytotoxic to osteoclasts. Further studies would be required to elucidate the molecular mechanism of bisphosphonate actions.     

p34<Superscript>cdc2</Superscript> expression is an independent indicator for lymph node metastasis in colorectal carcinoma

Purpose The significance of p34^cdc2 expression in human tumors has not been fully explained. The aim of the current study was to elucidate the clinicopathologic significance of immunohistochemical p34^cdc2 expression in carcinoma of the colon and rectum.Methods The immunohistochemical expression of p34^cdc2 was examined in 90 consecutive colorectal tumor cases, and p34^cdc2 expression and the clinicopathologic features of the patients and their tumors were compared.Results Lymph node metastasis was significantly more frequent in tumors expressing p34^cdc2 (47.8%, 11 of 23 tumors) than in tumors not expressing p34^cdc2 (22.4%, 15 of 67 tumors; P=0.020). Multivariate analysis demonstrated that tumor depth (P=0.008) and p34^cdc2 expression (P=0.022) were independently associated with lymph node metastases of colorectal carcinomas.Conclusions The immunohistochemical expression of p34^cdc2 is independently associated with lymph node metastasis in colorectal carcinoma.     

Study on changes in skin extensibility during the development of joint contracture due to joint immobilization in rats

[Purpose] The purpose of this study was to elucidate whether skin extensibility decreases when a contracture develops as a result of joint immobilization. [Subjects] This study was conducted on six female Wistar rats. [Methods] The rats were divided into two experimental groups. In the immobilized group, the right ankle joints were immobilized in complete plantar flexion by plaster casts for two weeks. In the control group, the left ankle joints had no intervention. On the final day, skin extensibility was determined from a length-tension curve by collecting skin from the posterior aspect of the ankle joint and using a tensile strength tester. [Results] Compared with the control group, the immobilized group showed a significant decrease in skin extensibility. [Conclusion] The results demonstrated that the extensibility of the skin itself decreases when joint contracture develops.Key words: Joint contracture, Skin, Rat