Paradise Lost: The relationships between neurological and psychological changes in nicotine-dependent patients

The neural reward circuit and cognitive distortion play an important role in addiction; however, the relationship between the two has not yet been addressed. In this article, we review recent findings on nicotine dependence and propose a novel hypothesis. Previous research using functional magnetic resonance imaging (fMRI) has shown that while activation of the reward circuit (ventral striatum) appears in response to tobacco-related rewards in nicotine dependence, responses to rewards other than tobacco (e.g. food and money) are reduced. Moreover, this change is observed at the very early stages of smoking, even when a person has smoked fewer than 10 cigarettes in his/her lifetime. Thus, we propose the following hypothesis, called the Paradise Lost theory: given addicts’ lower ventral striatal responses to non-tobacco rewards, nicotine addiction disables smokers from sensing the pleasures of ordinary life (the Paradise Lost state). However, since smokers do not notice this, they produce an overestimation of tobacco (cognitive distortion), such that they do not have many pastimes other than smoking or feel that quitting smoking would reduce the happiness and pleasure and increase the difficulty of life. Cognitive distortion thus makes it difficult for smokers to take the initiative to quit smoking and even causes relapse after smoking cessation. This theory furthers our understanding of addiction and could improve our approach to the prevention and treatment of addiction

Usefulness of Obese Animal Models in Antiobesity Drug Development

Obese animal models have played key roles to elucidate the etiology of obesity and develop antiobesity drugs. In the first half of the chapter, we introduce the characteristics of obese animal models. In the second half of the chapter, we show the results of pharmacological studies using obese animal models for new antiobesity drugs

Analysis of haemodynamics and angiogenic response to ischaemia in the obese type 2 diabetic model Spontaneously Diabetic Torii <i>Lepr^fa</i> (SDT fatty) rats

Peripheral artery disease (PAD) is defined as peripheral blood flow impairment, especially in the legs, caused by atherosclerotic stenosis. The disease decreases quality of life because of intermittent claudication or necrosis of the leg. The hindlimb ischaemia model, in which ischaemia is induced by femoral artery ligation, is often utilized as a PAD model. In the hindlimb ischaemia model, nonmetabolic syndrome animals are mainly used. In this study, we investigated the usefulness of Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a new model for obese type 2 diabetes, as a new PAD animal model. We found that hindlimb blood flow in SDT fatty rats was significantly lower than that in Sprague–Dawley (SD) rats under nonischaemic conditions. Furthermore, SDT fatty rats showed a significantly higher plasma nitrogen oxide level, shorter prothrombin time, and shorter activated partial thromboplastin time than SD rats. In addition, we found that the change in blood flow 7 days after induction of hindlimb ischaemia and the number of Von Willebrand factor‐positive vessels in gastrocnemius muscles were significantly lower in SDT fatty rats than in SD rats. These results suggest that excess production of reactive oxygen species and coagulation activation could be involved in lower blood flow in non‐ischaemic rats and that decreased angiogenesis could be involved in the poor recovery of blood flow in SDT fatty rats with hindlimb ischaemia. Taken together, our results suggest that SDT fatty rats might be useful as a new model for PAD with metabolic syndrome

A Rhabdomyosarcoma Arising in the Larynx of a Dog

A neoplastic nodular lesion, 2 × 3 cm in diameter, was found in the larynx of a 6-year-old spayed female dog. The tumor was ill-circumscribed, consisting histologically of large round cells with abundant cytoplasm interspersed with small round cells with less cytoplasm and occasional multinucleated cells (myotubes). Immunohistochemically, tumor cells were positive for myoglobin, desmin and vimentin in varying degrees, but negative for S-100 protein, GFAP or cytokeratin. Cytoplasmic myofilaments/myofibrils with a dense Z-line-like structure were seen, the fine structures of which were complemented by PTAH stain. Based on these findings, the tumor was diagnosed as a rhabdomyosarcoma, a very rare tumor in the larynx of dogs

Effect of forestation of hinoki and larch on soil chemistry in mountainous water source area for water supply to Tokyo

Effects of forestry on soil properties, stream water chemistry and mass balance in watersheds had been confieremed by many previous studies. However, they have not clarified in detail variation processes of soil chemistry and soil physics after the hinoki and larch forestation. To clarify the variation processes, it is important to confirm the difference of soil chemistry and soil physics on the artifitial and natural forest. In this research, we conducted the soil physical and chemical investigations on seven slopes covered by hinoki (chamecyparis obtusa) and larch (Larix leptolepis) artificial and beech (Fagus crenata) natural forest in a highland area, the western side of Tokyo. The water repellency of A_0 horizon was stronger on the artificial forest slope than on the natural forest. In addition, the permeability was low on the artificial forest due to the strong water repellency. On the artificial forest, both of the exchangeable base cation content and soil pH were low and Al concentration was high, as compared with those on the natural forest. These results suggest that the soil acidification is progressed on the artificial forest. The decline of soil pH by the forestation was controlled by the increase of H^+ supply at the A_0 horizon due to the property of litter decomposition and the decrease of base cation supply at the A-horizon. In general, the cation supply rate such as weathering rate is controlled by the infiltration rate and temperature. These soil physical and chemical properties suggest that infitration rate at the A-horizon. declines after the forestation, weathering rate declines and consequently soil is acidified

Comparison study between the mechanisms of allergic asthma amelioration by a cysteinylleukotriene type 1 receptor antagonist montelukast and methylprednisolone

ABSTRACT We investigated the effects of cysteinyl-leukotriene (cysLT) type 1 receptor antagonist montelukast (MK) and compared them with those of methylprednisolone (MP) in an allergic asthma model. Rats sensitized to ovalbumin (OVA) received repeated intratracheal exposure to OVA for up to 3 consecutive days. Pretreatment with MK or MP before OVA exposure inhibited late airway response (LAR) and reduced cellular infiltration into the bronchial submucosa after the triple OVA. The amount of N-acetyl-leukotriene E 4 in the bile was significantly reduced by pretreatment with MK or MP, suggesting that both drugs reduced the production of cysLTs in the lungs. In the in vitro study, when the fragments of lungs that had been repeatedly pretreated with MK or MP and exposed to OVA were removed and incubated with OVA, the coaddition of either drug significantly reduced cysLT production. In contrast, the cysLT production following the addition of OVA to the lung fragments that had not received in vivo pretreatment with either drug was inhibited by MK but not by MP. These results indicate that MK and MP inhibit LAR by suppressing the infiltration of inflammatory cells into the bronchial submucosa, thereby inhibiting the production of cysLTs in the lungs, and that MK but not MP may inhibit cysLT production directly. The different effects on cysLT production between the two drugs may provide a rationale for the use of combination therapy with cysLT 1 receptor antagonists and steroids for the treatment of asthma

Salivary Mucocele in a Laboratory Beagle

The histologic characteristics of a salivary mucocele in a beagle used in a toxicity study are described in this report. A pale yellowish cyst under the mandibular skin containing frothy mucus was observed at necropsy. Microscopically, numerous villous projections arose from the internal surface of the cyst and were lined by stratified epithelial-like macrophages, which were immunopositive for macrophage scavenger receptor A. A ruptured sublingual interlobar duct connected to the lumen was observed near the cyst. Luminal amorphous material showed a positive reaction with Alcian blue and periodic acid-Schiff staining as did mucin in the sublingual gland. Ultrastructurally, the epithelial-like macrophages had numerous vacuoles containing electron-lucent material, which was presumed to be lysosomal in origin, and had pseudopods on their cell surfaces interdigitating with those on the adjacent cells. This case report helps to understand the diversity of the background findings in beagles used in toxicity studies

Inhibitors of a Na⁺-pumping NADH-ubiquinone oxidoreductase play multiple roles to block enzyme function

The Na⁺-pumping NADH-ubiquinone (UQ) oxidoreductase (Na⁺-NQR) is present in the respiratory chain of many pathogenic bacteria and is thought to be a promising antibiotic target. Whereas many details of Na⁺-NQR structure and function are known, the mechanisms of action of potent inhibitors is not well-understood; elucidating the mechanisms would not only advance drug design strategies but might also provide insights on a terminal electron transfer from riboflavin to UQ. To this end, we performed photoaffinity labeling experiments using photoreactive derivatives of two known inhibitors, aurachin and korormicin, on isolated Vibrio cholerae Na⁺-NQR. The inhibitors labeled the cytoplasmic surface domain of the NqrB subunit including a protruding N-terminal stretch, which may be critical to regulate the UQ reaction in the adjacent NqrA subunit. The labeling was blocked by short-chain UQs such as ubiquinone-2. The photolabile group (2-aryl-5-carboxytetrazole (ACT)) of these inhibitors reacts with nucleophilic amino acids, so we tested mutations of nucleophilic residues in the labeled region of NqrB, such as Asp49 and Asp52 (to Ala), and observed moderate decreases in labeling yields, suggesting that these residues are involved in the interaction with ACT. We conclude that the inhibitors interfere with the UQ reaction in two ways: the first is blocking structural rearrangements at the cytoplasmic interface between NqrA and NqrB, and the second is the direct obstruction of UQ binding at this interfacial area. Unusual competitive behavior between the photoreactive inhibitors and various competitors corroborates our previous proposition that there may be two inhibitor binding sites in Na⁺-NQR

Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia

Biochemical experiments have shown that Smad6 and Smad ubiquitin regulatory factor 1 (Smurf1) block the signal transduction of bone morphogenetic proteins (BMPs). However, their in vivo functions are largely unknown. Here, we generated transgenic mice overexpressing Smad6 in chondrocytes. Smad6 transgenic mice showed postnatal dwarfism with osteopenia and inhibition of Smad1/5/8 phosphorylation in chondrocytes. Endochondral ossification during development in these mice was associated with almost normal chondrocyte proliferation, significantly delayed chondrocyte hypertrophy, and thin trabecular bone. The reduced population of hypertrophic chondrocytes after birth seemed to be related to impaired bone growth and formation. Organ culture of cartilage rudiments showed that chondrocyte hypertrophy induced by BMP2 was inhibited in cartilage prepared from Smad6 transgenic mice. We then generated transgenic mice overexpressing Smurf1 in chondrocytes. Abnormalities were undetectable in Smurf1 transgenic mice. Mating Smad6 and Smurf1 transgenic mice produced double-transgenic pups with more delayed endochondral ossification than Smad6 transgenic mice. These results provided evidence that Smurf1 supports Smad6 function in vivo