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The anatomical design of the human foot is considered to facilitate generation of bipedal walking. However, how the morphology and structure of the human foot actually contribute to generation of bipedal walking remains unclear. In the present study, we investigated the three-dimensional kinematics of the foot bones under a weight-bearing condition using cadaver specimens, to characterize the innate mobility of the human foot inherently prescribed in its morphology and structure. Five cadaver feet were axially loaded up to 588 N (60 kgf), and radiographic images were captured using a biplane X-ray fluoroscopy system. The present study demonstrated that the talus is medioinferiorly translated and internally rotated as the calcaneus is everted owing to axial loading, causing internal rotation of the tibia and flattening of the medial longitudinal arch in the foot. Furthermore, as the talus is internally rotated, the talar head moves medially with respect to the navicular, inducing external rotation of the navicular and metatarsals. Under axial loading, the cuboid is everted simultaneously with the calcaneus owing to the osseous locking mechanism in the calcaneocuboid joint. Such detailed descriptions about the innate mobility of the human foot will contribute to clarifying functional adaptation and pathogenic mechanisms of the human foot., Competing Interests: The authors have no competing interests.

Rationale: It is necessary to understand better how chronic food restriction (CFR) and psychostimulant drugs interact in motivated behavior unrelated to food or energy homeostasis., Objectives: We examined whether CFR augments methylphenidate (MPH)-potentiated responding reinforced by visual sensation (VS) and whether repeated MPH injections or prolonged CFR further augments such responses., Methods: Before starting the following experiments, rats on a CFR diet received a limited daily ration in such a way that their body weights decreased to 85-90% of their original weights over 2 weeks. In experiment 1, rats on CFR and ad libitum diet received four injections of varying MPH doses (0, 2.5, 5, and 10 mg/kg). In experiment 2, CFR and ad libitum groups received repeated injections of MPH (2.5 mg/kg). In experiment 3, half of CFR rats received repeated injections of MPH (2.5 mg/kg), and the other half received saline, and following a 7-day abstinence, they all received the 2.5-mg/kg dose of MPH., Results: CFR rats increased VS-reinforced responding more than ad libitum rats when they received MPH. Repeated injections of MPH with prolonged CFR further increased VS-reinforced responding. We found a double dissociation where prolonged CFR (3 vs. 6 weeks) made VS-reinforced responding, but not locomotor activity, more responsive to MPH, whereas repeated MPH injections made locomotor activity, but not VS-reinforced responding, more responsive to MPH., Conclusions: CFR markedly potentiates effects of MPH on VS-reinforced responding. The present study demonstrates that the longer CFR continues, the greater psychostimulant drugs augment behavioral interaction with salient stimuli.

The three-dimensional (3D) kinematics of the scapula were analyzed in vivo in 10 patients with scapular and 10 patients with clavicular fracture. Both the injured shoulder and normal contralateral shoulder were evaluated by computed tomography in the neutral and fully elevated positions. 3D rotational and translational movements of the scapula relative to the thorax during arm elevation were analyzed. A computer simulation program was used to compare rotational elevation/depression in the coronal plane, anterior/posterior tilting in the sagittal plane and protraction/retraction in the axial plane between the normal and affected sides. Anterior/ posterior translational movement along the X-axis, upward/downward movement along the Y-axis, and lateral/ medial movement along the Z-axis in the Euler space during forward elevation were also compared. In scapular fracture, rotational elevation of the scapula decreased in the coronal plane and posterior tilting of the scapula increased in the sagittal plane. Anterior and superior translation were higher in scapular fracture than in the corresponding normal sides. However, no significant abnormal rotational and translational kinematic changes were observed during elevation in clavicular fracture. In vivo 3D computerized motion analysis was useful for evaluating scapular dyskinesis. Scapular fracture can cause scapular dyskinesis, but not all clavicular fractures alter scapular motion biomechanics., Competing Interests: No potential conflict of interest relevant to this article was reported.

Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation., (Published by Elsevier Inc.)

A 3-year-old boy with normal development presented with acute cerebellitis at one year and 10 months of age. His truncal ataxia resolved without treatment. He experienced a relapse of truncal ataxia and atonic seizures at 2 years and one month of age. Five months later, he experienced myoclonic atonic seizures. By 3 years of age, the truncal ataxia had become severe, and the frequency of myoclonic atonic seizures increased. Compared to controls, we found higher levels of anti-C-terminal GluN2B and anti-N terminal GluD2 antibodies in the serum, and anti-N terminal GluN2B and anti-C terminal GluD2 antibodies in the cerebrospinal fluid (CSF). A cell-based assay revealed the presence of anti-NMDA-type glutamate receptor antibody in the serum, but absence in the CSF. Ictal EEG of myoclonic atonic seizures showed generalized spike and wave complexes. The patient was diagnosed with myoclonic atonic epilepsy. Adrenocorticotrophic hormone therapy resolved the truncal ataxia and myoclonic atonic seizures, along with the decreased serum anti-C-terminal GluN2B and anti-N-terminal GluD2 antibodies, and CSF anti-N-terminal GluN2B and anti-C-terminal anti-GluD2 antibodies. Our results suggest that the anti-GluN2B and anti-GluD2 antibodies may be associated with myoclonic atonic epileptic seizures and chronic cerebellitis.

It is well known nutrition education for 3- to 5-y-old children is important, and it is necessary to assess their nutrition knowledge before and after nutrition education to evaluate the effectiveness of an educational program. This study aimed to determine the necessary questions for inclusion in a questionnaire designed to assess the nutrition knowledge of young Japanese children in order to assess the effectiveness of the Shokuiku nutrition education program. Eighty and 124 children from 9 nursery schools in Japan participated in the intervention and control groups, respectively. A 15-item questionnaire was completed by the intervention group before and after total of 16 nutrition education lessons. The control group completed the questionnaire only once. The necessary questions for inclusion in the questionnaire were evaluated by comparing the frequency of correct answers given by the pre- and post-intervention groups using McNemar and Wilcoxon's signed rank sum tests, and by the post-intervention and control groups using Chi-square and Mann-Whitney tests. The frequency of correct answers given to questions in all categories except "Breakfast and life rhythm" significantly differed between the pre- and post-intervention groups (p<0.05). The frequency of correct answers given by the post-intervention group was significantly higher than that of the control group only in the category of "Three colors food groups" (p<0.05). The results suggest that it is necessary to include questions about functions of food and nutrients such as the role of food groups to assess the nutrition knowledge of young Japanese children in order to evaluate the effectiveness of the Shokuiku program.

Nutrition knowledge is necessary for individuals to adopt appropriate dietary habits, and needs to be evaluated before nutrition education is provided. However, there is no tool to assess general nutrition knowledge of adults in Japan. Our aims were to determine the validity and reliability of a general nutrition knowledge questionnaire for Japanese adults. We developed the pilot version of the Japanese general nutrition knowledge questionnaire (JGNKQ) and administered the pilot study to assess content validity and internal reliability to 1,182 Japanese adults aged 18-64 y. The JGNKQ was further modified based on the pilot study and the final version consisted of 5 sections and 147 items. The JGNKQ was administered to female undergraduate Japanese students in their senior year twice in 2015 to assess construct validity and test-retest reliability. Ninety-six students majoring in nutrition and 44 students in other majors who studied at the same university completed the first questionnaire. Seventy-five students completed the questionnaire twice. The responses from the first questionnaire and both questionnaires were used to assess construct validity and test-retest reliability, respectively. The students in nutrition major had significantly higher scores than the students in other majors on all sections of the questionnaire (p=0.000); therefore, the questionnaire had good construct validity. The test-retest reliability correlation coefficient value of overall and each section except "The use of dietary information to make dietary choices" were 0.75, 0.67, 0.67, 0.68 and 0.61, respectively. We suggest that the JGNKQ is an effective tool to assess the nutrition knowledge level of Japanese adults.

Cat's AB blood group system (blood types A, B, and AB) is of major importance in feline transfusion medicine. Type A and type B antigens are Neu5Gc and Neu5Ac, respectively, and the enzyme CMAH participating in the synthesis of Neu5Gc from Neu5Ac is associated with this cat blood group system. Rare type AB erythrocytes express both Neu5Gc and Neu5Ac. Cat serum contains naturally occurring antibodies against antigens occurring in the other blood types. To understand the molecular genetic basis of this blood group system, we investigated the distribution of AB blood group antigens, CMAH gene structure, mutation, diplotypes, and haplotypes of the cat CMAH genes. Blood-typing revealed that 734 of the cats analyzed type A (95.1%), 38 cats were type B (4.9%), and none were type AB. A family of three Ragdoll cats including two type AB cats and one type A was also used in this study. CMAH sequence analyses showed that the CMAH protein was generated from two mRNA isoforms differing in exon 1. Analyses of the nucleotide sequences of the 16 exons including the coding region of CMAH examined in the 34 type B cats and in the family of type AB cats carried the CMAH variants, and revealed multiple novel diplotypes comprising several polymorphisms. Haplotype inference, which was focused on non-synonymous SNPs revealed that eight haplotypes carried one to four mutations in CMAH, and all cats with type B (n = 34) and AB (n = 2) blood carried two alleles derived from the mutated CMAH gene. These results suggested that double haploids selected from multiple recessive alleles in the cat CMAH loci were highly associated with the expression of the Neu5Ac on erythrocyte membrane in types B and AB of the feline AB blood group system., Competing Interests: The authors have declared that no competing interests exist.

The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning., (Published by Elsevier Inc.)

The shoulder complex in the human body consists of the scapula, clavicle, humerus, and thorax and bears the load imposed by arm movements while at the same time realizing a wide range of motions. To mimic and exploit its role, several musculoskeletal robot arms with shoulder complex mechanisms have been developed. However, although many research groups have tried to design the structures using links and joints that faithfully correspond to the bones and joints in the human shoulder complex, its function has not been successfully reproduced because biologically plausible designs seriously compromise engineering plausibility. In this paper, we propose a linkage mechanism that can reproduce complex three-dimensional scapulo movements and considers the trade-off between biological and engineering plausibilities. Subsequently, the design was validated by driving the mechanism using pneumatic artificial muscles (PAMs) placed similarly to muscles in humans. Further, we present experiments in which the robot was controlled by surface electromyographic signals from a human. We show that the proposed design, due to its kinematic similarity with human musculoskeletal systems, eases the conversion between the surface electromyogram signals and the PAMs control inputs.

Dopamine neurons located in the midbrain play a role in motivation that regulates approach behavior (approach motivation). In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. Accumulating evidence suggests that such motivational role of dopamine neurons is not limited to those located in the ventral tegmental area, but also in the substantia nigra. The present paper reviews previous rodent work concerning dopamine's role in approach motivation and the connectivity of dopamine neurons, and proposes two working models: One concerns the relationship between extracellular dopamine concentration and approach motivation. High, moderate and low concentrations of extracellular dopamine induce euphoric, seeking and aversive states, respectively. The other concerns circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity alters approach motivation. These models should help to generate hypothesis-driven research and provide insights for understanding altered states associated with drugs of abuse and affective disorders., (Published by Elsevier B.V.)

Introduction: In some skeletal Class III adult patients with nasomaxillary hypoplasia, the LeFort I osteotomy provides insufficient correction. This case report describes a 20-year-old woman with a combination of nasomaxillary hypoplasia and a protrusive mandible with a congenitally missing mandibular second premolar., Methods: We performed a LeFort II osteotomy for maxillary advancement. Autotransplantation of a tooth was also performed; the donor tooth was used to replace the missing permanent tooth. To increase the chance of success, we applied light continuous force with an improved superelastic nickel-titanium alloy wire technique before extraction and after transplantation., Results: The patient's profile and malocclusion were corrected, and the autotransplanted tooth functioned well. The postero-occlusal relationships were improved, and ideal overbite and overjet relationships were achieved., Conclusions: The methods used in this case represent a remarkable treatment., (Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Background: Quantifying detailed 3-dimensional (3D) kinematics of the foot in contact with the ground during locomotion is crucial for understanding the biomechanical functions of the complex musculoskeletal structure of the foot. Biplanar X-ray fluoroscopic systems and model-based registration techniques have recently been employed to capture and visualise 3D foot bone movements in vivo, but such techniques have generally been performed manually. In the present study, we developed an automatic model-registration method with biplanar fluoroscopy for accurate measurement of 3D movements of the skeletal foot., Methods: Three-dimensional surface models of foot bones were generated prior to motion measurement based on computed tomography. The bone models generated were then registered to biplanar fluoroscopic images in a frame-by-frame manner using an optimisation technique, to maximise similarity measures between occluding contours of the bone surface models with edge-enhanced fluoroscopic images, while avoiding mutual penetration of bones. A template-matching method was also introduced to estimate the amount of bone translation and rotation prior to automatic registration., Results: We analysed 3D skeletal movements of a cadaver foot mobilized by a robotic gait simulator. The 3D kinematics of the calcaneus, talus, navicular and cuboid in the stance phase of the gait were successfully reconstructed and quantified using the proposed model-registration method. The accuracy of bone registration was evaluated as 0.27 ± 0.19 mm and 0.24 ± 0.19° (mean ± standard deviation) in translation and rotation, respectively, under static conditions, and 0.36 ± 0.19 mm and 0.42 ± 0.30° in translation and rotation, respectively, under dynamic conditions., Conclusions: The measurement was confirmed to be sufficiently accurate for actual analysis of foot kinematics. The proposed method may serve as an effective tool for understanding the biomechanical function of the human foot during locomotion.

This paper proposes a learning from demonstration system based on a motion feature, called phase transfer sequence. The system aims to synthesize the knowledge on humanoid whole body motions learned during teacher-supported interactions, and apply this knowledge during different physical interactions between a robot and its surroundings. The phase transfer sequence represents the temporal order of the changing points in multiple time sequences. It encodes the dynamical aspects of the sequences so as to absorb the gaps in timing and amplitude derived from interaction changes. The phase transfer sequence was evaluated in reinforcement learning of sitting-up and walking motions conducted by a real humanoid robot and compatible simulator. In both tasks, the robotic motions were less dependent on physical interactions when learned by the proposed feature than by conventional similarity measurements. Phase transfer sequence also enhanced the convergence speed of motion learning. Our proposed feature is original primarily because it absorbs the gaps caused by changes of the originally acquired physical interactions, thereby enhancing the learning speed in subsequent interactions.

Sharp wave-associated field oscillations (∼200 Hz) of the hippocampus, referred to as ripples, are believed to be important for consolidation of explicit memory. Little is known about how ripples are regulated by other brain regions. We found that the median raphe region (MnR) is important for regulating hippocampal ripple activity and memory consolidation. We performed in vivo simultaneous recording in the MnR and hippocampus of mice and found that, when a group of MnR neurons was active, ripples were absent. Consistently, optogenetic stimulation of MnR neurons suppressed ripple activity and inhibition of these neurons increased ripple activity. Notably, using a fear conditioning procedure, we found that photostimulation of MnR neurons interfered with memory consolidation. Our results demonstrate a critical role of the MnR in regulating ripples and memory consolidation.

Purpose: Although distraction osteogenesis has been widely accepted to treat craniosynostosis, it occasionally results in wound complications. Positing that they are attributable to the tense pericranium under the scalp, we developed a simple technique to relax the pericranial flap., Methods: In 12- to 15-month-old infants (mean 13 months), we placed a coronal skin incision and dissected the scalp at the subgaleal layer. Then, we peeled the intact pericranium away from the skull along the planned osteotomy to obtain flaps with pedicles on the caudal part. After osteotomy and setting of the distraction device, the pericranial flaps freed from the scalp flap were repositioned to fit the osteotomy line, dura, and distraction device. The galea and skin were approximated layer by layer., Results: The shape of the skull was successfully corrected, and the bone defect created by expansion was filled by osteogenesis in all patients. During a mean follow-up period of 42.2 months, we encountered no wound complications., Conclusions: The replaced relaxed pericranium closely adhered to the osteotomy, and the distraction device facilitated vascular growth and bone restoration. Bone resorption was prevented and skin expansion promoted. In patients with iatrogenic dural injury, the pericranium over the injured dura serves as a barrier to prevent cerebrospinal fluid leakage.

Midbrain dopamine neurons are implicated in motivation and learning. However, it is unclear how phasic excitation of dopamine neurons, which is implicated in learning, is involved in motivation. Here we used a self-stimulation procedure to examine how mice seek for optogenetically-induced phasic excitation of dopamine neurons, with an emphasis on the temporal dimension. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin-2 into the ventral tegmental area, resulting in selective expression of the opsin in dopamine neurons. These mice were trained to press on a lever for photo-pulse trains that phasically excited dopamine neurons. They learned to self-stimulate in a fast, constant manner, and rapidly reduced pressing during extinction. We first determined effective parameters of photo-pulse trains in self-stimulation. Lever-press rates changed as a function of the manipulation of pulse number, duration, intensity, and frequency. We then examined effects of interval and ratio schedules of reinforcement on photo-pulse train reinforcement, which was contrasted with food reinforcement. Reinforcement with food inhibited lever pressing for a few seconds, after which pressing was robustly regulated in a goal-directed manner. In contrast, phasic excitation of dopamine neurons robustly potentiated the initiation of lever pressing; however, this effect did not last more than 1 s and quickly diminished. Indeed, response rates markedly decreased when lever pressing was reinforced with inter-reinforcement interval schedules of 3 or 10 s or ratio schedules requiring multiple responses per reinforcement. Thus, phasic excitation of dopamine neurons briefly potentiates the initiation of approach behavior with apparent lack of long-term motivational regulation.

Rationale: Approach behavior is regulated by the brain integrating information about environment and body state. Psychoactive drugs interact with this process., Objectives: We examined the extent to which caloric (i.e., food) restriction, amphetamine (AMPH) and lithium interact in potentiating locomotor activity and responding reinforced by visual stimulus (VS), a reward unrelated to energy homeostasis., Methods: Rats either had ad libitum access to food or received daily rations that maintained 85-90 % of their original body weights. Leverpressing turned on a cue light for 1 s and turned off house light for 5 s. AMPH and lithium were administered through intraperitoneal injections and diet, respectively., Results: Food restriction or AMPH (1 mg/kg) alone had little effect on VS-reinforced responding; however, the combination of the two conditions markedly potentiated VS-reinforced responding (fourfold). Food restriction lasting 7 days or longer was needed to augment AMPH's effect on VS-reinforced responding. AMPH (0.3-3 mg/kg) potentiated locomotor activity similarly between food-restricted and ad libitum groups. Repeated injections of AMPH-sensitized locomotor activity, but not VS-reinforced responding. In addition, while chronic lithium treatments (0.2 % lithium carbonate chow) reduced VS-reinforced responding, chronic lithium further augmented AMPH-potentiated VS-reinforced responding., Conclusions: Food restriction interacts with psychoactive drugs to potentiate goal-directed responding unrelated to food seeking in a much more powerful manner than previously thought. The novel finding that lithium can augment a psychostimulant effect of AMPH suggests caution when combining lithium and psychostimulant drugs in clinical settings.

Dopamine neurons in the ventral tegmental area (VTA) are implicated in affective functions. However, it is unclear to what extent dopamine neurons in substantia nigra pars compacta (SNc) play such roles. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin2 (ChR2), halorhodopsin (NpHR), or control vector into the VTA or SNc, resulting in selective expression of these opsins in dopamine neurons. Mice with ChR2 learned instrumental responding to deliver photostimulation into the VTA or SNc and also sought for the compartment where they received photostimulation (i.e., operant place preference). Operant place preference scores were highly correlated with self-stimulation responses. In contrast, mice with NpHR avoided the compartment where they received photostimulation into the VTA, SNc, or dorsal striatum, whereas control mice did not. These observations suggest that the excitation and inhibition of SNc dopamine neurons elicit positive and negative affective effects, respectively, similar to those of VTA dopamine neurons.

In recent years, neuroscientists have produced profound conceptual and mechanistic advances on the neurocircuitry of reward and substance use disorders. Here, we will provide a brief review of intracranial drug self-administration and optogenetic self-stimulation studies that identified brain regions and neurotransmitter systems involved in drug- and reward-related behaviors. Also discussed is a theoretical framework that helps to understand the functional properties of the circuitry involved in these behaviors. The circuitry appears to be homeostatically regulated and mediate anticipatory processes that regulate behavioral interaction with the environment in response to salient stimuli. That is, abused drugs or, at least, some may act on basic motivation and mood processes, regulating behavior-environment interaction. Optogenetics and related technologies have begun to uncover detailed circuit mechanisms linking key brain regions in which abused drugs act for rewarding effects. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'., (Published by Elsevier Ltd.)

Arthrodesis of the first metatarsophalangeal (MTP-1) joint is a widely used procedure for the treatment of hallux valgus in patients with MTP-1 degeneration, severe or recurrent deformity, or inflammatory arthritis. In this case, ten years earlier, the patient's MTP-1 joint had been fused in a severe pronation deformity position. Subsequently, a laterally shifted tibial sesamoid and osseous rising of the phalanx base caused painful callosities. To correct the pronated deformity accurately, a custom-made surgical guide based on a three-dimensional computer tomography (3D-CT) simulation system was used. After correction of the deformity, the MTP-1 joint was again fused. Adequate correction was achieved, and the patient no longer complains of pain and can perform full weight-bearing on the forefoot. The difficulty and importance of placing the MTP-1 joint in an adequate rotational position in MTP-1 joint arthrodesis surgery were confirmed, as was the utility of 3D evaluation and a custom-made surgical guide for rotational adjustment between the metatarsal and the proximal phalanx. We believe that this system should be one of the indicators for adjusting the rotation, especially in revision MTP-1 joint fusion surgery.

This study examined the potential for osteogenesis via regenerative medicine using autologous tissues (umbilical cord (UC) and umbilical cord blood (UCB)) in nude mice. The study was designed to provide the three elements required for regenerative medicine (cell, scaffold, and growth factor) and autoserum for culture by means of autologous tissues. Mesenchymal stromal cells were obtained from UC (UC-MSCs). Fibrin, platelet-rich-plasma, and autoserum were obtained from UCB as scaffold, growth factor and serum for culture respectively. UC-MSCs were obtained from Wharton jelly and cultured with UCB-derived fibrin (UCB-fibrin) for 3-4 weeks to induce their differentiation into osteoblasts. They were implanted subcutaneously into the dorsum of male nude mice for 6 weeks prior to undergoing assessment. The assessments performed were haematoxylin and eosin, and alizarin red staining, immunohistochemical staining of human mitochondria, scanning electron microscopy, scanning electron microscopy with energy dispersive X-ray spectrometry and real-time reverse transcriptase-polymerase chain reaction to assess the expressions of osteoblast markers. Consequently, the differentiation of UC-MSCs into osteoblasts and the production of hydroxyapatite were verified. This study suggested the possible formation of bone tissue using biomedical materials obtained from UC and UCB., (Copyright © 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

The increase in obesity and lipid disorders in industrialized countries may be due to irregular eating patterns. Few studies have investigated the effects of nighttime snacking on energy metabolism. We examined the effects of nighttime snacking for 13 days on energy metabolism. Eleven healthy women (means ± SD; age: 23 ± 1 yr; body mass index: 20.6 ± 2.6 kg/m(2)) participated in this randomized crossover trial for a 13-day intervention period. Subjects consumed a specified snack (192.4 ± 18.3 kcal) either during the daytime (10:00) or the night time (23:00) for 13 days. On day 14, energy metabolism was measured in a respiratory chamber without snack consumption. An oral glucose tolerance test was performed on day 15. Relative to daytime snacking, nighttime snacking significantly decreased fat oxidation (daytime snacking: 52.0 ± 13.6 g/day; nighttime snacking: 45.8 ± 14.0 g/day; P = 0.02) and tended to increase the respiratory quotient (daytime snacking: 0.878 ± 0.022; nighttime snacking: 0.888 ± 0.021; P = 0.09). The frequency of snack intake and energy intake, body weight, and energy expenditure were not affected. Total and low-density lipoprotein (LDL) cholesterol significantly increased after nighttime snacking (152 ± 26 mg/dl and 161 ± 29 mg/dl; P = 0.03 and 76 ± 20 mg/dl and 83 ± 24 mg/dl; P = 0.01, respectively), but glucose and insulin levels after the glucose load were not affected. Nighttime snacking increased total and LDL cholesterol and reduced fat oxidation, suggesting that eating at night changes fat metabolism and increases the risk of obesity.

Objective: Osteogenesis in the bone defect at the site of an alveolar cleft is important to enable patients with cleft lip and palate to acquire dental articulation. The presence of umbilical cord-derived mesenchymal stem cells has been reported. In this study, we used autoserum derived from the umbilical cord blood (UCB) of neonates in an attempt to examine the osteoblastic differentiation potential of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in nude mice., Materials and Methods: UCB, hydroxyapatite, and rhBMP were used as the supply source of autoserum, scaffold, and osteoinductive growth factor, respectively. MSCs, obtained from Wharton's jelly and cultured for 3-4weeks to induce their differentiation into osteoblasts, were implanted subcutaneously into the dorsum of male nude mice for 6weeks before the assessment by real-time reverse transcriptase chain reaction of osteoblast marker expression., Results: UCB-derived autoserum was a viable source for the culture and implantation of UC-MSCs. The osteoblastic differentiation potential of UC-MSCs was demonstrated in nude mice by performing immunohistochemical staining and by the presence of osteoblast marker expression., Conclusions: Our results confirm the osteogenic potential of UC-MSCs and provide basic evidence for the realization of regenerative medicine using autologous tissues., (Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Rationale: The motivational process that regulates approach behavior toward salient distal stimuli (i.e., incentive motivation) plays a key role in voluntary behavior and motivational disorders such as addiction. This process may be mediated by many neurotransmitter systems and a network of many brain structures, including the median and dorsal raphe regions (MR and DR, respectively)., Objective: We sought to examine whether the blockade of excitatory amino acid receptors in the MR and DR is rewarding, using intracranial self-administration, and whether the self-administration effect can be explained by drug's effectiveness to enhance incentive motivation, using a visual sensation seeking procedure., Results: Rats learned to self-administer the AMPA receptor antagonist ZK 200775 into the vicinity of the MR, DR, or medial oral pontine reticular regions, but not the ventral tegmental area. The NMDA receptor antagonist AP5 was also self-administered into the MR, while it was not readily self-administered into other regions. When ZK 200775 was noncontingently administered into the MR, rats markedly increased approach responses rewarded by brief illumination of a light stimulus. In addition, contingent administration of ZK 200775 into the MR induced a conditioning effect on approach responses., Conclusions: Rats self-administer excitatory amino acid receptor antagonists into the MR and adjacent regions. Self-administration effect of AMPA receptor antagonists into the MR can be largely explained by the manipulation's properties to invigorate ongoing approach behavior and induces conditioned approach. Glutamatergic afferents to the median raphe and adjacent regions appear to tonically suppress incentive-motivational processes.

Introduction: Agonists at the mu opioid receptor (MOR) are widely recognized for their effects on reward and pain. Although prior studies have attributed some of these effects to MORs on GABA neurons in the ventral tegmental area (VTA), recent studies have identified a region of particularly strong MOR immunostaining residing caudal to the VTA, in a region denoted the rostromedial tegmental nucleus (RMTg)., Methods: Hence, we examined whether rats would self-administer small doses (50-250 pmol) of the selective MOR agonist endomorphin-1 (EM1) into the RMTg and adjacent sites. EM1 was chosen due to its short half-life, thus limiting drug spread, and due to its presence endogenously in brain neurons, including some afferents to the RMTg., Results: The highest rates of EM1 self-administration occurred within 0.5 mm of the RMTg center, in a region roughly 0.8-1.6 mm caudal to the majority of VTA DA neurons. In contrast, self-administration rates were much lower in the adjacent VTA, interpeduncular nucleus, central linear nucleus, or median raphe nucleus. Furthermore, EM1 infusions into the RMTg, but not surrounding regions, produced conditioned place preference, while EM1 infusions into the RMTg but not anterior VTA markedly reduced formalin-induced pain behaviors. EM1 effects were mimicked by infusions of the GABA agonist muscimol into the same region, consistent with EM1 having inhibitory actions on its target neurons., Conclusion: These results implicate a novel brain region in modulating MOR influences on both appetitive and aversive behavior.

This paper describes a self-protective whole body motor controller to enable life-long learning of humanoid robots. In order to reduce the damages on robots caused by physical interaction such as obstacle collision, we introduce self-protective behaviors based on the adaptive coordination of full-body global reactions and local limb reflexes. Global reactions aim at adaptive whole-body movements to prepare for harmful situations. The system incrementally learns a more effective association of the states and global reactions. Local reflexes based on a force-torque sensing function to reduce the impact load on the limbs independently of high-level motor intention. We examined the proposed method with a robot simulator in various conditions. We then applied the systems on a real humanoid robot., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Bronchial fistula due to bronchial compression is a rare complication following both open surgical and endovascular repair of thoracic aortic aneurysms. We report on the airway management for a case of emergent thoracic endovascular aortic repair (TEVAR) in a patient with left bronchial obstruction due to hemoptysis. A 68-year-old man had undergone total arch replacement 8 years before, and was preoperatively diagnosed with aortobronchial fistula in the left lung. To prevent obstruction of the right lung by rebleeding in the left bronchus, we planned to exchange the single lumen endotracheal tube placed following hemoptysis to a double lumen tube prior to the operation. With assisted spontaneous breathing, bronchoscopy performed before replacing of the endotracheal tube showed obstruction of the left bronchus with many clots. With bronchoscopic assistance, clots were removed from the left bronchus and oxygenation improved significantly. We found a blue nylon suture penetrating the bronchial wall, most likely from a previous operation. However, bronchoscopy did not disclose aortobronchial fistula. Following TEVAR, the patient was diagnosed with bronchopleural fistula induced by bronchial compression due to blood vessel prosthesis and surrounding felt strips. Cooperation from surgeons and careful airway management were required to prevent life-threatening oxygenation insufficiency.

Rationale: Noncontingent administration of amphetamine into the ventral striatum or systemic nicotine increases responses rewarded by inconsequential visual stimuli. When these drugs are contingently administered, rats learn to self-administer them. We recently found that rats self-administer the GABA(B) receptor agonist baclofen into the median (MR) or dorsal (DR) raphe nuclei., Objectives: We examined whether noncontingent administration of baclofen into the MR or DR increases rats' investigatory behavior rewarded by a flash of light., Results: Contingent presentations of a flash of light slightly increased lever presses. Whereas noncontingent administration of baclofen into the MR or DR did not reliably increase lever presses in the absence of visual stimulus reward, the same manipulation markedly increased lever presses rewarded by the visual stimulus. Heightened locomotor activity induced by intraperitoneal injections of amphetamine (3 mg/kg) failed to concur with increased lever pressing for the visual stimulus. These results indicate that the observed enhancement of visual stimulus seeking is distinct from an enhancement of general locomotor activity. Visual stimulus seeking decreased when baclofen was co-administered with the GABA(B) receptor antagonist, SCH 50911, confirming the involvement of local GABA(B) receptors. Seeking for visual stimulus also abated when baclofen administration was preceded by intraperitoneal injections of the dopamine antagonist, SCH 23390 (0.025 mg/kg), suggesting enhanced visual stimulus seeking depends on intact dopamine signals., Conclusions: Baclofen administration into the MR or DR increased investigatory behavior induced by visual stimuli. Stimulation of GABA(B) receptors in the MR and DR appears to disinhibit the motivational process involving stimulus-approach responses.

Animals are able to cope with the noise, uncertainties, and complexity of the real world. Often even elementary living beings, equipped with very limited sensory organs, are able to reach regions favorable to their existence, using simple stochastic policies. In this paper we discuss a minimalistic stochastic behavioral rule, inspired from bacteria chemotaxis, which is able to increase the value of a specified evaluation function in a similar manner. In particular, we prove that, under opportune assumptions, the direction that is taken with maximum probability by an agent that follows this rule corresponds to the optimal direction. The rule does not require a specific agent dynamics, needs no memory for storing observed states, and works in generic n-dimensional spaces. It thus reveals itself interesting for the control of simple sensing robots as well., (© 2012 American Physical Society)

Neuropeptide S (NPS) is an endogenous brain peptide produced by neurons located in the lower brainstem, and functional studies suggest that NPS has arousing effects. Because its receptors are found in reward-associated regions throughout the brain, we evaluated whether intraventricular NPS injections elicit reward-related effects in rats. Rats increased lever presses that led to intraventricular administration of NPS (0.34-34 pmol per infusion) in a dose dependent manner, with a cue-assisted procedure. Cue-assisted self-administration of NPS was decreased by systemic administration of the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.) or the hypocretin-1 (orexin-1) receptor antagonist SB 334867 (20 mg/kg, i.p.). In addition, intraventricular NPS injections (1000 pmol) induced conditioned place preference, whereas a lower dose (100 pmol) of NPS induced conditioned place aversion. Finally, NPS injections (100-1000 pmol) acutely facilitated locomotor activity, whereas repeated NPS injections did not lead to locomotor sensitization. Our data suggest that intraventricular NPS injections have reward-like effects in that NPS weakly facilitates seeking and induces positive reinforcement. These effects may depend on intact dopamine and hypocretin systems., (Published by Elsevier B.V.)

Stochastic resonance (SR) is a phenomenon occurring in nonlinear systems by which the ability to process information, for instance the detection of weak signals is statistically enhanced by a non-zero level of noise. SR effects have been observed in a great variety of systems, comprising electronic circuits, optical devices, chemical reactions and neurons. In this paper we report the SR phenomena occurring in the execution of an extremely simple behavioral rule inspired from bacteria chemotaxis. The phenomena are quantitatively analyzed by using Markov chain models and Monte Carlo simulations., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We investigated whether oral administration of palmitoleate ameliorates disorders of lipid metabolism to clarify the effects of one of the components of fish oil. Lipid levels in the liver and plasma were significantly decreased by palmitoleate and by EPA administration. These results suggest that palmitoleate, in addition to EPA, plays a role in the regulation of lipid metabolism by fish oil.

Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures-the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward. To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area., (Published by Elsevier Ltd.)

Background: Picrotoxin blocks GABAA receptors, whose activation typically inhibits neuronal firing activity. We recently found that rats learn to selectively self-administer picrotoxin or bicuculline, another GABAA receptor antagonist, into the supramammillary nucleus (SuM), a posterior hypothalamic structure localized anterior to the ventral tegmental area. Other drugs such as nicotine or the excitatory amino acid AMPA are also self-administered into the SuM. The SuM appears to be functionally linked with the mesolimbic dopamine system and is closely connected with other brain structures that are implicated in motivational processes, including the prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. Here, we hypothesized that these brain structures are activated by picrotoxin injections into the SuM., Results: Picrotoxin administration into the SuM markedly facilitated locomotion and rearing. Further, it increased c-Fos expression in this region, suggesting blockade of tonic inhibition and thus the disinhibition of local neurons. This manipulation also increased c-Fos expression in structures including the ventral tegmental area, medial shell of the nucleus accumbens, medial prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus., Conclusions: Picrotoxin administration into the SuM appears to disinhibit local neurons and recruits activation of brain structures associated with motivational processes, including the mesolimbic dopamine system, prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. These regions may be involved in mediating positive motivational effects triggered by intra-SuM picrotoxin.

In immunocompromised patients, influenza infection may progress to prolonged viral shedding from the respiratory tract despite antiviral therapy. We describe chronic influenza A virus infection in an immunocompromised child who had prolonged shedding of culturable influenza virus in stool.

Rationale: The midbrain raphe regions have long been implicated in affective processes and disorders. There is increasing evidence to suggest that the median (MR) and dorsal raphe nuclei (DR) tonically inhibit reward-related processes., Objectives: Stimulation of GABAB receptors in the midbrain raphe nuclei is known to inhibit local neurons, especially serotonergic neurons. We sought to determine if injections of the GABAB receptor agonist baclofen into the MR or DR are rewarding, using intracranial self-administration and conditioned place preference., Results: Rats quickly learned to lever press for infusions of baclofen (0.1–2.5 mM) into the MR, but not the ventral tegmental area or central linear nucleus. Rats increased lever pressing associated with intra-DR baclofen infusions, but not readily. Baclofen self-administration into the MR or DR was attenuated by coadministration of the GABAB receptor antagonist SCH 50911 (1 mM) or systemic pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). In addition, intra-DR and intra-MR injections of baclofen induced conditioned place preference; injection into DR was more effective., Conclusions: Baclofen injections into the midbrain raphe nuclei are rewarding. Baclofen was more readily self-administered into the MR than into the DR, while baclofen injections into the DR more readily induced conditioned place preference than those into the MR. These sites may be differentially involved in aspects of reward. These findings suggest that MR or DR neurons containing GABAB receptors are involved in tonic inhibitory control over reward processes.

Background: Administration of psychomotor stimulants like amphetamine facilitates behavior in the presence of incentive distal stimuli, which have acquired the motivational properties of primary rewards through associative learning. This facilitation appears to be mediated by the mesolimbic dopamine system, which may also be involved in facilitating behavior in the presence of distal stimuli that have not been previously paired with primary rewards. However, it is unclear whether psychomotor stimulants facilitate behavioral interaction with unconditioned distal stimuli., Principal Findings: We found that noncontingent administration of amphetamine into subregions of the rat ventral striatum, particularly in the vicinity of the medial olfactory tubercle, facilitates lever pressing followed by visual signals that had not been paired with primary rewards. Noncontingent administration of amphetamine failed to facilitate lever pressing when it was followed by either tones or delayed presentation or absence of visual signals, suggesting that visual signals are key for enhanced behavioral interaction. Systemic administration of amphetamine markedly increased locomotor activity, but did not necessarily increase lever pressing rewarded by visual signals, suggesting that lever pressing is not a byproduct of heightened locomotor activity. Lever pressing facilitated by amphetamine was reduced by co-administration of the dopamine receptor antagonists SCH 23390 (D1 selective) or sulpiride (D2 selective)., Conclusions: Our results suggest that amphetamine administration into the ventral striatum, particularly in the vicinity of the medial olfactory tubercle, activates dopaminergic mechanisms that strongly enhance behavioral interaction with unconditioned visual stimuli.

A 61-year-old man was referred to our department because of painless and stony hard mass beside the left testis. Serum levels of lactate dehydrogenase, alpha-fetoprotein and human chorionic gonadotropin were within normal ranges. The ultrasonography of the mass showed almost homogenous and relatively low intensity echogram. The mass which derived from the left spermatic cord and was partially surrounded by fat-like soft and yellow tissue, was removed with the left testis by usual orchiectomy. Histopathological diagnosis was liposarcoma, whose subtype was dedifferentiated type derived from well differentiated type. Postoperatively, a para-aortic mass, which resembled lymphnode metastasis, was pointed by computed tomographic scan and was removed surgically. However, it was histopathologically diagnosed as neurogenicganglioma irrelevant to liposarcoma. He has been free of disease for about 1 year without any adjuvant therapy.

Low calcium intake and physical inactivity are modifiable risk factors of osteoporosis; however, little information is available about the prevalence of these risk factors among urban Filipino women living on low-incomes. The present study, therefore, investigated daily calcium intake, main calcium sources, and physical activity status in this population. The study group comprised healthy women aged in their 30 s who had participated in our previous survey using heel speed of sound (SOS) measurement in Davao, Philippines. The women were stratified into three groups based on SOS score and 20 were randomly selected from each, giving 60 in total. Calcium intake was measured by direct analysis of the food samples collected from 3-days 24 hour-food duplicate method. Physical activity was estimated based on pedometer determined walking steps over 5 days. The median [25%, 75%] calcium intake per day was 289 [225, 434] mg. Traditional foods derived from local small fish and plants were the main calcium sources. The median walking steps per day was 8750 [6920, 10836]. Although three groups did not show significantly different calcium intakes and walking steps, consumption of low-cost small fish and plant foods could be encouraged along with walking in urban Filipino women living on low-incomes.

A 48-year-old man consulted our hospital complaining of painless swelling of the left scrotal contents that had gradually increased for 5 years. Serum LDH, alpha-fetoprotein and HCG were within normal ranges. The ultrasonography showed heterogeneous echogram including high-echogenic spots and relatively a low-echogenic hydrocele. Left high orchiectomy was performed and the removed tissue was 24 x 16 x 15 cm in size, which had large cystic cavity filled with cloudy and deep-green mucin. Pathological diagnosis was mucinous adenocarcinoma. Postoperatively analyzed serum CEA, CA19-9 and PSA were within normal ranges. Systemic X-ray examinations, such as lung, abdominal and pelvic CT scan, upper GI series and barium enema, did not show any abnormal SOL suggesting carcinoma. Therefore, we diagnosed this case as a primary adenocarcinoma in the scrotal contents. The patient has been observed without any adjuvant therapy since operation, but no signs of recurrence have been identified for one year and six months.

Increasing evidence suggests that the activation of medial A10 neurons mediates positive affective encoding. However, little is known about the functions of the inhibition of midbrain dopamine neurons. Here we show evidence suggesting that the inhibition of medial A10 neurons mediates a negative affective state, leading to negative affective encoding, whereas blunting the activation of medial A10 neurons disrupts positive affective encoding involving food reward. We used a microinjection procedure, in which the D(2) dopamine receptor agonist quinpirole was administered into the cell body region of the dopamine neurons, a procedure that reduces dopamine cell firing. Microinjections of quinpirole into the posteromedial ventral tegmental area, but not its more lateral counterparts, led to conditioned place aversion. Quinpirole administration to this site also decreased food intake and basal dopamine concentration in the ventromedial striatum, a major projection area of medial A10 neurons. In addition, moderate quinpirole doses that did not lead to conditioned place aversion or disrupt food intake abolished food-conditioned place preference, suggesting that blunting dopamine impulse activity in response to food reward disrupts positive affective encoding in associated external stimuli. Our data support the hypothesis that activation of medial A10 dopamine neurons mediates a positive affective state, leading to positive affective encoding, while their inhibition mediates a negative affective state, leading to negative affective encoding. Together with previous findings, we propose that medial A10 neurons are an important component of the mechanism via which animals learn to avoid negative incentive stimuli.

Rationale: Behavioral and anatomical data suggest that the ventral striatum, consisting of the nucleus accumbens and olfactory tubercle, is functionally heterogeneous. Cocaine and D: -amphetamine appear to be more rewarding when administered into the medial olfactory tubercle or medial accumbens shell than into their lateral counterparts, including the accumbens core., Objectives: We sought to determine whether rats self-administer the popular recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA) into ventrostriatal subregions and whether the medial olfactory tubercle and medial accumbens shell mediate MDMA's positive reinforcing effects more effectively than their lateral counterparts., Results: Rats receiving 30 mM MDMA into the medial olfactory tubercle, medial accumbens shell, or accumbens core, but not the lateral tubercle or lateral shell, showed higher self-administration rates than rats receiving vehicle. The medial shell supported more vigorous self-administration of MDMA at higher concentrations than the core or medial olfactory tubercle. In addition, intra-medial shell MDMA self-administration was disrupted by co-administration of the D1 or D2 receptor antagonists SCH 23390 (1-3 mM) or raclopride (3-10 mM)., Conclusions: Our data suggest that the ventral striatum is functionally heterogeneous. The medial accumbens shell appears to be more important than other ventrostriatal subregions in mediating the positive reinforcing effects of MDMA via both D1- and D2-type receptors. Together with previous data, our data also suggest that unidentified actions of MDMA interfere with the positive reinforcing effects of dopamine in the medial olfactory tubercle.

Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.

A patient who had been on long-term hemodialysis (HD) was diagnosed as having renal cell carcinoma (RCC) and pheochromocytoma. Abdominal computed tomography scanning demonstrated a right renal mass and a right adrenal mass, whereas positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG) revealed increased accumulation in both the renal and adrenal masses. FDG-PET is useful for detecting RCC in HD patients because FDG is not excreted in the urine, but it is difficult to distinguish pheochromocytoma from an adrenal metastasis by this imaging method.

Although intravesical instillation of bacillus Calmette-Guerin (BCG) is a clinically well-recognized therapy for bladder carcinoma in situ and recurrence prophylaxis, these mechanisms have not been fully understood. We studied the effects of BCG infection (Connaught strain) on target cancer cells and host immune systems in murine bladder cancer. The bladder cancer cell line, MB49, was used in C57/BL6 mice in vivo and in vitro. In vitro cytotoxicities against the cancer cell line were measured by 24-h 51Cr release assay. For effector cells, spleen mononuclear cells were obtained from mice injected intraperitoneally with BCG or BCG-infected irradiated MB49 cells. Although BCG infection of cancer cells did not affect the proliferation speed in vitro, the mice injected subcutaneously with BCG-infected MB49 cells survived significantly longer than those given untreated cancer cells. The mice surviving without tumor growth after injection of BCG-infected cancer cells could not reject a second injection of intact MB49 cells. In vitro cytotoxicity was enhanced by BCG infection of target cancer cells, but not by immunizing the mice with BCG from which effector cells were obtained. Moreover, cytotoxicity disappeared by depleting natural killer (NK) cells from effector cells. Although in vitro cytotoxicity was increased by immunizing the mice with BCG-infected irradiated MB49 cells, survival did not improve in these mice. These results suggest that a major part of BCG's anti-tumor effects can be attributed to the elimination of BCG-infected cancer cells by NK cells.

Because rats learn to lever-press for brief electrical stimulation of the median and dorsal raphe nuclei (MRN and DRN, respectively), these brain sites have long been implicated in reward processes. However, it is not clear whether the MRN and DRN integrate reward-related signals or merely contain fibers of passage involved in reward processes. To shed light on this issue, the present study employed chemicals that selectively modulate neurotransmission, in particular the GABA(A) receptor agonist muscimol. Rats quickly learned to lever-press for muscimol infusions (50 and 100 microM) into the MRN or DRN. Muscimol was not self-administered when cannulae were placed just outside these nuclei. The reinforcing effects of muscimol appeared to be greater when the drug was administered into the MRN than into the DRN, as demonstrated by higher infusion rates and better response discrimination. These observations are consistent with the additional finding that muscimol administration into the MRN, but not the DRN, induced conditioned place preference. The reinforcing effects of muscimol administration into the MRN were blocked by coadministration of the GABA(A) antagonist picrotoxin (100 microM) and by pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). The present results suggest that median and dorsal raphe neurons presumably inhibited by muscimol via GABA(A) receptors are involved in integration of primary reinforcement, and that median raphe neurons exert tonic inhibition over dopamine-dependent reward circuitry. The midbrain raphe nuclei may be involved in a variety of reward-related phenomena including drug addiction.

Purpose: Bisphosphonates have been reported to be effective in reducing bone pain and skeletal-related events associated with bone metastases in hormone-refractory prostate cancer (HRPC). However, whether bone resorption is reduced primarily by these particular drugs is difficult to evaluate because patients with HRPC are usually treated with secondary or tertiary hormonal manipulations including second-line antiandrogens, high-dose diethylstilbestrol, or low-dose dexamethasone therapies, some of which may also be effective. Thus, we assessed changes in the level of the carboxyterminal telopeptide of type-I collagen (ICTP), a bone resorption marker, before and after pamidronate administration in HRPC patients with increasing prostate-specific antigen (PSA) levels., Patients and Methods: Twenty-one HRPC patients with bone metastases and increasing PSA levels were intravenously treated with pamidronate at a dose of 30 mg either every 2 or every 4 weeks. Pamidronate administration was started immediately after confirmation of three consecutive increases in the PSA level., Results: In 14 patients (67%), the ICTP levels decreased after the administration of pamidronate, despite increasing PSA levels. In 7 of these cases, the ICTP levels were lower than those recorded for 6 months or longer before the start of pamidronate administration. The characteristics of the responders were compared with those of the non-responders., Conclusion: In 67% of the HRPC patients with increasing PSA levels, pamidronate reduced the accelerated turnover of bone metabolism caused by metastases of prostate cancer.

Tissue engineering requires the delivery and survival of cells to organ sites needing repair. Previously, we showed that an active laminin peptide (AG73: RKR-LQVQLSIRT)-conjugated chitosan membrane promoted cell adhesion and spreading in vitro. Here, we seeded human keratinocytes onto AG73-chitosan membranes and found that nearly 80% of the cells were attached to the membranes within 2 h. The membranes carrying the keratinocytes were inverted and placed onto exposed muscle fascia on the backs of nude mice. After 3 days, the keratinocytes had migrated from the membrane and established a stratified epidermis-like structure on the fascia. Cells recognize the AG73 through transmembrane proteoglycan syndecans, which recognition system has not previously been tested in tissue engineering applications. We suggest that the AG73-chitosan membrane is useful as a therapeutic formulation and is applicable as a cell delivery system such as delivering keratinocytes to a wound bed.