Twenty Years After Enactment of the Organ Transplant Law in Japan: Why Are There Still So Few Deceased Donors?

BACKGROUND: Twenty years have passed since the 1997 enactment of the Organ Transplant Law in Japan, but the number of deceased donors remains extremely low. In this study we examine why deceased donation has continued to remain so infrequent. METHODS: This investigation was a secondary analysis of published data from the Japan Organ Transplant Network, 2016 Fact Book of Organ Transplantation in Japan, and International Registry on Organ Donation and Transplantation. RESULTS: In the past 20 years, donation intent declarations, knowledge, and respect for family member's wishes have increased, whereas resistance toward transplantation has decreased. Despite this, the traditional perspective on corpses of gotai manzoku (ie, the soul cannot be put to rest without being physically intact and without defect), the family-centricism, and reward-seeking altruism have not changed much. Living organ transplants have alleviated the organ deficiency somewhat, and the law requiring family consent seems to have contributed to the observed small increase in deceased donors. CONCLUSION: The number of deceased donors is unlikely to increase suddenly. However, 8 strategies are proposed to increase the number of deceased donors, including: increasing the number of donor procurement coordinators and establishing a training system; increasing the number of organ procurement facilities; creating hub transplant centers and training transplant surgeons; implementing radical reform in public education; reducing workload and improving education of emergency physicians, neurosurgeons, and pediatricians; revisiting the stringent standards of brain-death determination; revisiting the registration process; and considering development of a Japanese version of organ procurement organizations as well as revisions to the Organ Transplant Law. The Japanese government and academic societies must work together to increase the number of deceased donors in Japan.

Phenotypic characterization of orofacial movement topography in mutants with disruption of amino acid mechanisms: glutamate N2A/B/D [GluRε1/2/4] subtypes and the GABA synthesizing enzyme GAD65.

To investigate the role of glutamate receptor subtypes and GABA in orofacial function, six individual topographies of orofacial movement, both spontaneous and induced by the dopamine D1-like receptor agonist [R/S]-3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 83959), were quantified in mutant mice with deletion of (a) GluN2A, B or D receptors, and (b) the GABA synthesizing enzyme, 65-kD isoform of glutamate decarboxylase (GAD65). In GluN2A mutants, habituation of head movements was disrupted and vibrissae movements were reduced, with an overall increase in locomotion; responsivity to SKF 83959 was unaltered. In GluN2B mutants, vertical and horizontal jaw movements and incisor chattering were increased, with an overall decrease in locomotion; under challenge with SKF 83959, head and vibrissae movements were reduced. In GluN2D mutants, horizontal jaw movements, incisor chattering and vibrissae movements were increased, with reduced tongue protrusions and no overall change in locomotion; under challenge with SKF 83959, horizontal jaw movements were increased. In GAD65 mutants, vertical jaw movements were increased, with disruption to habituation of locomotion; under challenge with SKF 83959, vertical and horizontal jaw movements and incisor chattering were decreased. Effects on orofacial movements differed from their effects on regulation of overall locomotor behavior. These findings (a) indicate novel, differential roles for GluN2A, B and D receptors and for GAD65-mediated GABA in the regulation of individual topographies of orofacial movement and (b) reveal how these roles differ from and/or interact with the established role of D1-like receptors in pattern generators and effectors for such movements.

Impact of sarcopenia on survival in patients undergoing living donor liver transplantation.

Skeletal muscle depletion, referred to as sarcopenia, predicts morbidity and mortality in patients undergoing digestive surgery. However, the impact on liver transplantation is unclear. The present study investigated the impact of sarcopenia on patients undergoing living donor liver transplantation (LDLT). Sarcopenia was assessed by a body composition analyzer in 124 adult patients undergoing LDLT between February 2008 and April 2012. The correlation of sarcopenia with other patient factors and the impact of sarcopenia on survival after LDLT were analyzed. The median ratio of preoperative skeletal muscle mass was 92% (range, 67-130%) of the standard mass. Preoperative skeletal muscle mass was significantly correlated with the branched-chain amino acids to tyrosine ratio (r = -0.254, p = 0.005) and body cell mass (r = 0.636, p < 0.001). The overall survival rate in patients with low skeletal muscle mass was significantly lower than in patients with normal/high skeletal muscle mass (p < 0.001). Perioperative nutritional therapy significantly increased overall survival in patients with low skeletal muscle mass (p = 0.009). Multivariate analysis showed that low skeletal muscle mass was an independent risk factor for death after transplantation. In conclusion, sarcopenia was closely involved with posttransplant mortality in patients undergoing LDLT. Perioperative nutritional therapy significantly improved overall survival in patients with sarcopenia.

[Solid follicular bronchiolitis].

A 64-year-old man presented a nodular shadow in the right lower lobe on a chest computed tomography (CT) scan. The nodule had grown remarkably in 3 years and was suspected to be a lung cancer. An open lung biopsy showed a solid lesion adjacent to lung abscess, and histopathological examination of a biopsy specimen revealed follicular bronchiolitis. Follicular bronchiolitis is a rare condition and is reported to occur mainly in association with connective tissue disorders or immunodeficiency syndromes. In such conditions, it generally exhibits bilateral, diffuse, small nodular lesions or ground-glass opacities. The present case was not associated with such underlying diseases and was thought to have occurred in association with lung abscess. Few cases of follicular bronchiolitis caused by non-specific airway infection have been reported in Japan.

Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway.

Carbon monoxide (CO) provides protection against oxidative stress via anti-inflammatory and cytoprotective actions. In this study, we tested the hypothesis that a low concentration of exogenous (inhaled) CO would protect transplanted lung grafts from cold ischemia-reperfusion injury via a mechanism involving the mitogen-activated protein kinase (MAPK) signaling pathway. Lewis rats underwent orthotopic syngeneic or allogeneic left lung transplantation with 6 h of cold static preservation. Exposure of donors and recipients (1 h before and then continuously post-transplant) to 250 ppm CO resulted in significant improvement in gas exchange, reduced leukocyte sequestration, preservation of parenchymal and endothelial cell ultrastructure and reduced inflammation compared to animals exposed to air. The beneficial effects of CO were associated with p38 MAPK phosphorylation and were significantly prevented by treatment with a p38 MAPK inhibitor, suggesting that CO's efficacy is at least partially mediated by activation of p38 MAPK. Furthermore, CO markedly suppressed inflammatory events in the contralateral naïve lung. This study demonstrates that perioperative exposure of donors and recipients to CO at a low concentration can impart potent anti-inflammatory and cytoprotective effects in a clinically relevant model of lung transplantation and support further evaluation for potential clinical use.

Role of alpha adrenoceptors in the nucleus accumbens in the control of accumbal noradrenaline efflux: a microdialysis study with freely moving rats.

Microdialysis technique was used to study the effects of the locally applied alpha adrenoceptor agonist phenylephrine and antagonist phentolamine on the basal noradrenaline efflux as well as on the noradrenaline uptake inhibitor desipramine-elicited noradrenaline efflux in the nucleus accumbens (NAc) of freely moving rats. Tetrodotoxin reduced basal noradrenaline efflux by 72%, whereas desipramine increased it by 204%. Phenylephrine reduced the basal noradrenaline efflux by 32% and phentolamine blocked this effect. Phentolamine elevated the basal noradrenaline efflux by 150% and phenylephrine counteracted this effect. The desipramine-elicited noradrenaline efflux was not affected by phenylephrine, but enhanced by phentolamine. Desipramine counteracted the effects of phenylephrine and potentiated those of phentolamine. These results indicate that the accumbal noradrenaline efflux is under inhibitory control of alpha adrenoceptors that are suggested to be presynaptically located on adrenergic nerve terminals in the NAc. Furthermore, this study suggests that the conformational state of alpha adrenoceptors varies across the available amount of noradrenaline. The clinical impact of these data is discussed.

Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury.

Carbon monoxide (CO), a byproduct of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. In vivo recipient CO inhalation at low concentrations prevented ischemia/reperfusion (I/R) injury associated with small intestinal transplantation (SITx). This study examined whether ex vivo delivery of CO in University of Wisconsin (UW) solution could ameliorate intestinal I/R injury. Orthotopic syngenic SITx was performed in Lewis rats after 6 h cold preservation in control UW or UW that was bubbled with CO gas (0.1-5%) (CO-UW). Recipient survival with intestinal grafts preserved in 5%, but not 0.1%, CO-UW improved to 86.7% (13/15) from 53% (9/17) with control UW. At 3 h after SITx, grafts stored in 5% CO-UW showed improved intestinal barrier function, less mucosal denudation and reduced inflammatory mediator upregulation compared to those in control UW. Preservation in CO-UW associated with reduced vascular resistance (end preservation), increased graft cyclic guanosine monophosphate levels (1 h), and improved graft blood flow (1 h). Protective effects of CO-UW were reversed by ODQ, an inhibitor of soluble guanylyl cyclase. In vitro culture experiment also showed better preservation of vascular endothelial cells with CO-UW. The study suggests that ex vivo CO delivery into UW solution would be a simple and innovative therapeutic strategy to prevent transplant-induced I/R injury.

A rare case of recurrent alpha-fetoprotein-producing gastric cancer without re-elevation of serum AFP.

We report an extremely rare case of recurrent alpha-fetoprotein (AFP)-producing gastric cancer without re-elevation of serum AFP. The patient was a 78-year-old woman with AFP-producing gastric cancer, a rare type of gastric adenocarcinoma. A Borrmann III gastric tumour was surgically resected and AFP-producing gastric cancer was diagnosed based on high levels of serum AFP (705.44 ng/ml) and immunohistochemical examination of the tumour. The serum AFP level decreased to the normal range after resection without any sign of recurrence by imaging, but the patient developed local recurrence of the cancer and died 13 months after surgery. No re-elevation of serum AFP levels was observed after recurrence. Although serum AFP levels are believed to be useful for follow-up in the post-operative period, the possibility that serum AFP levels do not always correlate with the extent of the cancer should be kept in mind.

[Surgically treated mucoepidermoid carcinoma in a 6-year-old boy; report of a case].

A 6-year-old boy was admitted to our hospital with a history of recurrent obstructive pneumonia and hemoptysis. A chest computed tomography (CT) showed atelectasis in the left lower lobe. Angiograpy, which was performed for the suspicion of pulmonary sequestration, showed no feeding artery and revealed bleeding from the bronchial artery in the left lower lobe. As hemoptysis would not stop, an emergency left lower lobectomy was performed. Macroscopic examination of the resected specimen revealed a mass measuring 20 x 15 x 17 mm in the S8 proximal lung parenchyma, bronchiectasis, and an abscess in the distal lung parenchyma. Histopathologic examination determined the tumor was a mucoepidermoid carcinoma. Immunohistochemical staining revealed some tumor cells were positive for CA 19-9. The child has not had a recurrence 3 years postoperatively.

Phenotypic resolution of spontaneous and D1-like agonist-induced orofacial movement topographies in congenic dopamine D1A receptor 'knockout' mice.

A novel system was used to assess the role of D(1)-like dopamine receptors in distinct topographies of orofacial movements in mice with congenic D(1A) receptor knockout. Under spontaneous conditions, vertical jaw movements in wild-types declined with time at a rate that was reduced in D(1A) mutants, while horizontal jaw movements emerged progressively in wild-types but not in D(1A) mutants; tongue protrusions were absent in D(1A) mutants, while incisor chattering was initially reduced in D(1A) mutants but rose subsequently to reach the level of wild-types. D(1A) receptors exert a topographically specific role in regulating individual spontaneous orofacial movements, and these involve interactions with psychomotor processes which 'sculpt' behavioural change over time. The anomalous D(1)-like agonist SK&F 83959, which fails to stimulate, and indeed inhibits the stimulation of adenylyl cyclase induced by dopamine, readily stimulated vertical jaw movements, tongue protrusions and incisor chattering, and these response topographies were absent in D(1A) mutants. These results suggest that D(1A) receptors may exert some form of permissive role over orofacial topographies initiated via a novel, putative D(1)-like site not linked to adenylyl cyclase, or that some D(1A) receptors might be coupled to a transduction system other than adenylyl cyclase.

Hemoglobin-vesicles as oxygen carriers: influence on phagocytic activity and histopathological changes in reticuloendothelial system.

Hemoglobin-vesicles (HbV) have been developed for use as artificial oxygen carriers (particle diameter, 250 nm) in which a purified Hb solution is encapsulated with a phospholipid bilayer membrane. The influence of HbV on the reticuloendothelial system was studied by carbon clearance measurements and histopathological examination. The HbV suspension ([Hb] = 10 g/dl) was intravenously infused in male Wistar rats at dose rates of 10 and 20 ml/kg, and the phagocytic activity was measured by monitoring the rate of carbon clearance at 8 hours and at 1, 3, 7, and 14 days after infusion. The phagocytic activity transiently decreased one day after infusion by about 40%, but it recovered and was enhanced at 3 days, showing a maximum of about twice the quiescent level at 7 days, and then returned to the normal value at 14 days. The initial transient decreased activity indicates a partly, but not completely, suppressed defensive function of the body. The succeeding increased phagocytic activity corresponds to the increased metabolism of HbV. The histopathological examination with anti-human Hb antibody, hematoxylin/eosin, and oil red O stainings showed that HbV was metabolized within 7 days. Hemosiderin was very slightly confirmed with Berlin blue staining at 3 and 7 days in liver and spleen, though they completely disappeared at 14 days, indicating that the heme metabolism, excretion or recycling of iron proceeded smoothly and iron deposition was minimal. Electron microscopic examination of the spleen and liver tissues clearly demonstrated the particles of HbV with a diameter of about 1/40 of red blood cells in capillaries, and in phagosomes as entrapped in the spleen macrophages and Kupffer cells one day after infusion. The vesicular structure could not be observed at 7 days. Even though the infusion of HbV modified the phagocytic activity for 2 weeks, it does not seem to cause any irreversible damage to the phagocytic organs. These results offer important information for evaluating the safety issues of HbV for clinical use.

The psychopharmacology-molecular biology interface: exploring the behavioural roles of dopamine receptor subtypes using targeted gene deletion ('knockout').

In the absence of selective agonists and antagonists able to discriminate between individual members of the D1-like and D2-like families of dopamine receptor subtypes, functional parcellation has remained problematic. 'Knockout' of these subtypes by targeted gene deletion offers a new approach to evaluating their roles in the regulation of behaviour. Like any new technique, 'knockout' has associated with it a number of methodological limitations that are now being addressed in a systematic manner. Studies on the phenotype of D1(A/1), D(1B/5), D2, D3 and D4 'knockouts' at the level of spontaneous and agonist/antagonist-induced behaviour are reviewed, in terms of methodological issues, neuronal implications and potential clinical relevance. Dopamine receptor subtype 'knockout' is a nascent technology that is now beginning to fulfil its potential. It is being complemented by more systematic phenotypic characterisation at the level of behaviour and additional, molecular biologically-based approaches.

Topographical assessment and pharmacological characterization of orofacial movements in mice: dopamine D(1)-like vs. D(2)-like receptor regulation.

A novel procedure for the assessment of orofacial movement topographies in mice was used to study, for the first time, the individual and interactive involvement of dopamine D(1)-like vs. D(2)-like receptors in their regulation. The dopamine D(1)-like receptor agonists A 68930 ([1R,3S]-1-aminomethyl-5,6-dihydroxy-3-phenyl-isochroman) and SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine) each induced vertical jaw movements with tongue protrusions and incisor chattering. The dopamine D(1)-like receptor antagonists SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and BW 737C ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) antagonised these responses, while the dopamine D(2)-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide) attenuated those to SK&F 83959 and released horizontal jaw movements. These findings suggest some role for a dopamine D(1)-like receptor that is coupled to a transduction system other than/additional to adenylyl cyclase, and for dopamine D(1)-like:D(2)-like receptor interactions, in the regulation of individual orofacial movement topographies in the mouse. This methodology will allow the use of knockout mice to clarify the roles of individual dopamine receptor subtypes in their regulation.

Differential diagnosis of a lateral cervical cyst and solitary cystic lymph node metastasis of occult thyroid papillary carcinoma.

We present a case of solitary cystic lymph node metastasis from an occult thyroid papillary carcinoma mimicking a lateral cervical cyst, and a case of thyroid papillary carcinoma with a true lateral cervical cyst. Based on a comparison of the radiographical findings of the two cases, differential diagnosis between cystic lymph node metastasis of papillary carcinoma and branchial cyst is discussed.

Homogeneous epithelial gamma delta T cell repertoire of the skin is shaped through peripheral selection.

In contrast to the T cell receptor (TCR) diversity of major alpha beta T cells in lymphoid tissues, epithelial T cells of the murine skin, called dendritic epidermal T cells (DETC), express exclusively an invariant gamma delta TCR. Fetal thymic precursors of DETC immigrate to the skin before birth, and in adult mice T cells expressing the canonical gamma delta TCR identical to that of DETC are not found in other lymphoid or epithelial tissues. Here, we show that DETC precursors migrate to the gut as well as to the skin during fetal periods, but preferentially survive and expand in the skin after birth. We propose that similar to the thymic selection of the diverse alpha beta T cell repertoire, 'peripheral selection' of the homogeneous epithelial gamma delta T cell repertoire may be mediated by TCR signaling upon the recognition of the self-ligand, because the ligand for the DETC TCR was expressed only in the skin.

[Approaches to sella turcica in endoscopic pituitary surgery].

Recent advances in endoscopic sinus surgery suggested the potential for its surgical application to pituitary surgery. A number of institutions have reported the advantage of endoscope use in pituitary surgery, which is now widely accepted, but approaches to the sella vary in the literature. We retrospectively studied sella approaches in endoscopic pituitary surgery as rhinologists. Subjects included 6 cases of pituitary adenoma and 2 cases of Rathke's cleft cyst. A both-nostril transnasal transsphenoidal approach, our standard technique, was used in 6 cases. This approach consisted of elevation of mucoperiosteal flaps, resection of the vomer and sphenoid anterior wall, and opening of the sellar floor. Elevated mucoperiosteal flaps were used to close of the sella after tumor resection. All tumors were removed and no significant postoperative complications occurred. We found the both-nostril transnasal approach to be easy and time-saving and provided surgeon with a broad surgical field necessary to treat large tumors and accidental cases. Postoperative observation of the sella was easy for wide opening of the anterior wall of the sphenoid sinus. In our experience with reoperation, we quickly accessed the sella and easily removed tumors in the second operation. Our technique therefore has an advance in treatment of recurrence. The both-nostril transnasal approach involves the same procedures as median drainage of the sphenoid sinus, so our technique may have advantages in preventing mucocele of the sphenoid sinus as a late complication of transsphenoidal surgery. The transnasal transsphenoidal approach via both nostrils is preferable rhinologically.

Magnetic resonance angiography evaluation of basilar artery stenosis in patients with vertebrobasilar insufficiency.

To assess the usefulness of evaluating basilar arterial flow by magnetic resonance angiography (MRA), MRA results for patients with vertebrobasilar insufficiency (VBI) were compared with those for age-matched individuals with no vestibular disorders. The presence of stenosis in the basilar artery, its severity and the presence of complications associated with atherosclerosis in the two groups were statistically compared. Analyses revealed significant differences in the incidence of stenosis, its severity, and the incidence of complications between the two groups. These findings suggest that MRA is valuable for the estimation of vertebrobasilar hemodynamics. MRA evaluation of basilar artery stenosis appears to be suitable for identifying a high-risk group among VBI patients, since basilar artery stenosis can result in serious disabilities.