High-dose granulocyte-colony stimulating factor promotes neointimal hyperplasia in the early phase and inhibits neointimal hyperplasia in the late phase after vascular injury

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) affects injured arteries through early endothelialization. Some reports, however, have cautioned that the restenosis rate may increase after G-CSF injection. In the present study, high-dose G-CSF was administered to mice with vascular injury to clarify its effect. METHODS AND RESULTS: Mice were received daily subcutaneous injections of saline or a high dose (300 microg/kg) of G-CSF for 5 days after vascular injury. In the FACS analysis, CD34-/Sca-1-positive progenitor cells were more abundant in the G-CSF group (p<0.05). Neointimal hyperplasia was more evident in the G-CSF group at 1 week (p<0.05), whereas at 4 weeks it was more evident in the control group (p<0.01). TUNEL-positive cells in the arterial wall were more numerous in the G-CSF group at day 1 (p<0.01). CD34-positive cells were observed in the G-CSF group at 1 week. Re-endothelialization appeared earlier in the G-CSF group (at 4 weeks; p<0.01). An increased number of 1A4-positive smooth muscle cells were found in bone marrow cell culture treated with G-CSF. CONCLUSION: High-dose G-CSF induced neointimal proliferation through excessive inflammation and bone marrow cell mobilization in the early phase. In the late phase, however, it induced early re-endothelialization and thereby inhibited neointimal hyperplasia.     

Altered accumbens neural response to prediction of reward associated with place in dopamine D2 receptor knockout mice

Midbrain dopaminergic activity seems to be important in forming the prediction of future events such as rewards. The nucleus accumbens (NAc) plays an important role in the integration of reward with motor function, and it receives dense dopamine innervation and extensive limbic and cortical afferents. Here, we examined the specific role of the dopamine D2 receptor (D2R) in mediating associative learning, locomotor activity, and regulating NAc neural responses by using D2R-knockout (KO) mice and their wild-type littermates. D2R-KO mice displayed reduced locomotor activity and slower acquisition of a place-learning task. D2R-KO eliminated the prereward inhibitory response of neurons in the NAc. In contrast, an increased number of neurons in D2R-KO mice displayed place-related activity. These results provide evidence that D2R in the NAc participates in coding for a specific type of neural response to incentive contingencies and partly in spatial learning.     

Impact of Arterial Reconstruction With Recipient's Own Internal Iliac Artery for Multiple Graft Arteries on Living Donor Kidney Transplantation: Strobe Study

The aim of this study is to investigate the usefulness of arterial reconstruction using the recipient''s own internal iliac artery for multiple kidney graft arteries.The safety and efficacy of various arterial reconstruction methods have been demonstrated. Although some reports have documented arterial reconstruction with the recipient''s own internal iliac artery for multiple kidney graft arteries using the interposition method, usefulness of this technique has not yet been investigated compared with other arterial reconstruction methods.Between January 2008 and April 2014, 532 living donor kidney transplants in adult recipients were performed at 1 center. Of these, 389 kidney grafts had a single artery and did not need arterial reconstruction (nonarterial reconstruction group). Among the bench surgery patients, 19 kidney grafts for multiple arteries were performed using the interposition method with the recipient''s own internal iliac artery (interposition group). Seventy-nine kidney grafts were performed using conjoined reconstruction (conjoined group) and 15 kidney grafts were performed using end-to-side reconstruction (end-to-side group). Total ischemic time (the period between arterial clamp and blood reperfusion), time to initial urination, perioperative and postoperative estimated glomerular filtration rate (eGFR), and complication rates between the interposition group and other 3 groups were retrospectively investigated. This study was based on the STROBE compliant.Warm ischemic time (the period between arterial clamp and beginning of the cold perfusion) of interposition group was significantly longer than that of nonarterial reconstruction group. Total ischemic time of the interposition group was significantly longer than those of other 3 groups. But time to initial urination, perioperative and postoperative eGFR, and complications were similar to other 3 groups.The interposition method was shown to be a useful standard method for multiple kidney graft arteries of living donor kidney transplantation in carefully selected recipients without calcification of the iliac arteries.     

A Retrospective Study of the Impact of Intraoperative Intact Parathyroid Hormone Monitoring During Total Parathyroidectomy for Secondary Hyperparathyroidism: STARD Study

The study aimed to evaluate the diagnostic accuracy of intraoperative intact parathyroid hormone (IO-iPTH) in patients with secondary hyperparathyroidism (HPT).The cut-off for IO-iPTH monitoring remains unknown.This was a single-center retrospective review of 226 consecutive patients (107 males and 119 females) who underwent parathyroidectomy data for secondary HPT between May 2010 and March 2014. The predetermined cut-off for IO-iPTH was a 70% IO-iPTH drop from baseline 10 minutes after total parathyroidectomy and thymectomy. We used <60 pg/mL iPTH value on postoperative day 1 (POD1) as an indicator of successful removal of parathyroid glands and reviewed the frequency of reoperation other than in autografted sites during the observation period. This study was based on the Standards for the Reporting of Diagnositic accuracy compliant.The reoperation rate in patients with >60 pg/mL iPTH value (POD1) was significantly higher than that in patients with <60 pg/mL iPTH value (POD1), (13.0% versus 0.5% P = 0.003). Sensitivity, specificity, and accuracy of >70% IO-iPTH drop were 97.5%, 52.2%, and 92.9%, respectively, this criterion was demonstrated to be beneficial in 26 patients. In 5 patients, <70% IO-iPTH drop was observed and further exploration enabled sufficient removal of parathyroid glands. In 21 patients, although fewer than 4 parathyroid glands were removed after enough explorations, >70% IO-iPTH drop enabled termination of operations and iPTH value (POD1) was <60 pg/mL.An iPTH value of <60 pg/mL (POD1) was a good predictor for successful parathyroidectomy. A 70% IO-iPTH drop from the baseline was appropriate to determine sufficient parathyroid gland removal during parathyroidectomy for patients with secondary HPT.     

Restenosis after percutaneous transluminal coronary angioplasty--a histopathological study using autopsied hearts

Restenosis was studied histopathologically by serial step sectioning of 22 coronary arteries from 21 patients in whom percutaneous transluminal coronary angioplasty (PTCA) had been performed (9 arteries from patients who had died shortly after PTCA and 13 from those who had died considerably later). Nine of the 13 arteries from the patients who had died long after PTCA were immunohistochemically stained using anti-actin antibody for examination of spindle-shaped cells proliferating in the intima. In the patients who had died shortly after PTCA, all 9 arteries showed fresh thrombus formation. In the patients who had died considerably later after PTCA, however, there was fragmentation of the internal elastic lamina (IEL) in 9 arteries. In each of these 9 arteries, a remarkable proliferation of intimal cells was observed on the intimal side, mainly at the site of the IEL fragmentation. These spindle-shaped cells were identified as smooth muscle cells (SMC) because they stained reddish-brown with Masson's trichrome, and because immunohistochemical staining with anti-actin antibody was also positive. In 2 arteries, proliferation of SMC and elastic fibers was observed on the luminal side of the intima, despite absence of fragmentation in the IEL. Proliferation of SMC in false lumens was identified in 2 patients with medial dissection. From the above findings, the following 4 forms of restenosis after PTCA have been identified: 1. thrombus formation; 2. proliferation of SMC on the intimal side, mainly around fragmentation in the IEL; 3. proliferation of SMC on the luminal side of the intima where there was no fragmentation of the IEL; and 4. proliferation of SMC in dissected false lumen. The proliferation of SMC on the intimal side of the disrupted IEL was thought to have been a result of migration of SMC from the media to the intima, because SMC proliferation was seen around the disrupted region.     

Contribution of cardiac muscle cell disorganization to the clinical features of hypertrophic cardiomyopathy

Heart failure rarely develops in the setting of hypertrophic cardiomyopathy (HCM). Because of this, cardiac muscle cell disorganization (CD), which is a histologic characteristic of HCM, is not believed to be responsible for the development of systolic dysfunction. The aim of the present study was to clarify whether CD can cause systolic dysfunction and ventricular dilation in patients with HCM. Sixteen hearts from patients with HCM obtained at autopsy were divided into two groups: group A (n = 11), without biventricular dilation, and group B (n = 5), with dilation. Specimens consisting of transverse and longitudinal tissue sections of the ventricles were prepared, and the extent of CD and interstitial fibrosis was quantified, using light microscopy. None of the patients in group A had had chronic congestive heart failure, while all of the patients in group B had died of congestive heart failure. In group B, CD was not limited to the interventricular septum. Rather, diffuse CD was observed in both ventricular free walls. The extent of CD was significantly greater in group B than in group A, while the degree of interstitial fibrosis was similar in the two groups (13.6% in group A vs 14.6% in group B). These results suggest that CD may be responsible for systolic dysfunction and ventricular dilation. Received: July 11, 2000 / Accepted: November 25, 2000     

Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis

Agaricus blazei Murill (ABM) is one of the most popular complementary alternative medicines (CAM). We experienced a case of a 60-year-old woman with severe hepatitis associated with extract of ABM and extract of Ganoderma lucidum, and a case of a 75-year-old man with drug-induced liver injury (DILI) associated with extract of ABM and fucoidan. Their clinical courses from the start of CAM until the onset of DILI were observed unexpectedly, because they were under observation for stable malignant neoplasms: stage III malignant thymoma and stage IV lung cancer, respectively. However, they did not talk about taking CAM with their physicians. There were two common points between these two cases. First, they were diagnosed as compatible with DILI by using an international diagnostic scale, the Roussel Uclaf Causality Assessment Method. The second point was that histological findings of the liver were very similar to autoimmune hepatitis (AIH). In addition, serum immunoglobulin G and zinc sulfate turbidity tests gradually increased from the start of CAM to the onset of DILI. Their clinical course and liver histology suggested that the immunostimulating action of ABM caused liver injury which was very similar to that seen in AIH.     

Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors

The basal ganglia–thalamocortical circuitry plays a central role in selecting actions that achieve reward-seeking outcomes and avoid aversive ones. Inputs of the nucleus accumbens (NAc) in this circuitry are transmitted through two parallel pathways: the striatonigral direct pathway and the striatopallidal indirect pathway. In the NAc, dopaminergic (DA) modulation of the direct and the indirect pathways is critical in reward-based and aversive learning and cocaine addiction. To explore how DA modulation regulates the associative learning behavior, we developed an asymmetric reversible neurotransmission-blocking technique in which transmission of each pathway was unilaterally blocked by transmission-blocking tetanus toxin and the transmission on the intact side was pharmacologically manipulated by local infusion of a receptor-specific agonist or antagonist. This approach revealed that the activation of D1 receptors and the inactivation of D2 receptors postsynaptically control reward learning/cocaine addiction and aversive learning in a direct pathway-specific and indirect pathway–specific manner, respectively. Furthermore, this study demonstrated that aversive learning is elicited by elaborate actions of NMDA receptors, adenosine A2a receptors, and endocannabinoid CB1 receptors, which serve as key neurotransmitter receptors in inducing long-term potentiation in the indirect pathway. Thus, reward and aversive learning is regulated by pathway-specific neural plasticity via selective transmitter receptors in the NAc circuit.