Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Single center experience of 39 patients with preoperative portal vein thrombosis among 404 adult living donor liver transplantations.

Living donor liver transplantation (LDLT) for patients with portal vein thrombosis (PVT) involves technical difficulty. The aim of this research was to analyze their preoperative diagnosis of PVT, operative procedures, and postoperative courses of patients with preoperative PVT. Thirty-nine patients of 404 adult patients (9.7%) undergoing LDLT in our hospital from 1996 June to 2004 December had PVT at their transplantation. Twenty-nine patients had intractable ascites, 21 had gastrointestinal bleeding, and 18 had encephalopathy. The thrombus was located in the portal trunk in 23, in the portal trunk and superior mesenteric vein (SMV) in 7, and developed into the SMV and the splenic vein in 8. The occlusive grade was partial in 29, and complete in 10 patients. The thrombus was removed by a simple technique, and eversion and/or incision technique, or total removal of the portal vein (PV). The PV was reconstructed with the thrombectomized native PV, with an interposed vein graft, or porto-caval hemitransposition. Advanced PVT had a significant impact on blood loss and hospital mortality. Three out of 10 patients with residual PVT required radiological and/or surgical intervention after transplantation. In conclusion, thorough planning is essential for a successful LDLT outcome for patients with preexisting PVT.     

Living donor liver transplantation for biliary atresia complicated by situs inversus: technical highlights.

Living-donor liver transplantation (LDLT) has become an established technique to treat children with end-stage liver disease. Biliary atresia (BA), one of the most common indications for liver transplantation in children, can be associated with situs inversus (SI). In the past, the presence of SI has been considered to be an absolute contraindication for liver transplantation because of the technical difficulties. Recently, some reports of successful diseased-donor liver transplantation in patients with BA complicated by SI have been published; however, few reports of that with LDLT exist. The technical difficulties involved with LDLT for such cases have not been described. Herein, we present 4 successful cases of LDLT for BA with SI. Complex anomalies associated with SI, such as a hepatic artery arising from the supraceliac aorta, a preduodenal portal vein, and absence of the retrohepatic inferior vena cava, increase the technical difficulties involved with the operation. Additional caution is required in LDLT because a living-donor graft has short vessels and the availability of vascular grafts from the donor is limited. In conclusion, LDLT for BA complicated by SI can be managed successfully with technical modifications and scrupulous attention. This series represents the largest reported group of patients with BA complicated by SI who underwent a successful LDLT procedure.     

Successful treatment with balloon dilatation using a double‐balloon enteroscope for a stricture in the small bowel of a patient with Crohn's disease

The requirement for endoscopic access to a stricture is a major limitation of the endoscopic dilatation for the treatment of strictures in the gastrointestinal tract. We have developed the double‐balloon enteroscopy method that enables visualization of the entire small bowel. In addition, double‐balloon enteroscopy has a potential for the interventional therapy including dilatation of strictures. We present here a case of jejunal strictures in a 47‐year‐old woman with Crohn's disease successfully treated with a balloon catheter in combination with double‐balloon enteroscopy. Balloon dilation with double‐balloon enteroscopy is a promising method for the treatment of small bowel strictures in Crohn's disease.     

Initial steroid bolus injection promotes vigorous CD8+ alloreactive responses toward early graft acceptance immediately after liver transplantation in humans.

We have found that steroid bolus withdrawal prior to graft reperfusion increased the incidence of acute cellular rejection (ACR). This study aims to clarify how initial steroid bolus (ISB) injection at reperfusion influences the kinetics of CD8(+) alloreactive immune responses immediately after living donor liver transplantation (LDLT). A total of 49 hepatitis C virus (HCV)-infected recipients were classified into 3 groups according to hierarchical clustering by preoperative CD8(+)CD45 isoforms. The naive T cell proportion was considerably higher in Group I than in Groups II and III, whereas Group II recipients had the highest effector memory (EM) T cells and Group III the highest effector T cells. The frequency of ACR was significantly higher in recipients without ISB than in those with ISB. In particular, the ACR rates were the highest in Group II without ISB. Following ISB, the proportion of effector T cells was promptly upregulated within 6 hours after graft reperfusion, simultaneously with the upregulation of CD27(-)CD28(-) subsets, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha and perforin expression, which significantly correlated with increasing interleukin (IL)-12 receptor beta 1 cells. These were then downregulated to below preoperative levels by tacrolimus (Tac) administered at 24 hours. These changes did not occur in the absence of ISB. In Group II without ISB, the downregulation of IL-12Rbeta1(+) cells was the greatest, consistent with the highest rates of ACR and mortality (60%). In conclusion, ISB must be done in place, especially in Group II with preexisting high EM T cells, to enable the development of early allograft acceptance.     

CURRENT STATUS OF DOUBLE BALLOON ENDOSCOPY

Yamamoto and colleagues have developed a novel insertion method of the endoscope, the ‘double balloon method’ for enteroscopy and, recently, a specialized system for the ‘double balloon method’ has been commercialized by Fujinon. The double balloon endoscopy enables visualization of the entire small bowel and also allows for interventional therapy in the small intestine. This method could be used either from the oral or anal approach. Observation of an affected area with controlled movement of the endoscope enables interventions, including biopsies, hemostasis, balloon dilatation, stent placement, polypectomy, and endoscopic mucosal resection. The procedure is safe and useful, and it provides high diagnostic yields and therapeutic capabilities.     

Reconstruction of the distal foot dorsum with a distally based extensor digitorum brevis muscle flap.

We have successfully applied a reverse flow island flap of extensor digitorum brevis muscle for coverage of tissue defects in the distal portion of the foot dorsum in 2 patients. This flap covered the metatarsophalangeal area well with cadaver limb dissection and seems useful to cover the defect in the distal foot dorsum.     

Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University.

To address the current role of liver transplantation (LT) for urea cycle disorders (UCDs), we reviewed the worldwide English literature on the outcomes of LT for UCD as well as 13 of our own cases of living donor liver transplantation (LDLT) for UCD. The total number of cases was 51, including our 13 cases. The overall cumulative patient survival rate is presumed to be more than 90% at 5 years. Most of the surviving patients under consideration are currently doing well with satisfactory quality of life. One advantage of LDLT over deceased donor liver transplantation (DDLT) is the opportunity to schedule surgery, which beneficially affects neurological consequences. Auxiliary partial orthotopic liver transplantation (APOLT) is no longer considered significant for the establishment of gene therapies or hepatocyte transplantation but plays a significant role in improving living liver donor safety; this is achieved by reducing the extent of the hepatectomy, which avoids right liver donation. Employing heterozygous carriers of the UCDs as donors in LDLT was generally acceptable. However, male hemizygotes with ornithine transcarbamylase deficiency (OTCD) must be excluded from donor candidacy because of the potential risk of sudden-onset fatal hyperammonemia. Given this possibility as well as the necessity of identifying heterozygotes for other disorders, enzymatic and/or genetic assays of the liver tissues in cases of UCDs are essential to elucidate the impact of using heterozygous carrier donors on the risk or safety of LDLT donor-recipient pairs. In conclusion, LT should be considered to be the definitive treatment for UCDs at this stage, although some issues remain unresolved.     

Classification of human liver transplant recipients by their preoperative CD8+ T cell subpopulation and its relation to outcome.

The primed status of T cells is markedly different among liver transplant recipients, due to a lifetime of antigen exposure and reduced thymopoiesis by aging, and diseases. This study aims to characterize the preoperative immunological status of CD8+ T cell subpopulations and relate it to the outcome for liver transplant recipients. We classified 112 liver transplant recipients into 5 groups, based on hierarchical clustering of the CD8+CD45 isoform proportion of T cells. In Groups I and II (pediatric), the naive T cell proportion was more than 50%. In adult recipients, Group III was characterized by a naive T cell proportion of 50%, Group IV had the greatest effector/memory T cells (EM), and Group V had the greatest proportion of effector T cells. In Groups IV and V, the effector T cell proportion was considerably higher, and was accompanied by marked downregulation of the CD27+CD28+ subsets and upregulation of interferon gamma (IFN)-gamma, tumor necrosis factor-alpha, and perforin expression. Group V recipients tended to be complicated postoperatively, with a significantly reduced survival rate (1 yr, 66.8%) and markedly reduced Eastern Cooperative Oncology Group performance status.