Remarkable Improvement of Cardiac Function After Pre-emptive Kidney Transplant in a Patient With Severe Mitral Regurgitation Accompanied by Low Cardiac Function: A Case Report.

Patients with end-stage renal disease are at a high risk for cardiovascular diseases. It is controversial whether end-stage renal disease patients with low cardiac function can safely accept kidney transplant. Here, we present a 42-year-old kidney transplant recipient with severe mitral regurgitation accompanied by low cardiac function. He wanted to undergo a pre-emptive kidney transplant from his uncle. We decided to perform living kidney transplant prior to cardiac surgery. Despite adequate ultrafiltration and hemodiafiltration before operation, the patient's ejection fraction still remained 35% 1 day before transplant. He showed complete recovery of cardiac function in only 2 days after pre-emptive kidney transplant, although his body weight did not change before and after the operation. Early removal of the uremic toxin or inflammatory cytokines may play a role in rapid improvement of the cardiac function. Increase of vasoactive substances by improvement of kidney function may lead to reduction of afterload and amelioration of cardiac microcirculation. This report also suggests that optimal timing for operation might be important.

Living Kidney Donation From a Donor With Pulmonary Sarcoidosis: A Case Report and Review of the Literature.

BACKGROUND: Sarcoidosis is a chronic systemic disease that is characterized by the formation of noncaseating granuloma and whose etiology is unclear. It is unclear whether patients with sarcoidosis are suitable organ donors. CASE: We treated a 56-year-old woman with pulmonary sarcoidosis who donated her kidney. She was previously in good health and was diagnosed with pulmonary sarcoidosis during her preoperative examination. Because she presented with no symptoms and was otherwise in good condition, donor nephrectomy was performed. RESULTS: Baseline biopsy examination showed no evidence of sarcoidosis. One year after transplantation, both the donor and the recipient had not developed kidney dysfunction or recurrence of sarcoidosis. CONCLUSION: This is a rare case in which a patient with pulmonary sarcoidosis donated a kidney for transplantation, and both the recipient and the donor were clinically healthy. A patient with sarcoidosis and no kidney lesion can donate a living kidney, because transplantation appears to be safe for both the recipient and the donor.

Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment.

S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.

Understanding the epigenetics of neurodevelopmental disorders and DOHaD.

The Developmental Origins of Health and Disease (DOHaD) hypothesis refers to the concept that 'malnutrition during the fetal period induces a nature of thrift in fetuses, such that they have a higher change of developing non-communicable diseases, such as obesity and diabetes, if they grow up in the current well-fed society.' Epigenetics is a chemical change in DNA and histones that affects how genes are expressed without alterations of DNA sequences. Several lines of evidence suggest that malnutrition during the fetal period alters the epigenetic expression status of metabolic genes in the fetus and that this altered expression can persist, and possibly lead to metabolic disorders. Similarly, mental stress during the neonatal period can alter the epigenetic expression status of neuronal genes in neonates. Moreover, such environmental, stress-induced, epigenetic changes are transmitted to the next generation via an acquired epigenetic status in sperm. The advantage of epigenetic modifications over changes in genetic sequences is their potential reversibility; thus, epigenetic alterations are potentially reversed with gene expression. Therefore, we potentially establish 'preemptive medicine,' that, in combination with early detection of abnormal epigenetic status and early administration of epigenetic-restoring drugs may prevent the development of disorders associated with the DOHaD.

Association of genetic variants in the HNF4A and HNF1B genes with early onset Type 2 diabetes mellitus in the Indo and Afro-Trinidadian populations

OBJECTIVE: To determine if variation in HNF4A, HNF1B and PAX4 genes is associated with increased risk of early onset Type 2 diabetes mellitus (T2DM) in Indo and Afro-Trinidadians. DESIGN AND METHODS: The promoter, exons and flanking intronic regions of the HFN4A, HNF1B and PAX4 genes were sequenced in 167 T2DM and 61 non-diabetic subjects of South Asian Indian ancestry, and 66 T2DM and 59 non- diabetic subjects of African ancestry. Differences in SNP allele and haplotype frequency between T2DM patients and non-diabetic subjects were calculated, and pairwise linkage disequilibrium was also assessed for regions within these genes. RESULTS: Three variants identified in intron 4 of the HNF4A gene, demonstrated association with early onset T2DM in the Indo-Trinidadian population, rs11574739, P = 0.0032, OR 2.99 (95% CI 1.44-6.22), rs3212194, P = 0.02, OR 2.57 (95% CI 1.17-5.65), rs321219, P = 0.0083, OR 2.72 (95% CI 1.29-5.71). In the HNF1B gene, an intron 7 SNP, rs2269842, was associated with early onset T2DM in both the Indo and Afro-Trinidadian groups, P = 0.012, OR 0.42 (95% CI 0.20-0.87) and, P = 0.012, OR 0.44(95% CI 0.23-0.86) respectively. Both findings are previously unreported. No association was demonstrated with variants typed within the PAX4 gene. CONCLUSIONS: Variants in the HNF4A and HNF1B genes may contribute to increased risk of early onset T2DM in Indo-Trinidadians. HNF1B variants may similarly influence diabetes susceptibility in Afro-Trinidadians. However, further studies are required to fully elucidate the contribution of such variants to the prevalence of diabetes in the Trinidadian population.

Risk factors for early hemorrhagic complications after endovascular coiling of ruptured intracranial aneurysms.

BACKGROUND AND PURPOSE: The risk factors of early hemorrhagic complications after endovascular coiling are not well-known. We identified the factors affecting early hemorrhagic complications, defined as any expansion or appearance of hemorrhage shown by head CT in the initial 48 hours after coiling. MATERIALS AND METHODS: We retrospectively reviewed a series of 93 patients who underwent coiling for a ruptured saccular aneurysm between 2006 and 2012 at our hospital. RESULTS: Five patients showed early hemorrhagic complications, and all involved an expansion of the existing intracerebral hematoma immediately after coiling. The associated risk factors were accompanying intracerebral hemorrhage at onset (P < .001), postoperative antiplatelet therapy (P < .001), and thromboembolic complications (P = .044). In the accompanying intracerebral hemorrhage group, the associated risk factors were postoperative antiplatelet therapy (P = .044) and earlier initiation of coiling (9.8 ± 6.5 versus 28.1 ± 24.0 hours, P = .023). Early hemorrhagic complications were significant risk factors for worse clinical outcome (modified Rankin Scale, 2.02 ± 2.21 versus 4.4 ± 2.30, P = .022). None of the 93 patients showed further hemorrhage after the initial 48 hours after coiling. CONCLUSIONS: The accompanying intracerebral hemorrhage at onset, thromboembolic complications, postoperative antiplatelet therapy, and earlier initiation of coiling were the risk factors for early hemorrhagic complications.

Effect of molecular orientation angle of imidazolium ring on frictional properties of imidazolium-based ionic liquid.

Ionic liquids have significant potential as lubricants, and it is known that ionic liquids exhibit characteristic behavior at solid-liquid interfaces. Although it is believed that the structure of ionic liquids at the interface contributes to the tribological properties in the region of boundary-mixed lubrication, this contribution has not been clarified because such analysis is difficult. In this research, we clarify the lubrication mechanism of an imidazolium-based ionic liquid by comparing the results of friction tests with interfacial molecular orientation analysis using sum frequency generation spectroscopy. Consequently, we clarify that the tilt angle of the imidazolium ring affects the friction coefficient of the ionic liquid; that is, the larger tilt angle, the lower the friction coefficient.

Inhibition of S100A6 induces GVL effects in MLL/AF4-positive ALL in human PBMC-SCID mice.

Mixed-lineage leukemia (MLL)/AF4-positive ALL is associated with a poor prognosis even after allogeneic hematopoietic SCT (allo-HSCT). We reported previously that MLL/AF4-positive ALL shows resistance to TNF-α, which is the main factor in the GVL effect, by upregulation of S100A6 expression followed by interference with the p53-caspase 8-caspase 3 pathway in vitro. We examined whether inhibition of S100A6 can induce an effective GVL effect on MLL/AF4-positive ALL in a mouse model. MLL/AF4-positive ALL cell lines (SEM) transduced with lentiviral vectors expressing both S100A6 siRNA and luciferase (SEM-Luc-S100A6 siRNA) were produced. SEM-Luc-S100A6 siRNA cells and SEM-Luc-control siRNA cells were injected into groups of five SCID mice (1 × 10(7)/body). After confirmation of engraftment of SEM cells by in vivo imaging, the mice in each group were injected with 4.8 × 10(7) human PBMCs. SEM-Luc-S100A6 siRNA-injected mice showed significantly longer survival periods than SEM-Luc-control siRNA-injected mice (P=0.002). SEM-Luc-S100A6 siRNA-injected mice showed significantly slower tumor growth than those injected with SEM-Luc-control siRNA (P<0.0001). These results suggested that inhibition of S100A6 may be a promising therapeutic target for MLL/AF4-positive ALL in combination with allo-HSCT.

Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector.

As both the immune system and the blood-brain barrier (BBB) are likely to be developmentally immature in the perinatal period, neonatal gene transfer may be useful for the treatment of lysosomal storage disease (LSD) with neurological involvements such as metachromatic leukodystrophy (MLD). In this experiment, we examined the feasibility of single-strand adeno-associated viral serotype-9 (ssAAV9)-mediated systemic neonatal gene therapy of MLD mice. ssAAV9 vector expressing human arylsulfatase A (ASA) and green fluorescent protein (GFP) (ssAAV9/ASA) was injected into the jugular vein of newborn MLD mice. High levels of ASA expression were observed in the muscle and heart for at least 15 months. ASA was continuously secreted into plasma without development of antibodies against ASA. Global gene transfer into the brain and spinal cord (SC), across the BBB, and long-term ASA expression in the central nervous system were detected in treated mice. Significant inhibition of the accumulation of sulfatide (Sulf) in the brain and cervical SC was confirmed by Alcian blue staining and biochemical analysis of the Sulf content. In a behavior test, treated mice showed a greater ability to traverse narrow balance beams than untreated mice. These data clearly demonstrate that MLD mice model can be effectively treated through neonatal systemic injection of ssAAV9/ASA.

Split-gate organic field-effect transistors for high-speed operation.

Split-gate organic field-effect transistors have been developed for high-speed operation. Owing to the combination of reduced contact resistance and minimized parasitic capacitance, the devices have fast switching characteristics. The cutoff frequencies for the vacuum-evaporated devices and the solution-processed devices are 20 and 10 MHz, respectively. A speed of 10 MHz is the fastest device reported so far among solution-processed organic transistors.

Methylation levels of LINE-1 in primary lesion and matched metastatic lesions of colorectal cancer.

BACKGROUND: LINE-1 methylation level is a surrogate marker of global DNA methylation. LINE-1 methylation in primary colorectal cancers (CRCs) is highly variable and strongly associated with a poor prognosis. However, no study has examined LINE-1 methylation levels of metastatic CRCs in relation to prognosis or assessed the heterogeneity of LINE-1 methylation level within the primary CRCs. METHODS: Pyrosequencing was used to quantify LINE-1 methylation level in 42 liver metastases, 26 matched primary tumours, and 6 matched lymph node (LN) metastases. KRAS, BRAF, and PIK3CA mutation status and microsatellite instability (MSI) status were also examined. RESULTS: The distribution of LINE-1 methylation level in liver metastases was as follows: mean, 67.3; range, 37.1-90.1. Primary tumours showed LINE-1 methylation levels similar to those of matched liver and LN metastases. The difference in LINE-1 methylation level between superficial areas and invasive front areas was within 7.0 in all six cases evaluated. Prognostic impact of LINE-1 hypomethylation in liver metastases on overall survival was not observed. The concordance rate was 94% for KRAS, 100% for BRAF, 88% for PIK3CA, and 97% for MSI. CONCLUSION: Alteration of LINE-1 methylation level may occur in early CRC tumorigenesis, and the LINE-1 methylation level is relatively stable during CRC progression.

Meropenem as predictive risk factor for isolation of multidrug-resistant Pseudomonas aeruginosa.

The objective of this study was to explore independent risk factors for the isolation of multidrug-resistant (MDR) Pseudomonas aeruginosa in a Japanese university hospital between January 1997 and December 2010. MDR P. aeruginosa was defined when the organism was resistant or intermediately susceptible to all five antimicrobials tested. In all, 159 patients with MDR P. aeruginosa were identified over the 14-year period. Multivariate logistic regression analysis revealed that prolonged hospital stay, prior exposure to meropenem and fluoroquinolones, and patients suffering from diabetes mellitus or receiving surgery were predictive risk factors for the isolation of MDR P. aeruginosa.

Association of the KCNJ11 Variant E23K with Type 2 Diabetes in Indo-Trinidadians / La Asociación de la Variante E23K de KCNJ11 con la Diabetes de Tipo 2 en Indo-Trinitenses

OBJECTIVE: To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians. METHODS: The coding and bordering intronexon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non-diabetic subjects who historically were thought to be of South Asian Indian ancestry, as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region. RESULTS: We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo-Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098). CONCLUSIONS: Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population.

OBJETIVO: Examinar el efecto de la variación genética en KCNJ11 sobre el riesgo de la diabetes tipo 2 en trinitenses. MÉTODOS: Las regiones codificantes y las regiones de la frontera intrón-exón del gen KCNJ11 fueron secuenciadas en 168 sujetos diabéticos y 61 no diabéticos - históricamente de ascendencia del sur de la India - así como 66 sujetos diabéticos y 59 no diabéticos, de ascendencia africana. Se calcularon las diferencias de la frecuencia de los aleles y los haplotipos entre los casos y los controles, evaluándose asimismo el equilibrio de ligamiento de la región de KCNJ11. RESULTADOS: Se identificaron novedosas mutaciones de sentido erróneo en ambos grupos de sujetos, incluyendo A94P y R369C en un sujeto indo-trinitense diabético, y S118L en un sujeto afro-trinitense diabético. No se sabe si estas mutaciones son patogénicas ya que no se disponía de otros miembros de la familia para estudiar el caso. Además, la variante E23K estaba asociada con la diabetes tipo 2 en el grupo indo-trinitense (OR = 1.797 (1.148-2.814), p = 0.0098). CONCLUSIONES: Variantes raras en el KCNJ11 se están segregando en las poblaciones indo - y afro-trinitenses, y se requieren estudios ulteriores para determinar si de algún modo contribuyen a la prevalencia general de la diabetes en estos grupos. Las variantes comunes como la E23K pueden aumentar el riesgo en la población de indo-trinitense.

Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia.

Recently, c-kit mutations have been reported as a novel adverse prognostic factor of acute myeloid leukemia with t(8;21)(q22;q22) translocation (t(8;21) AML). However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive mutation detection method known as mutation-biased PCR (MB-PCR) and investigated the relationship between c-kit mutations and prognosis. When c-kit mutations were analyzed for 26 cases of t(8;21) AML using the direct sequence (DS) and MB-PCR, the latter had a much higher detection rate of c-kit mutations at initial presentation (DS 5/26(19.2%) vs MB-PCR 12/26(46.2%)). Interestingly for the three cases, in which c-kit mutations were observed only at relapse with the DS, c-kit mutations were detected at initial presentation using the MB-PCR. This result suggests that a minor leukemia clone with c-kit mutations have resistance to treatment and are involved in relapse. In univariate analyses, the presence of a c-kit mutation using DS was not an adverse prognostic factor (P = 0.355), but was a factor when using MB-PCR (P = 0.014). The presence of c-kit mutations with MB-PCR was also an independent adverse prognostic factor by multivariate analyses (P = 0.006). We conclude that sensitivity of c-kit mutation detection method is important to predict prognosis for t(8;21) AML.

Resistance of MLL-AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation.

Mixed-lineage leukemia (MLL)-AFF1 (MLL-AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL-AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-α) was reported to contribute to the GVL effect. We showed that MLL-AFF1-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL-AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53-caspase 8-caspase 3 pathway were observed only in MLL-AFF1-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53-caspase 8-caspase 3 pathway of MLL-AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL-AFF1 transgenic mice. These results suggest that MLL-AFF1-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53-caspase 8-caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL-AFF1-positive ALL in combination with allo-HSCT.

Association of the KCNJ11 variant E23K with type 2 diabetes in Indo-Trinidadians.

OBJECTIVE: To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians. METHODS: The coding and bordering intron-exon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non-diabetic subjects who historically were thought to be of South Asian Indian ancestry as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region. RESULTS: We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo-Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098). CONCLUSIONS: Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population.

An amplification of IL-10 and TGF-beta in patients with IgG4-related tubulointerstitial nephritis.

BACKGROUND: IgG4-related tubulointerstitial nephritis (TIN) shows characteristic serum IgG4 elevation and increased IgG4-positive plasma cells in the renal interstitium, and inclusion of TIN as an IgG4-related systemic disease has been suggested. IgG4 is the rarest IgG subclass and is a Th2-dependent isotype with low affinity for target antigen. Although the pathogenesis of this disease has not been elucidated, positive serum immune complex and hypocomplementemia in some patients with this disease suggest that immune complex mechanisms are involved in the causation of this disease. METHOD: We selected 20 cases of histological diagnosed TIN. These cases were etiologically different and included 4 cases of IgG4-related TIN. We extracted RNA from paraffin embedded biopsied kidney and evaluated expression levels of various cytokines for each case by real time PCR. RESULTS: Comparison of cytokine production patterns among different disease-associated TINs revealed that IgG4-related TIN exhibited a quite distinct pattern. On the one hand, there was no expression of IL-2, IFN-gamma IL-17 and IL-6, whereas production of IL-4, IL-10 and TGF-beta was, on the other hand, remarkably increased in IgG4-related TIN. CONCLUSION: Based on these cytokine production results, Th2 and Treg appear to play a central role in IgG4-related TIN.

Fabrication of nanostripe surface structure by multilayer film deposition combined with micropatterning.

Top-down fabrication processes for nanostructures are superior to bottom-up processes from the aspect of long-range order, but have limitations in their processing time and/or material selection. Here we developed a nanopatterning method for 'nanostripes' that incorporates deposition of a multilayer film on a microscale slope array and mechanical polishing. This method is used to fabricate a nanostripe structure consisting of two kinds of materials to form a stripe array on a silicon substrate. Although this nanopatterning method is categorized as a top-down fabrication process, the fabrication efficiency is quite high, because the number of nanostripes is 'multiplied' by the number of multilayered films. Another feature of the nanostripe is renewability; even if the nanostripe surface is damaged, the underlying nanostructure can be exposed and form a similar nanostripe by polishing. The nanostripe structure can be easily applied to a wide range of fields due to its ease of production.

Duodenogastric reflux induced by endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) may cause excessive duodenogastric reflux (DGR) in a similar manner to distal gastrectomy, particularly after antral resections. We aimed to examine the occurrence of DGR after ESD. PATIENTS AND METHODS: Patients with gastric neoplasm for whom ESD was indicated were categorized according to lesion site: the antral group (lower [L] stomach, n = 46) and the nonantral group (upper or middle [U or M] stomach, n = 49). Endoscopy was performed before ESD, the day after ESD, and 3 months after ESD, and the fasting bile acid concentration (BAC) in the gastric juice was analyzed. RESULTS: BAC values showed significant interaction between time point and group, although this association differed in the antral and nonantral groups. BACs on the day after ESD were higher in the antral group than in the nonantral group, but not the pre-ESD and 3 months post-ESD levels. In the antral group only, fasting BACs increased significantly the day after ESD and decreased to baseline levels 3 months post-ESD. There was also a correlation between BAC and lesion location in the antral subgroups, with significantly higher BACs found the day after ESD in patients with lesser curvature lesions. CONCLUSIONS: ESD of lesions in the antral lesser curvature may lead to a transient early increase in DGR. However, ESD does not result in long-term DGR, a factor that is known to increase the risk of carcinogenesis following gastrectomy.