Facilely Fabricated Zero-Bias Silicon-Based Plasmonic Photodetector in the Near-Infrared Region with a Schottky Barrier Properly Controlled by Nanoalloys.

Plasmonic Schottky devices have attracted considerable attention for use in practical applications based on photoelectric conversion, because they enable light to be harvested below the bandgap of semiconductors. In particular, silicon-based (Si) plasmonic Schottky devices have great potential for useful photodetection in the near-infrared region. However, the internal quantum efficiency (IQE) values of previously reported devices are low because the Schottky barrier is excessively high. Here, we are the first to develop AuAg nanoalloy-n-type Si plasmonic Schottky devices by cathodic arc plasma deposition. Interestingly, it is found that a novel nanostructure, which leads to the improvement of responsivities, is formed. Moreover, these plasmonic nanostructures can be fabricated in only ∼1 min. The fabricated AuAg nanoparticle-film structure enables proper control of the Schottky barrier height and increases the area of the Schottky interface for electron transfer. As a result, the considerably enhanced IQE of our device at a telecommunication wavelength of 1310 nm (1550 nm) without external bias is 4.6 (6.5) times higher than those in previous reports, and these responsivities are a record high. This approach can be applied to realize efficient photodetection in the NIR region and extend the use of light below the bandgap of semiconductors. This paves the way for future application advancements in a variety of fields, including photodetection, imaging, photovoltaics, and photochemistry.

Pharmacist's Intervention Considering the Prognosis for a Terminal Cancer Patient: A Case Report.

Prognostic prediction has been reported to affect the decision of doctors and non-physician health care providers such as nurses, social workers, pastors, and hospice volunteers on the selection of appropriate medical interventions. This was a case of a 65-year-old woman who presented with a poor oral intake. The patient had a history of sigmoid colon cancer with abdominal wall metastasis and peritoneal dissemination. On the day of admission, nausea, anorexia, and malaise were noted, requiring immediate intervention. The patient's prognosis was predicted using the Palliative Prognostic Index. The pharmacist suggested the use of dexamethasone tablets in order to alleviate the patient's symptoms. Indeed, the administration of dexamethasone alleviated the symptoms of nausea, loss of appetite, and malaise. To the best of our knowledge, this is the first case report to demonstrate that prognosis prediction is important not only for other medical staff but also for pharmacists when deciding the need to initiate a treatment and continue such treatment, and when providing pharmacist interventions.

A case report of fetus in fetu with an aorta-like structure visualized by contrast-enhanced CT.

Fetus in fetu (FIF) is a rare congenital anomaly resulting from abnormal embyogenesis in monochorionic diamniotic twins and appears as a cystic mass containing fetus-like structures mainly in the retroperitoneum of infants. Although there is a theory that FIF is a highly differentiated teratoma, it is commonly distinguished from teratoma as a mass containing a vertebral axis with appropriate arrangement of limbs or other organs around this axis. Here we present a case of FIF with aorta-like structure visualized by contrast-enhanced computed tomography. A 5-day-old girl was pointed out a cystic mass in the abdomen by ultrasound examination. Abdominal contrast-enhanced computed tomography revealed a retroperitoneal cystic mass with spine- and limb-like bone structures and blood vessel-like elongated structures and it was confirmed as FIF by surgery. The presence of major vascular structures along the skeletal axis is clearly different from teratoma and suggests that it occurred as an embryo and underwent some stage of development. Our findings strongly support the monozygotic twin theory.

Development and validation of risk models for mortality and morbidity in 12 major pediatric surgical procedures: A study from the National Clinical Database-Pediatric of Japan.

PURPOSE: To establish and validate risk models of mortality and morbidity associated with 12 major pediatric surgical procedures using the National Clinical Database-Pediatric (NCD-P) data. METHODS: We used the NCD-P data for the development and validation datasets. By using multivariate logistic regression to analyze the development dataset, we created a prediction model for 30-day mortality and morbidity in 12 major pediatric surgical procedures, including tracheoplasty, pneumonectomy, fundoplication, total/subtotal excision of malignant tumor, and surgeries for Hirschsprung disease, anorectal malformation, biliary atresia, choledocal cyst, midgut volvulus, funnel chest, gastrointestinal perforation, and intestinal obstruction. We selected variables that were almost identical to those used in the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P). The primary outcomes were 30-day mortality and composite morbidity. We assessed the obtained models using the C-indices of the development and validation datasets. RESULTS: Overall, 10 and 21 variables were identified for mortality and morbidity, respectively. C-indices of mortality were 0.940 and 0.924 in the development and validation datasets, respectively. C-indices of morbidity were 0.832 and 0.830 in the development and validation datasets, respectively. CONCLUSIONS: Based on the NCD-P data, we developed satisfactory risk models for mortality and morbidity prediction in major pediatric surgeries. LEVEL OF EVIDENCE: Level I (Prognosis Study).

Efficacy of xanthine oxidase inhibitor for chronic kidney disease patients with hyperuricemia.

BACKGROUND: Hyperuricemia is a known risk factor for end-stage renal disease. Although xanthine oxidase (XO) inhibitors are expected to protect the kidney function, evidence to this end is insufficient at present. METHODS: This study was a multi-center, open-labeled, randomized study conducted in Mie Prefecture in Japan. Patients were included if they were between 20 and 80 years old and had a serum uric acid (sUA) level ≥ 7.0 mg/dl with or without gout, estimated glomerular filtration rate (eGFR) of 15-60 ml/min/1.73 m2, and urinary protein creatinine ratio (uPCR) of 0.15-3.5 g/gCr. Patients were randomly assigned to a Topiroxostat or Febuxostat group, and the treatment target for the sUA level was < 6.0 mg/dl. The primary outcome was the change in the uPCR after 24 weeks. RESULTS: The change in the median uPCR after 24 weeks was not statistically significant after treatment in the Topiroxostat or Febuxostat group (0.05 g/gCr and - 0.04 g/gCr, respectively). However, the sUA levels decreased significantly in both groups (Topiroxostat group: 8.6 ± 1.1 at baseline to 6.0 ± 1.1 mg/dl at 24 weeks, Febuxostat group: 8.4 ± 1.1 mg/dl at baseline to 5.9 ± 1.3 mg/dl at 24 weeks). No significant change in the eGFR after 24 weeks was noted in either the Topiroxostat or Febuxostat group (- 0.04 ± 4.59 ml/min/1.73 m2 and 0.31 ± 4.70 ml/min/1.73 m2, respectively). CONCLUSIONS: In this study, XO inhibitors did not significantly reduce the uPCR in chronic kidney disease stage 3 and 4 patients with hyperuricemia.

Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

Pediatric liver transplantation for neonatal-onset Niemann-Pick disease type C: Japanese multicenter experience.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive inherited disease characterized by lysosomal accumulation of free cholesterol in macrophages within multiple organs. Infantile-onset NPC often presents with jaundice and hepatosplenomegaly from birth, but these symptoms usually improve during early childhood, and it rarely progresses to liver failure. We report three cases from different hospitals in Japan; the patients developed neonatal-onset NPC, and liver transplantation (LT) was performed as a life-saving procedure. LT was performed at 19 days, 59 days, and 4 months of age, respectively. The last patient was diagnosed with NPC before LT, while the first two patients were diagnosed with neonatal hemochromatosis at LT. In these two patients, the diagnosis of NPC was made more than a year after LT. Even though oral administration of miglustat was started soon after the diagnosis of NPC, all patients showed neurological regression and required artificial respiratory support. All patients survived more than one year after LT; however, one patient died due to tracheal hemorrhage at 4.5 years of age, and another one patient was suspected as recurrence of NPC in liver graft. In conclusion, while LT may be a temporary life-saving measure in patients with neonatal-onset NPC leading to liver failure, the outcome is poor especially due to neurological symptoms. A preoperative diagnosis is thus critical.

Early post-operative intravenous tacrolimus in pediatric liver transplant recipients is not superior to oral tacrolimus.

We aimed to compare the early results of i.v. with p.o. TAC as a primary immunosuppressant in pediatric patients undergoing LT. This retrospective study enrolled 75 children who underwent LT and received TAC-steroid regimens as a primary immunosuppressant between September 2011 and October 2015 at our institution. Thirty-five recipients received TAC i.v. and 40 received TAC p.o. Early results were evaluated and compared, including ACR, EBV, or CMV infection; renal adverse effects; and hospital stay. Comparisons of 90-day post-transplant results showed that the rates of overall viral (74% vs 40% P < 0.002), EBV (46% vs 17.5% P < 0.008), and CMV (51% vs 30% P = 0.05) infections were significantly higher in the i.v. than in the p.o. group. Neither regimen has any adverse effects on renal function. There were no between-group differences in ACR incidence and severity, serum creatinine concentration, and hospital stay. Patient and graft survival rates at 3 months and 1 year did not differ significantly between the two groups. Compared with p.o. treatment, i.v. administration of high TAC concentration did not have beneficial post-transplant effects on ACR incidence and severity, while increasing the incidence of viral infections in pediatric LT.

Cytomegalovirus infection in pediatric patients with hepatoblastoma after liver transplantation.

No studies have examined CMV infection in pediatric patients with HB receiving LT. Here, we retrospectively analyzed the incidence of and risk factors for CMV infection in 24 pediatric patients with HB who underwent LT between 1997 and 2015. CMV infection was monitored by measuring expression of pp65 CMV antigen for up to 4 months post-LT. CMV infection, defined as detection of at least one pp65-positive leukocyte, was detected in nine (37.5%) patients who did not develop CMV disease. Nine (47.4%) of nineteen patients who received post-LT chemotherapy experienced CMV infection; however, no CMV infection was observed in the five patients who did not receive post-LT chemotherapy (P = 0.012). There were no significant differences in the incidence of CMV infection between patients with ACR (60.0%) and those without (21.4%, P = 0.092), or between CMV seropositive (55.6%) and seronegative patients (33.3%, P = 0.675). All nine patients with CMV infection did not experience CMV disease due to the use of preemptive antiviral therapy. Close monitoring of CMV infection is recommended for patients with HB, particularly those receiving post-LT chemotherapy. Preemptive antiviral therapy is feasible for prophylaxis of CMV disease.

Prognostic and therapeutic factors influencing the clinical outcome of hepatoblastoma after liver transplantation: A single-institute experience.

LT has contributed to an elevation in cure rates for patients with unresectable HB; however, patients with recurrent HB after LT have poor prognosis. To analyze the prognostic and therapeutic factors that influence the clinical outcome of patients with HB receiving LT, we retrospectively analyzed 24 patients with HB who underwent LT between 1997 and 2015. The 5-year OS rate of all patients was 69.6±9.7%. The 5-year OS rate of 11 patients receiving salvage LT for recurrent tumor after a primary resection was comparable to that of 13 patients receiving primary LT. Among 12 evaluable patients receiving primary LT, six of 10 patients with a decline of serum AFP >95% at LT are currently alive and in remission, whereas two patients with a decline of AFP ≤95% experienced post-LT relapse. Among 9 evaluable patients receiving salvage LT, all three patients with any decline of AFP at LT are currently alive in remission, and three of six patients with no response to pre-LT salvage chemotherapy are also alive and in remission. Response to chemotherapy may be a reliable marker for prediction of post-LT relapse, even for patients receiving salvage LT.

Antialbuminuric effect of eplerenone in comparison to thiazide diuretics in patients with hypertension.

This study investigated the effects and safety of eplerenone or thiazide diuretics in patients with hypertension and albuminuria (pretreatment urinary albumin/creatinine ratio ≥10 mg/gCr) treated with an angiotensin II receptor blocker. The primary end point was the mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks. An efficacy analysis was performed in 195 patients (98 in the eplerenone group and 97 in the thiazide group). Systolic and diastolic blood pressures at 48 weeks were similar in the two groups. The mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks was similar in the two groups (P=.804). In the safety analysis, the withdrawal rates for adverse events were similar in both groups. The antialbuminuric effects and safety of eplerenone therapy were similar to those of thiazide diuretics when combined with an angiotensin II receptor blocker in patients with hypertension and albuminuria.

Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs.

Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. l-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches.

Impact of Antibodies That React With Liver Tissue and Donor-Specific Anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis.

BACKGROUND: The cause of late graft dysfunction has not been elucidated. Although an antibody-mediated reaction is suspected as a potential mechanism, the target antigens have not been clarified. METHODS: To clarify the etiology of idiopathic posttransplantation hepatitis (IPTH), we simultaneously examined the presence of antibodies that react with liver tissue (ARLT) by means of indirect immunofluorescence staining, as well as the presence of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA). A subanalysis of the IPTH group was also performed. Within the IPTH group, the correlation between ARLT titer and clinical data were analyzed. RESULTS: In the sera of patients with IPTH (30 patients), ARLT were found at a significantly higher frequency than in patients without IPTH (42 patients; P < 0.001). Moreover, the ARLT titer appeared to be correlated with the severity of hepatitis or hepatic injury. In contrast, the frequency of HLA-DSA was significantly lower in patients with IPTH than in patients without IPTH (P = 0.001). CONCLUSION: Our findings indicate that ARLT, and not HLA-DSA, profoundly influence the etiology of IPTH.

Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report.

Patients with desmoplastic small round cell tumors (DSRCTs) have an extremely poor outcome despite the use of aggressive therapy. The current study presents the case of 16-year-old male with metastatic DSRCT, in which multimodal therapy, including intensive chemotherapies using frequent autologous stem cell support, gross resection of primary and metastatic lesions, and whole abdominopelvic intensity-modulated radiation therapy, was administered. Subsequent to these treatments, there was no evidence of active disease. However, cerebellar and pineal body lesions, and bone metastasis to the left humerus were detected 1 year and 2 months after the initial diagnosis. Combination chemotherapy with irinotecan and temozolomide was initially effective against the central nervous system (CNS) metastatic lesions; however, the patient succumbed due to progressive CNS disease after seven courses of combination chemotherapy. Additional studies are required to accumulate information regarding CNS recurrence of DSRCT.

Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function.

Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.

Replication-competent adenoviruses with the type 35-derived fiber-knob region achieve reactive oxygen species-dependent cytotoxicity and produce greater toxicity than those with the type 5-derived region in pancreatic carcinoma.

Pancreatic carcinoma is relatively resistant to chemotherapy and cell death induced by replication of adenoviruses (Ad) can be one of the therapeutic options. Transduction efficacy of conventional type 5 Ad (Ad5) is however low and the cytotoxic mechanism by replication-competent Ad was not well understood. We constructed replication-competent Ad5 of which the E1A promoter region was replaced with a transcriptional regulatory region of the midkine, the survivin or the cyclooxygenase-2 gene, all of which were expressed at a high level in human tumors. We also prepared replication-competent Ad5 that were activated with the same region but had the type 35 Ad-derived fiber-knob region (AdF35) to convert the major cellular receptor for Ad infection from the coxsackie adenovirus receptor to CD46 molecules. Replication-competent AdF35 that were activated with the exogenous region produced cytotoxic effects on human pancreatic carcinoma cells greater than the corresponding Ad5 bearing with the same regulatory region. Cells infected with the AdF35 showed cytopathic effects and increased sub-G1 fractions. Caspase-9, less significantly caspase-8 and poly (ADP-ribose) polymerase, but not caspase-3 was cleaved and expression of molecules involved in autophagy and caspase-independent cell death pathways remained unchanged. Nevertheless, H2A histone family member X molecules were phosphorylated, and N-acetyl-L-cystein, an inhibitor for reactive oxygen species, suppressed the AdF35-mediated cytotoxicity. These data indicated a novel mechanism of Ad-mediated cell death and suggest a possible clinical application of the fiber-knob modified Ad.

Cytotoxic effects of replication-competent adenoviruses on human esophageal carcinoma are enhanced by forced p53 expression.

BACKGROUND: Improvement of transduction and augmentation of cytotoxicity are crucial for adenoviruses (Ad)-mediated gene therapy for cancer. Down-regulated expression of type 5 Ad (Ad5) receptors on human tumors hampered Ad-mediated transduction. Furthermore, a role of the p53 pathways in cytotoxicity mediated by replication-competent Ad remained uncharacterized. METHODS: We constructed replication-competent Ad5 of which the E1 region genes were activated by a transcriptional regulatory region of the midkine or the survivin gene, which is expressed preferentially in human tumors. We also prepared replication-competent Ad5 which were regulated by the same region but had a fiber-knob region derived from serotype 35 (AdF35). We examined the cytotoxicity of these Ad and a possible combinatory use of the replication-competent AdF35 and Ad5 expressing the wild-type p53 gene (Ad5/p53) in esophageal carcinoma cells. Expression levels of molecules involved in cell death, anti-tumor effects in vivo and production of viral progenies were also investigated. RESULTS: Replication-competent AdF35 in general achieved greater cytotoxic effects to esophageal carcinoma cells than the corresponding replication-competent Ad5. Infection with the AdF35 induced cleavages of caspases and increased sub-G1 fractions, but did not activate the autophagy pathway. Transduction with Ad5/p53 in combination with the replication-competent AdF35 further enhanced the cytotoxicity in a synergistic manner. We also demonstrated the combinatory effects in an animal model. Transduction with Ad5/p53 however suppressed production of replication-competent AdF35 progenies, but the combination augmented Ad5/p53-mediated p53 expression levels and the downstream pathways. CONCLUSIONS: Combination of replication-competent AdF35 and Ad5/p53 achieved synergistic cytotoxicity due to enhanced p53-mediated apoptotic pathways.