Factors associated with changes in tacrolimus blood concentration after food initiation in patients with ulcerative colitis.

The therapeutic effect of tacrolimus against ulcerative colitis (UC) is correlated with its trough blood concentration. Conventionally, oral tacrolimus for the treatment of UC is initiated under fasting conditions; once the symptoms improve, food intake is resumed. Tacrolimus blood concentration decreases with food intake compared with that under fasting conditions. The aim of this study was to explore the characteristics of patients with UC whose tacrolimus blood concentrations tended to decrease after food initiation. Medical data of 13 patients with UC and treated with tacrolimus were retrospectively obtained. The participant characteristics associated with the changes in tacrolimus blood concentrations after food initiation were analyzed using regression analysis based on the rate of decrease in the concentration/dose (C/D) ratio after food initiation. Single regression analysis showed that the number of days required from tacrolimus initiation to food resumption (P = 0.0071) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0247) were significantly associated with the rate of decrease in the C/D ratio after food initiation. Furthermore, multiple regression analysis showed a significant effect of the number of days to food resumption (P = 0.0004) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0012). The results suggest that the degree of change in blood tacrolimus concentration after food initiation may be related to the severity of the symptoms and pathology of UC. Early identification of participant characteristics may help control tacrolimus blood concentration fluctuations after food initiation.

Retrospective analysis of risk factors for liposomal amphotericin B-associated nephrotoxicity.

In this study, we examined patients who received liposomal amphotericin B (L-AMB) to determine the risk factors associated with nephrotoxicity before and during L-AMB treatment. In this retrospective, single-center, observational cohort study, we examined 37 patients who received L-AMB treatment between April 2018 and December 2019. Nephrotoxicity was observed in 11 (29.7%) patients. We focused on the baseline albumin level and body surface area (BSA) before L-AMB treatment. Univariate analysis showed that the BSA and baseline albumin levels in patients with nephrotoxicity were significantly higher than those in patients without nephrotoxicity. Moreover, univariate analysis showed that albumin supplementation was significantly associated with the frequency of nephrotoxicity during L-AMB treatment. Multiple logistic regression analysis revealed the following independent risk factors for nephrotoxicity before or during L-AMB treatment: baseline albumin level (odds ratio [OR] = 16.000; 95% CI 1.480-172.000; P = 0.022) and albumin supplementation (OR = 40.800; 95% CI 2.210-753.000; P = 0.013). In conclusion, we identified baseline albumin level and albumin supplementation as novel risk factors for L-AMB-induced nephrotoxicity.

Improved apple latent spherical virus-induced gene silencing in multiple soybean genotypes through direct inoculation of agro-infiltrated Nicotiana benthamiana extract.

BACKGROUND: Virus induced gene silencing (VIGS) is a powerful genomics tool for interrogating the function of plant genes. Unfortunately, VIGS vectors often produce disease symptoms that interfere with the silencing phenotypes of target genes, or are frequently ineffective in certain plant genotypes or tissue types. This is especially true in crop plants like soybean [Glycine max (L.) Merr]. To address these shortcomings, we modified the inoculation procedure of a VIGS vector based on Apple latent spherical virus (ALSV). The efficacy of this new procedure was assessed in 19 soybean genotypes using a soybean Phytoene desaturase (GmPDS1) gene as the VIGS target. Silencing of GmPDS1 was easily scored as photo-bleached leaves and/or stems. RESULTS: In this report, the ALSV VIGS vector was modified by mobilizing ALSV cDNAs into a binary vector compatible with Agrobacterium tumefaciens-mediated delivery, so that VIGS-triggering ALSV variants could be propagated in agro-infiltrated Nicotiana benthamiana leaves. Homogenate of these N. benthamiana leaves was then applied directly onto the unifoliate of young soybean seedlings to initiate systemic gene silencing. This rapid inoculation method bypassed the need for a particle bombardment apparatus. Among the 19 soybean genotypes evaluated with this new method, photo-bleaching indicative of GmPDS1 silencing was observed in nine, with two exhibiting photo-bleaching in 100% of the inoculated individuals. ALSV RNA was detected in pods, embryos, stems, leaves, and roots in symptomatic plants of four genotypes. CONCLUSIONS: This modified protocol allowed for inoculation of soybean plants via simple mechanical rubbing with the homogenate of N. benthamiana leaves agro-infiltrated with ALSV VIGS constructs. More importantly, inoculated plants showed no apparent virus disease symptoms which could otherwise interfere with VIGS phenotypes. This streamlined procedure expanded this functional genomics tool to nine soybean genotypes.

Microrelief suppresses large wrinkling appearance: an in silico study.

BACKGROUND AND PURPOSE: Extensive skin wrinkling during facial expressions is one of the considerable problems in aesthetic dermatology. Although a few in silico studies have been performed with the aim of revealing the mechanism of a wrinkled appearance, there have been few studies that take into account the influence of skin roughness (i.e. microrelief), which exists on human skin in vivo. In this study, finite element simulations were performed using multilayer skin models with microrelief to investigate how extensive wrinkling appears on human skin, especially focusing on the role of surface roughness in the wrinkling mechanism. METHODS: Linear and post-buckling analyses were performed on soft elastic laminate models using the finite element method. A simplified multilayer model of human skin was employed to examine the contribution of skin's multilayer structure to the large-wrinkle mechanism. Microrelief was included in the model to assess its effect on the mechanism. RESULTS: A large wrinkle was observed as dermal buckling following a number of buckling events on the stratum corneum. The existence of microrelief had an effect on the suppression of dermal buckling. CONCLUSION: Skin's multilayer structure should play a major role in the appearance of large wrinkles on human skin via its post-buckling behavior. This study suggested that fine microrelief on the skin surface hampers large wrinkles. These findings should be valuable for the development of cosmetic or medical treatments to prevent unfavorable skin deformations.

Detoxification mechanism of asbestos materials by microwave treatment.

The detoxification mechanism of asbestos materials was investigated through simulations and experiments. The permittivities of pure CaO and Mg3Si4O12, as quasi-asbestos materials, were measured using the cavity perturbation method. The real and imaginary parts of the relative permittivity (ɛr' and ɛr″) of CaO are functions of temperature, and numerical simulations revealed the thermal distributions in an electromagnetic field with respect to both asbestos shape and material configuration based on permittivity. Optical microscopic observation revealed that the thickness of chrysotile fibers decreased as a result of CaO heating. The heating mechanism of asbestos materials has been determined using CaO phase, and the detoxification mechanism of asbestos materials was discussed based on the heating mechanism.

Reversible logic gate using adiabatic superconducting devices.

Reversible computing has been studied since Rolf Landauer advanced the argument that has come to be known as Landauer's principle. This principle states that there is no minimum energy dissipation for logic operations in reversible computing, because it is not accompanied by reductions in information entropy. However, until now, no practical reversible logic gates have been demonstrated. One of the problems is that reversible logic gates must be built by using extremely energy-efficient logic devices. Another difficulty is that reversible logic gates must be both logically and physically reversible. Here we propose the first practical reversible logic gate using adiabatic superconducting devices and experimentally demonstrate the logical and physical reversibility of the gate. Additionally, we estimate the energy dissipation of the gate, and discuss the minimum energy dissipation required for reversible logic operations. It is expected that the results of this study will enable reversible computing to move from the theoretical stage into practical usage.

Presentation of epitope sequences from foreign viruses on the surface of apple latent spherical virus particles.

Apple latent spherical virus (ALSV) has small isometric particles that are comprised of two single-stranded RNA species (RNA1 and RNA2) and three capsid proteins (Vp25, Vp20, and Vp24). We constructed ALSV vectors for presenting foreign peptides on the surface of virus particles. In these vectors, peptides can be fused to either of two C-terminal regions of Vp20 (amino acid positions between G171 and P172 or between P172 and L173) or the C-terminus (T192) of Vp24. An ALSV vector presenting the epitope sequences of the coat protein (CP) of zucchini yellow mosaic virus (ZYMV) could systemically infect host plants and was specifically recognized by antiserum against ZYMV by ELISA, immunoelectron microscopy, and immunoblotting. RT-PCR showed that the epitope sequences up to 20 amino acids were stably maintained in the chimeric ALSV for more than 10 serial passages and at least six months. Purified chimeric ALSV particles induced an immune response and the production of antibodies against ZYMV-CP in rabbits. The ALSV vector was also used for expression of an epitope from VP1 of foot-and-mouth disease virus.

The pilot study: sphingomyelin-fortified milk has a positive association with the neurobehavioural development of very low birth weight infants during infancy, randomized control trial.

AIM: This study was a randomised control trial to examine the effects of sphingomyelin (SM), on the mental, motor and behavioural development of premature infants. PATIENTS AND METHODS: Randomised, double-blind controlled trial, enroling infants born with a birth weight of less than 1500 g between January 2004 and October 2007 at Juntendo University Hospital, with follow-up to 18 months. Twenty-four preterm babies were randomly assigned; 12 were assigned to a test group and fed SM-fortified milk (SM 20% of all phospholipids in milk) and 12 were assigned to a control group (SM 13% of all phospholipids in milk). We analysed the composition of the plasma phospholipids and red-cell-membrane fatty acids, after which VEP, Fagan, BSID-II, attention and memory tests were performed. RESULTS: The percentage of SM in the total phospholipids was significantly higher in the trial group than in the control group at 4, 6 and 8 weeks. The Behaviour Rating Scale of the BSID-II, the Fagan test scores, the latency of VEP, and sustained attention test scores at 18 months were all significantly better in the trial group than in the control group. CONCLUSION: This study is the first to report that nutritional intervention via administration of SM-fortified milk has a positive association with the neurobehavioural development of low-birth-weight infants. However, detailed studies on the effects of SM on longer-term development are required.

ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease.

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

Ideal shear strength under compression and tension in C, Si, Ge, and cubic SiC: an ab initio density functional theory study.

Ideal shear strength under superimposed normal stress of cubic covalent crystals (C, Si, Ge, and SiC) is evaluated by ab initio density functional theory calculation. Shear directions in [112] and [110] on the (111) plane are examined. The critical shear stress along the former direction is lower than that along the latter in all the crystals unless the hydrostatic tension is extremely high. In both the [112]-shear and [110]-shear, critical shear stress is increased by compression in C but is decreased in the other crystals. The different response of the critical shear stress to normal stress is due to the strength of the bond-order term, i.e., dependence of the short-range interatomic attraction on the bond-angle.

Studies of severe acute respiratory syndrome coronavirus pathology in human cases and animal models.

During the severe acute respiratory syndrome (SARS) outbreak of 2003, approximately 10% of SARS patients developed progressive respiratory failure and died. Since then, several animal models have been established to study SARS coronavirus, with the aim of developing new antiviral agents and vaccines. This short review describes the pathologic features of SARS in relation to their clinical presentation in human cases. It also looks at animal susceptibility after experimental infection, animal models of SARS, and the pathogenesis of this disease. It seems that adaptation of the virus within the host animal and the subsequent abnormal immune responses may be key factors in the pathogenesis of this new and fatal respiratory disease. The proteases produced in the lung during inflammation could also play an important role for exacerbation of SARS in animals.

IGF-I, leptin and active ghrelin levels in very low birth weight infants during the first 8 weeks of life.

AIM: We investigated the relationship between plasma insulin-like growth factor I (IGF-I), leptin, active ghrelin levels, and postnatal growth in very low birth weight (VLBW) infants. METHOD: Plasma IGF-I, leptin, and active ghrelin levels were measured at birth and at 2, 4, 6 and 8 weeks after birth in 61 VLBW infants, including 31 appropriate-for-gestational-age (AGA) and 30 small-for-gestational-age (SGA) infants. RESULTS: Insulin-like growth factor I levels were the lowest at birth, but increased gradually over the first 8 weeks of life. IGF-I was positively correlated with body weight, body length and body mass index at all time points. Leptin levels did not change over the study period. Ghrelin levels were significantly lower at birth; however, there were no significant differences between the levels after 2 weeks of age. Leptin and ghrelin levels were not correlated with anthropometrical measures. IGF-I levels at birth were significantly lower in SGA than in AGA infants, but the leptin and ghrelin levels were not significantly different between the two groups. CONCLUSION: Insulin-like growth factor I is related to length and weight gain in the prenatal and the early postnatal periods in VLBW infants, but this does not appear to be the case for leptin and ghrelin.

Two types of myeloperoxidase-antineutrophil cytoplasmic autoantibodies with a high affinity and a low affinity in small vessel vasculitis.

OBJECTIVE: Myeloperoxidase (MPO) -anti-neutrophil cytoplasmic autoantibodies (ANCAs) are detected at a high rate in microscopic polyangiitis and renal-limited vasculitis. MPO-ANCA titers are not always reflected in the disease activity. We studied the titer and affinity of MPO-ANCA in sera from patients in relation to vasculitis activity. METHODS: Blood samples were collected from 27 newly diagnosed or relapsed patients with MPO-ANCA-associated vasculitides. The MPO-ANCA titer was determined by a direct enzyme-linked immunosorbent assay (ELISA) using homogeneously purified human MPO of leukocytes. The MPO-ANCA affinity was expressed as IC50 that was determined by a competitive inhibition method using the ELISA. RESULTS: The MPO-ANCA affinity of 27 sera from 27 patients could be classified into a high-affinity type (14 sera) and a low-affinity type (13 sera). The mean values for IC50 in the two types were 0.15+/-0.06 microg/ml and 0.54+/-0.15 microg/ml, and the difference was statistically significant (p<0.0000000684). Between the two groups of patients divided by the affinity, there were differences in the Birmingham Vasculitis Activity Score (BVAS): and in C-reactive protein (CRP): (p<0.00093 and p<0.00129, respectively). However, the difference in titer was not statistically significant (p<0.0265). The affinity remained steady from the disease onset to remission or relapse. CONCLUSIONS: The affinity of MPO-ANCA from patients with MPO-ANCA-associated vasculitides were largely distinguished into a high and a low affinity, irrespective of the level of MPO-ANCA titers, and may be helpful for assessment of vasculitis activity affecting mainly the kidney and the lung.

Does breastfeeding in the neonatal period influence the cognitive function of very-low-birth-weight infants at 5 years of age?

AIM: Breast milk is rich in docosahexaenoic acid (DHA), which is selectively concentrated in neuronal membranes and is thought to be necessary for optimal neurodevelopment. This study evaluated the relationship between breastfeeding, especially the resultant DHA level in the red blood cell (RBC) membranes of infants, and the cognitive function of very-low-birth-weight infants at 5 years of age. METHODS: Eighteen patients were classified into groups that were breastfed or formula-fed or both. We measured the DHA concentration in the RBC membranes of 18 preterm infants at 4 weeks of age. To evaluate cognitive function at the age of 5 years, we asked the children to perform five tests: the Kaufman Assessment Battery for Children, Day-Night Test, Kansas Reflection Impulsivity Scale for Preschoolers (KRISP), Motor Planning Test, and Strengths and Difficulties Questionnaire. RESULTS: The DHA level at 4 weeks after birth was significantly higher in the breastfed infants than in the formula-fed infants. The scores for the Day-Night Test, KRISP, and Motor Planning Test were significantly higher in the breastfed group. There were significant correlations between the scores for the Day-Night Test and for the KRISP and the level of DHA at 4 weeks of age. CONCLUSION: Breastfeeding in the neonatal periods increases the DHA level in preterm infants and may have an important influence on brain development not only during early infancy but also during the preschool years, especially in terms of cognitive function.

Microwave radiation processing of metallic glassy powders.

In the present study we investigate the stability of Cu50Zr45Al5 and Ni59Ti16Zr20Sn5 glassy powders and the formation of the bulk metallic glassy samples by microwave heating in a single mode cavity (915 MHz) in the alternating magnetic field maximum. Metallic glasses exhibit low viscosity at temperatures close to the glass-transition which allows for the processing of glassy powders. Microwave heating being a volumetric heating has significant advantages over conventional heating in materials processing, such as substantial energy savings, high heating rates and process cleanness.

Evaluation of cotton rats as a model for severe acute respiratory syndrome.

Experimental studies were conducted to evaluate two species of cotton rats, Sigmodon hispidus and Sigmodon fulviventer, as a model for severe acute respiratory syndrome (SARS). Blood and turbinate wash samples, and lung tissue were collected from each animal at different time points after SARS coronavirus (CoV) infection for determining the growth curve of virus, if any, by the standard infectivity assay in Vero E6 cells. In addition, sections of the lung, liver, spleen, and kidney were taken and used for histology analysis. All animals were observed daily for signs of illness, and in some experiments, animals were weighed on the day when they were sacrificed. The results indicated that the cotton rat species, S. hispidus and S. fulviventer, were not a useful model for either SARS-CoV infection or disease. This observation was supported by the absence of any signs of illness, the failure to consistently demonstrate virus in the blood and tissues, and the absent of any notable histopathology. However, infected animals were capable of producing neutralizing antibodies against SARS-CoV, suggesting the seroconversion did occur. Further studies are warranted to consider other animal species in efforts to find better animal models for the evaluation of SARS-CoV vaccines and antiviral drugs.

Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness.

BACKGROUND: Bartter syndrome (BS) is a genetic disorder accompanied by hypokalaemic metabolic alkalosis. BS with sensorineural deafness (SND, OMIM602522) is a newly identified phenotype caused by mutations in the BSND gene that encodes barttin, a beta-subunit for chloride channel ClC-Ka and ClC-Kb and classified as type IV BS. Type IV BS features the most severe phenotype entailing life-threatening neonatal volume depletion and chronic renal failure developing during infancy. A recent report described a case of BS with SND from a consanguineous family who showed homozygous mutations in the CLCNKA and CLCNKB genes. This case indicated the possibility of the occurrence of digenic inheritance in BS with SND resulting from double mutations in the CLCNKA and CLCNKB genes. SUBJECT AND RESULTS: The current report concerns a 2-year-old girl from a non-consanguineous family with BS accompanied by SND. In our case, four loss-of-function mutations, consisting of mutations in both parental alleles in both CLCNKA and CLCNKB, were identified. The paternal allele had a nonsense mutation (Q260X) in CLCNKA and a splicing site mutation (IVS17+1 g>a) in CLCNKB. The maternal allele had a large deletion mutation (about 12 kbp) extending from CLCNKA to CLCNKB. Our case provides clear evidence that loss-of-function alleles in both alleles of both CLCNKA and CLCNKB results in a phenotype indistinguishable from that of mutations in BSND (type IV BS). CONCLUSIONS: Recent advances in genetics have resulted in a better understanding of many human inherited diseases, but most of them are monogenic disorders and more complex inheritance patterns remain unresolved. Our case provides clear evidence of digenic inheritance outside the scope of Mendelian inheritance disorders.

Effective and safe treatment with cyclosporine in nephrotic children: a prospective, randomized multicenter trial.

We conducted a prospective, open-label multicenter trial to evaluate the efficacy and safety of treating children with frequently relapsing nephrotic syndrome with cyclosporine. Patients were randomly divided into two groups with both initially receiving cyclosporine for 6 months to maintain a whole-blood trough level between 80 and 100 ng/ml. Over the next 18 months, the dose was adjusted to maintain a slightly lower (60-80 ng/ml) trough level in Group A, while Group B received a fixed dose of 2.5 mg/kg/day. The primary end point was the rate of sustained remission with analysis based on the intention-to-treat principle. After 2 years, the rate of sustained remission was significantly higher while the hazard ratio for relapse was significantly lower in Group A as compared with Group B. Mild arteriolar hyalinosis of the kidney was more frequently seen in Group A than in Group B, but no patient was diagnosed with striped interstitial fibrosis or tubular atrophy. We conclude that cyclosporine given to maintain targeted trough levels is an effective and relatively safe treatment for children with frequently relapsing nephrotic syndrome.

Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations.

Management of idiopathic glomerular disease associated with nephrotic syndrome (INS) remains controversial and one of the most complex areas relates to utilization of the drug cyclosporin. This is despite its demonstrated effectiveness in several histologic types of the INS in randomized controlled trials. Cyclosporin is effective in inducing remission of proteinuria in approximately 80% of steroid-sensitive cases of minimal change disease (MCD). Cyclosporin is also effective in both the induction of remission and long-term preservation of renal function in steroid-dependent/-resistant MCD and steroid-resistant focal segmental glomerulosclerosis (FSGS). The overall response rate in FSGS is lower than in MCD, and long-term therapy (>12 months) may be required to both achieve remission and sustain it. Cyclosporin therapy is also of benefit in reducing proteinuria in 70-80% of patients with steroid-resistant membranous nephropathy (MGN). In MGN, the maximum benefit is often delayed compared to MCD (>12 weeks). Cyclosporin is generally well tolerated and safe. The major concern remains the nephrotoxicity, but with careful monitoring of the patient's renal function; minimizing the maintenance dose and utilizing repeat renal biopsy in those receiving long-term therapy, this risk can be minimized. The algorithms have been developed derived from the best evidence in the literature in each of the histologic types to help provide a guide to the integration of cyclosporin into the management of INS for the practicing nephrologist.

Characterization of virus-induced gene silencing in tobacco plants infected with apple latent spherical virus.

Apple latent spherical virus (ALSV) expressing green fluorescent protein (GFP-ALSV) was used for analysis of virus-induced gene silencing (VIGS) in tobacco plants expressing GFP (GFP-tobacco). In GFP-tobacco inoculated with GFP-ALSV, small dark spots appeared on inoculated leaves at 5 days post-inoculation (dpi), then expanded, and finally covered the whole area of the leaves after 12 dpi. Most of the fluorescence of upper leaves above the 12th true leaf disappeared at 21 dpi. Thus, GFP-ALSV infection efficiently triggered VIGS of a transgene (GFP gene) in tobacco plants. Analysis of GFP-silenced leaves showed that viral RNAs and proteins accumulated in all leaves where most GFP mRNA had been degraded. The siRNAs derived from ALSV-RNAs were not detected in samples from which siRNA of GFP mRNA could be easily detected. Direct tissue blot analysis showed that the spread of GFP-ALSV always preceded the induction of VIGS in infected leaves of GFP-tobacco. GFP leaf patch tests using Nicotiana benthamiana line 16c showed that Vp20, one of the three capsid proteins, is a silencing suppressor which interferes with systemic silencing.