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.

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.

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.

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.

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.

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.

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.

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.

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.

Thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. Cross talk between endocrine control of stress response and cellular antioxidant defense system.

Adaptation to stress evokes a variety of biological responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and synthesis of a panel of stress-response proteins at cellular levels: for example, expression of thioredoxin (TRX) is significantly induced under oxidative conditions. Glucocorticoids, as a peripheral effector of the HPA axis, exert their actions via interaction with a ligand-inducible transcription factor glucocorticoid receptor (GR). However, how these stress responses coordinately regulate cellular metabolism is still unknown. In this study, we demonstrated that either antisense TRX expression or cellular treatment with H2O2 negatively modulates GR function and decreases glucocorticoid-inducible gene expression. Impaired cellular response to glucocorticoids is rescued by overexpression of TRX, most possibly through the functional replenishment of the GR. Moreover, not only the ligand binding domain but the DNA binding domain of the GR is also suggested to be a direct target of TRX. Together, we here present evidence showing that cellular glucocorticoid responsiveness is coordinately modulated by redox state and TRX level and propose that cross talk between neuroendocrine control of stress responses and cellular antioxidant systems may be essential for mammalian adaptation processes.

Plasma levels of active ghrelin until 8 weeks after birth in preterm infants: relationship with anthropometric and biochemical measures.

This study investigated the relationship between plasma levels of ghrelin and postnatal growth in preterm infants. The levels of active ghrelin in cord blood and in plasma in 25 very low birthweight (VLBW) infants were measured. The results indicate that the levels of circulating active ghrelin markedly increases after birth in VLBW infants, and suggest that the increased levels of ghrelin reflects the maturation of ghrelin production in the stomach and an increased physiological need for ghrelin.

Plasma angiotensin II concentrations in the early neonatal period.

BACKGROUND: There have been only a few reports on the renin-angiotensin system in low birthweight infants; in particular, plasma angiotensin II concentrations have not been studied. AIM: To investigate plasma angiotensin II concentrations in early neonatal infants including low birthweight infants. METHODS: Forty six patients were studied, of whom 14 weighed not less than 2500 g (normal birth weight), 16 weighed less than 2500 g but not less than 1500 g (moderately low birth weight), and 16 weighed less than 1500 g (very low birth weight). Blood samples were collected twice, on day 0 and day 7. Angiotensin II concentration was assayed using an enzyme immunoassay kit with a microplate. RESULTS: Geometric means of angiotensin II concentrations on day 7 were 19 pg/ml in the normal birthweight group, 28 pg/ml in the moderately low birthweight group, and 76 pg/ml in the very low birthweight group. The concentrations on day 7 in the very low birthweight group were significantly higher than those in the normal birthweight and moderately low birthweight groups (p = 0.005, p = 0.031). There were significant correlations between angiotensin II concentration on day 7 and gestational age (r(s) = -0.4, p = 0.007) and birth weight (r(s) = -0.36, p = 0.016). CONCLUSIONS: Specific physiological conditions associated with a very low birth weight are thought to be responsible for the increased concentration of angiotensin II on day 7. It is necessary to measure angiotensin II concentration for a longer period after birth and study the factors that could influence it.

Interference of Long-Distance Movement of Grapevine berry inner necrosis virus in Transgenic Plants Expressing a Defective Movement Protein of Apple chlorotic leaf spot virus.

ABSTRACT Transgenic Nicotiana occidentalis plants expressing a movement protein (P50) and partially functional deletion mutants (DeltaA and DeltaC) of the Apple chlorotic leaf spot virus (ACLSV) showed resistance to Grapevine berry inner necrosis virus (GINV). The resistance is highly effective and GINV was below the level of detection in both inoculated and uninoculated upper leaves. In contrast, GINV accumulated in inoculated and uninoculated leaves of nontransgenic (NT) plants and transgenic plants expressing a dysfunctional mutant (DeltaG). On the other hand, in some plants of a transgenic plant line expressing a deletion mutant (DeltaA', deletion of the C-terminal 42 amino acids), GINV could spread in inoculated leaves, but not move into uninoculated leaves. In a tissue blot hybridization analysis of DeltaA'-plants inoculated with GINV, virus could be detected in leaf blade, midribs, and petiole of inoculated leaves, but neither in stems immediately above inoculated leaves nor in any tissues of uninoculated leaves. Immunohistochemical analysis of GINV-inoculated leaves of DeltaA'-plants showed that GINV could invade into phloem parenchyma cells through bundle sheath of minor veins, suggesting that the long-distance transport of GINV might be inhibited between the phloem cells and sieve element (and/or within sieve element) rather than bundle sheath-phloem interfaces. Immunogold electron microscopy using an anti-P50 antiserum showed that P50 accumulated on the parietal layer of sieve elements and on sieve plates. The results suggested that resistance in P50-transgenic plants to GINV is due to the interference of both long-distance and cell-to-cell movement of the virus.

Exact static solutions for discrete phi4 models free of the Peierls-Nabarro barrier: discretized first-integral approach.

We propose a generalization of the discrete Klein-Gordon models free of the Peierls-Nabarro barrier derived in Spreight [Nonlinearity 12, 1373 (1999)] and Barashenkov [Phys. Rev. E 72, 035602(R) (2005)], such that they support not only kinks but a one-parameter set of exact static solutions. These solutions can be obtained iteratively from a two-point nonlinear map whose role is played by the discretized first integral of the static Klein-Gordon field, as suggested by Dmitriev [J. Phys. A 38, 7617 (2005)]. We then discuss some discrete phi4 models free of the Peierls-Nabarro barrier and identify for them the full space of available static solutions, including those derived recently by Cooper [Phys. Rev. E 72, 036605 (2005)] but not limited to them. These findings are also relevant to standing wave solutions of discrete nonlinear Schrödinger models. We also study stability of the obtained solutions. As an interesting aside, we derive the list of solutions to the continuum phi4 equation that fill the entire two-dimensional space of parameters obtained as the continuum limit of the corresponding space of the discrete models.

In vitro production of myeloperoxidase anti-neutrophil cytoplasmic antibody and establishment of Th1-type T cell lines from peripheral blood lymphocytes of patients.

OBJECTIVE: To investigate the pathogenic role of T cells in the development of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. METHODS: Peripheral blood lymphocytes (PBL) were isolated from myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis patients and cultured in medium. The production of MPO-ANCA in the medium of PBL stimulated with Concanavalin-A (Con-A), with or without cyclosporin (CyA), was measured by enzyme-linked immunosorbent assay (ELISA) on MPO coated plates. RNA isolated from PBMC of one patient was used for polymerase chain reaction (PCR) and single stranded conformational polymorphism (SSCP) studies, and MPO-specific T cell lines (TCL) were established by antigen stimulation techniques. RESULTS: PBL of patients with MPO-ANCA-associated vasculitis produced MPO-ANCA following Con-A stimulation, and this effect was inhibited by treatment with cyclosporin A (CyA) or elimination of CD4 cells. PCR-SSCP showed autoantigen-reactive oligoclonal T-cell accumulation in PBMC of one of these patients. We established MPO-specific TCL which secreted interferon-gamma (IFN-gamma), but not interleukin-4 (IL-4); all TCL were CD4 positive, CD8 negative, and HLA-DR restricted. CONCLUSIONS: Our results suggest that Th1-type T cells may mediate MPO-ANCA production, and may play a role in the onset of MPO-ANCA vasculitis.

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.

Shear-stress causes polarized change in cytoplasmic calcium concentration in human umbilical vein endothelial cells (HUVECs).

Using a newly developed, parallel-plate flow-chamber for confocal laser scanning microscopy (CLSM), we studied the distribution and temporal changes in intracellular Ca2+ concentration ([Ca2+]i) in individual HUVECs stimulated by shear-stress. In the presence of ATP, shear-stress (1-10 dyne/cm2) caused a rise in [Ca2+]i, whereas no such response was observed in the absence of ATP or in the presence of Ni2+, a nonspecific, plasma membrane Ca2+ channel blocker. These results suggest that both ATP and Ca2+ influx are essential for the increase in [Ca2+]i in response to shear stress at less than 10 dyne/cm2. Analysis of [Ca2+]i distribution revealed a repetitive intracellular 'Ca2+ wave' originating from the upstream edge of the cell in some populations of HUVECS, which was transmitted to the downstream of the cell. The polarized [Ca2+]i response induced by shear-stress might be integral to polarized cellular reactions such as remodeling of endothelial lining.