Persistent Primary Cytomegalovirus Infection After Deceased Donor Kidney Transplant: Ganciclovir Susceptibility of Human Cytomegalovirus With UL97 D605E Mutation: A Case Report.

BACKGROUND: Cytomegalovirus (CMV) could cause rejection in immunocompromised patients during early post-renal transplant stage. The American Transplant Society guidelines recommend prophylactic therapy with ganciclovir (GCV) for 3 to 6 months to prevent CMV infections in adult renal transplant patients. However, there is no recommended CMV treatment regimen for pediatric patients. MAIN FINDINGS: We performed deceased donor kidney transplant from an anti-CMV antibody-positive donor to an anti-CMV antibody-negative 15-year-old female recipient with end-stage renal disease caused by bilateral renal hypoplasia. One month after transplant, increase in positive cells in the CMV antigenemia assay indicated a primary CMV infection in the patient, who immediately received GCV. She was switched to foscarnet after 4 months of anti-CMV therapy because of clinical GCV resistance. CMV was isolated from the peripheral blood mononuclear cells but neutralizing antibody was not detected. Isolated CMV was susceptible to GCV and foscarnet, although it carried the UL97 D605E mutation, assumed to be associated with GCV resistance. CONCLUSIONS: The primary CMV infection presented a phenotypic clinical drug resistance, but all recovered CMV isolates were drug-susceptible even if isolated after prolonged anti-CMV therapy, indicating that immune status was more important for recovery from primary CMV infection than anti-CMV therapy.

Lower urinary tract symptoms in children and adolescents with Williams-Beuren syndrome.

INTRODUCTION: Williams-Beuren syndrome (WBS) is a genetic condition caused by a microscopic deletion in the chromosome band 7q11.23. Individuals with WBS may present with congenital cardiovascular defects, neurodevelopmental disturbances and structural abnormalities of the urinary tract. Lower urinary tract symptoms (LUTS) seem to be frequent in this population, but studies on this topic are scarce and based on small case series. OBJECTIVE: To systematically evaluate the prevalence of lower urinary tract symptoms (LUTS) and the acquisition of bladder control in a large population with WBS. STUDY DESIGN: A cross-sectional study evaluating 87 consecutive patients with WBS; there were 41 girls and 46 boys. Genetic studies confirmed WBS in all patients. Subjects were clinically evaluated with: a history of LUTS obtained from the parents and child, a structured questionnaire of LUTS, a 3-day urinary frequency-volume chart, a quality of life question regarding LUTS, and physical examination. A history regarding the acquisition of bladder control was directly evaluated from the parents. RESULTS: Mean age of patients was 9.0 ± 4.2 years, ranging from 3 to 19 years. Based on the symptoms questionnaire and the frequency-volume chart, 70 patients (80.5%) were symptomatic. The most common symptom was urgency, affecting 61 (70.1%) patients, followed by increased urinary frequency in 60 (68.9%) patients, and urge-incontinence in 53 (60.9%), as shown in Summary Fig. More than half of the children reported nocturnal enuresis, including 61% of the girls and 52% of the boys. Twenty-three patients (25.6%) had a history of urinary tract infections. The mean age for acquisition of dryness during the day was 4.4 ± 1.9 years. Parents of 61 patients (70.1%) acknowledged that LUTS had a significant impact on the quality of life of their children. DISCUSSION: A high prevalence of LUTS was confirmed with a significant negative impact on quality of life in a large population of children and adolescents with WBS. It was shown for the first time that the achievement of daytime bladder control is delayed in children with WBS. Although LUTS are not recognized as one of the leading features of the syndrome, it is believed that it should be considered as a significant characteristic of the clinical diagnosis of WBS. CONCLUSIONS: LUTS are highly prevalent in children and adolescents with WBS and have a significant negative impact on patient's quality of life.

Molecular genetic analysis of 30 families with Joubert syndrome.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Epstein-Barr virus load for early detection of lymphoproliferative disorder in pediatric renal transplant recipients.

AIM: The aims of this study were to establish a protocol for monitoring Epstein-Barr virus (EBV) infection for identification of pediatric renal transplant recipients with a high risk of developing posttransplant lymphoproliferative disorder (PTLD) and to predict the development of PTLD. SUBJECTS AND METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma EBV loads were measured by nested PCR (n-PCR) and real-time PCR (r-PCR) every 1 - 3 months after grafting in 17 pediatric recipients who were seronegative for EBV before grafting (4 with EBV-associated symptoms, including 2 with PTLD (Group A); 6 with asymptomatic persistent high EBV loads in PBMCs of > 1,000 copies/µgDNA for over 6 months (Group B); and 7 with neither EBV-associated symptoms nor persistent high EBV loads in PBMCs (Group C)). RESULTS: n-PCR revealed EBV-DNA in PBMCs from all patients. The EBV genome was present in plasma in 3 (75%), 1 (17%), and 0 (0%) in Groups A, B and C (p < 0.01 for A vs. B and A vs. C). EBV loads detected by r-PCR in PBMCs were significantly higher in Groups A (p < 0.05) and B (p < 0.01) compared to Group C. EBV genomes in plasma were detected by n- and r-PCR in only the 2 cases with PTLD. One patient with lymphadenitis in Group A and 1 patient in Group B had EBV-DNA in plasma based on n-PCR, but the viral loads using r-PCR were < 250 copies/ml. CONCLUSION: EBV loads in PBMCs alone are insufficient for predicting EBV-associated symptoms including PTLD. Plasma EBV loads (over 250 copies/ml) estimated by r-PCR may be useful to distinguish PTLD from other EBV-associated diseases or asymptomatic viremia.

Vitamin B6 deficiency and anemia in pregnancy.

Iron deficiency is the most common cause of anemia in pregnancy. Pregnant women with anemia are, in general, exclusively treated with iron supplementation. We observed that several pregnant women with anemia who were nonresponsive to iron supplementation also had vitamin B6 deficiency, and that anemia in these cases improved with the administration of vitamin B6. Our prospective study in healthy pregnant women showed that blood levels of iron, ferritin and vitamin B6, in particular, fell to the lower limit of the nonpregnant reference range by the third trimester. We conclude that it is important to take into account the deficiency of vitamin B6 besides iron in the evaluation of anemia during pregnancy.

Monitoring of Epstein-Barr virus load and killer T cells in pediatric renal transplant recipients.

AIM: The aim of this study is to establish a monitoring method to prevent Epstein-Barr virus (EBV)-associated symptoms including post-transplant lymphoproliferative disorder (PTLD) that occur after pediatric renal transplantation. SUBJECTS AND METHODS: Circulating EBV loads were quantified by real-time PCR every 1 - 3 months after grafting in 22 pediatric recipients (13 EBV-seronegative [R(-)] and 9 EBV-seropositive [R(+)] recipients before grafting). The peripheral blood cell populations of non-specific activated killer cells (CD8+HLA-DR+ phenotype) in 13 R(-) recipients and EBV-specific cytotoxic T cells (CTLs) reactive with a tetramer expressing HLA-A24-restricted EBV-specific antigens in 8 of 13 R(-) recipients were determined by flow cytometry. RESULTS: EBV-associated symptoms including PTLD (2 cases) were found in 4 R(-) and none of the R(+) recipients. The maximum of EBV load in the R(-) group was significantly higher that in the R(+) group. In R(-) recipients, 4 symptomatic cases had significantly more EBV genome than asymptomatic cases. EBV-specific CTLs were detected in 6 of the 8 R(-) recipients, but these CTLs could not be detected in 1 of the 2 cases at onset of PTLD. The percentage of CD8+HLA-DR+ cells was significantly higher in asymptomatic recipients than in recipients with EBV-associated symptoms whose EBV loads were over 400 copies/microg DNA. CONCLUSION: Monitoring of killer T cells and EBV loads may allow assessment of the risk of EBV-associated symptoms, and high EBV loads and low EBV-specific and/or non-specific CTL responses may be predictive for development of EBV-associated symptoms such as PTLD.

Effect of biomechanical disturbance of the temporomandibular joint on the prevalence of internal derangement in mandibular asymmetry.

The aim of the present study was to elucidate the relationship between biomechanical changes of the temporomandibular joint (TMJ) and internal derangement (ID) symptoms in mandibular asymmetry. Posteroanterior cephalograms (PA) of 140 patients with TMJ ID associated with mandibular asymmetry were used to investigate the inclination of the frontal occlusal plane (FOP), and were analysed in conjunction with the results of a report providing information on ID symptoms. A three-dimensional (3D) finite element model (FEM) of the entire mandible was created to investigate the distribution of TMJ forces during clenching. The inclination of the FOP was modified to simulate various degrees of vertical asymmetry. The stresses on the TMJ on the ipsilateral and contralateral sides were analysed and their values were compared with those of the standard model. The results showed that the symptomatic sides were significantly related to the degree of inclination of the FOP. Increasing its angulation resulted in a decrease of the symptoms on the ipsilateral side and an increase of those on the contralateral side. The analysis showed that stress-distribution patterns and overall stresses of the articular disc were influenced by the angulation of inclination of the FOP. These mechanical changes exhibited a distinct relationship with the prevalence of ID in the patients. These results suggest that disturbances in the stresses either in amount or direction due to occlusal inclination can be responsible for ID. Therefore, an attempt to establish a flat occlusal plane is an important orthodontic treatment objective in maintaining the normal health and structure of the TMJ.

Temporomandibular joint internal derangement in mandibular asymmetry. What is the relationship?

The purpose of this study was to clarify the contributing factors and their influences on temporomandibular joint internal derangement (TMJ ID) symptoms in subjects with mandibular asymmetry. Postero-anterior (PA) cephalograms of 187 pre-orthodontic treatment subjects (aged 18-45 years, mean 23.9 years) were used to investigate the inclination of the frontal occlusal (FOP) and frontal mandibular (FMP) planes to determine vertical asymmetry. Mandibular dental midline shift (DMS) and mandibular midline shift (MMS) were studied to determine transverse asymmetry. The degree of asymmetry was analysed in conjunction with the results from self-administered TMJ ID history forms. A prevalence of TMJ ID was most related to the inclination of the FMP (P < 0.01), with the symptoms being notably higher when the cant was greater than 3 degrees. The symptomatic side was related only to the inclination of the FOP and FMP. Symptoms confined to the ipsilateral side were primarily found in subjects with mild asymmetry, whereas symptoms on both sides and those on the contralateral side were greater in those with moderate and severe asymmetry, respectively. No significant correlation was found for DMS and MMS. The results suggest that the degree of asymmetry in the vertical dimension is significantly correlated with TMJ ID symptoms.

Urinary leukotriene E4 in Henoch-Schonlein purpura.

BACKGROUND: Children with Henoch-Schonlein purpura (HSP) occasionally have allergic disease. We have previously shown that pranlukast hydrate was effective for purpura in HSP. Pranlukast hydrate is a leukotriene (LT) receptor antagonist; therefore, it is likely that LTs take part in the cause of HSP. Urinary leukotriene E4 (LTE4u) levels are a useful index of whole-body cysteinyl LT production in vivo. In this study, LTE4u was examined in children with HSP. OBJECTIVE: The purpose of this study was to examine the relation between the level of LTE4u and the cause of HSP. METHODS: Eighteen HSP children (six boys and 12 girls) and six healthy children were enrolled. RESULTS: LTE4u levels in patients with HSP were significantly higher (P< 0.05) at the onset than those in healthy children. Four weeks therapy with pranlukast hydrate lowers LTE4u levels in patients with HSP (P< 0.05). There were no differences in LTE4u between the group of HSP patients with purpura nephritis and the group of HSP patients without purpura nephritis. CONCLUSION: These results indicate that csyteinyl LTs may play a role in the pathophysiology of purpura in HSP.

Dynamic analysis for clarifying occlusal force transmission during orthodontic archwire application: difference between ISW and stainless steel wire.

The purpose of our study was to utilize the dynamic finite element analysis to clarify the difference between Improved Super-elastic Ti-Ni alloy Wire (ISW) and Stainless Steel Wire (SSW) on occlusal force transmission during orthodontic treatment. ABAQUS/Standard was used to analyze three finite models over a 30-ms period: ISW, SSW, and wireless models; which consisting of premolar, molar, periodontal ligament (PDL), and alveolar bone. Wire model was established by beam element. A Joint C, which exhibits viscoelasticity to buffer occlusal force, was applied between the wire and bracket. The load was applied on the occlusal surface. At load withdrawal point, the average amounts of von Mises stress on PDL in three models were of the same value. However as time progressed, the stress in wireless model became higher than ISW and SSW models. In contrast, as time progressed further, the stress in SSW model became higher than the other two models and maintained its higher level until the end of analysis. Results showed that high damping capacity of ISW had an ability to buffer the transmission of occlusal force to the PDL. Besides, the dynamic analysis demonstrated an advantage to investigate the stress alterative response between models versus time period.

The interrelationship between bolus breakdown, mandibular first molar displacement and jaw movement during mastication.

The purpose of this study was to clarify the interrelationship between food bolus breakdown, mandibular first molar displacement and jaw movement during mastication. Finite element models were constructed of the maxillary first molar crown, the mandibular first molar consisting of crown, root, periodontal ligament and alveolar bone, as well as the food bolus were constructed. Based on the actual measurement of the jaw movement pattern and the characteristics of food bolus, the patterns of mandibular first molar displacement and bolus breakdown on time course in the progress of mastication were simulated, to investigate the biomechanical significance of tooth displacement and jaw movement during mastication, using finite element non-linear dynamic analysis. The results showed that the patterns of tooth displacement and jaw movement and characteristics of food bolus changed with an interrelationship to each other as mastication progressed. Particularly at the initial phase, it was suggested that the patterns of mandibular first molar displacement and jaw movement worked inter-dependently to accomplish an efficient hard-bolus breakdown.

Relationship between the flow of bolus and occlusal condition during mastication--computer simulation based on the measurement of characteristics of the bolus.

The purpose of the present study was to clarify the relationship between the flow of a bolus and occlusal condition during mastication. First, the characteristics of a bolus under mastication was measured in subjects having different occlusal conditions. Secondly, the flow of a bolus between the upper and lower first molars under mastication was simulated using finite element non-linear dynamic analysis. Measurement of the elasticity of the bolus clarified the phenomenon of its communition. The measurement of the viscosity of the bolus clarified the phenomenon of its mixing with saliva. In addition, a relationship between the elasticity and the viscosity of the bolus at the point of just before swallowing was investigated. The flow of the bolus under mastication was revealed to vary according to the occlusal condition. These results suggest a close relationship between the occlusal condition, the flow of the bolus and its characteristics.

Immunomodulatory effect of gold sodium thiomalate on murine acquired immunodeficiency syndrome.

Induction of IL-2 production and increased expression of CD25 were observed in C57BL/10 mice after weekly treatment with gold sodium thiomalate (GST). LP-BM5 murine leukemia virus (MuLV) infected mice treated with GST survived longer, had less cervical lymph node swelling, lower spleen weight, and fewer abnormalities in the expression of the cell surface markers, CD4, CD8a and CD45R/B220 on spleen cells than those that were not treated with GST. Thus, GST treatment may be beneficial through a decrease in disease progression via IL-2 induction in MuLV infected mice. This may have application in human immunodeficiency virus-infected individuals.

Tyrosine phosphorylation of the linker for activator of T cells in mast cells by stimulation with the high affinity IgE receptor.

Aggregation of the high affinity IgE receptors (FcepsilonRI) on basophils and mast cells, members of the immune receptor family, initiates a cascade of events that results in the release of inflammatory mediators. This pathway involves the activation of several protein-tyrosine kinases, including Lyn, Syk, Btk, and Fak that induce the tyrosine phosphorylation of various proteins. The linker for activation of T cells (LAT), was originally found as a ZAP-70 tyrosine kinase substrate that linked T cell receptors to cellular activation, and was expressed in T cells, NK cells and mast cells. Here we show that LAT expressed in the RBL-2H3 rat mast cell line is tyrosine-phosphorylated after aggregation of FcepsilonRI. The tyrosine phosphorylation of the LAT was dramatically enhanced after receptor aggregation. Furthermore, a tyrosine-phosphorylated 80-kDa protein associated with LAT transiently after receptor aggregation. GST fusion proteins containing parts of PLCgamma or PI3 kinase can bind LAT. These results suggest that LAT plays an important role not only in T cell, but also in mast cell activation, and that the association among these signaling molecules is critical for FcepsilonRI-mediated intracellular signal transduction in mast cells.

The inhibitory effect of anti-allergic agent suplatast tosilate (IPD-1151T) on methacholine- and allergen-induced bronchoconstriction in sensitized mice. asakazu@med.showa-u.dc.jp.

The influence of an anti-allergic agent, suplatast tosilate (IPD-1151T; (+/-)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenyl-carbamoyl]-ethyl] dimethylsulfonium p-toluenesulfonate) on allergic bronchoconstriction induced by allergen and methacholine (MCh) were examined in mice. BALB/c mice were sensitized by intraperitoneal injection of dinitrophenylated-keyhole limpet hemocyanin (DNP-KLH) mixed with A1(OH)3 (DNP-KLH). IPD-1151T was administered orally once a day for either 5 or 14 days in doses of 10, 30 or 100 mg/kg. Bronchoconstriction was measured 24h after the final drug administration. IPD-1151T inhibited both antigen- and MCh-mediated bronchoconstriction in actively sensitized mice. The inhibition induced was closely related to the dose and frequency of oral administration of the agent. We also examined the effect of IPD-1151T on IgE production in response to DNP-KLH immunization. IPD-1151T inhibited dose-dependently both total and specific IgE concentrations in serum prepared from mice 15 days after immunization. These results strongly indicate that IPD-1151T inhibits IgE production in vivo and results in attenuating effect on bronchoconstriction.

Energy-based re-evaluation of Angle's class I molar relationship.

The energy used to break down food was calculated in Angle Class I and rigid interdigitation, as well as in various malocclusions using a computer simulation. As a result, the energy applied to the food was the highest in Angle's Class I molar relationship and rigid interdigitation, with a simple pattern of masticatory movement. This relationship also tended to produce maximum efficiency in the posterior teeth, including the premolars. Furthermore, energy decreased with the degree of malocclusion. Thus, we were able to provide an alternative definition of Angle's Class I molar relationship and rigid interdigitation. In addition, the extent of malocclusion could be evaluated quantitatively.

Energy-based evaluation of occlusion.

The purpose of this study was to establish an index for evaluating occlusal conditions using energy levels. For this purpose, first, the movement of mastication under five occlusal conditions in which the positional relationship varied mesiodistally was simulated and the energy applied to the food being masticated was calculated, based on theoretical values of computing mechanics using finite element static analysis. As a model experiment, the energy generated under each occlusal condition was then measured using the electrical output from an occlusion pressure sensor composed of pressure-sensitive rubber. By comparing the theoretical values of computing mechanics and the measured values, the changes in the energy level under occlusal conditions were consistent with the trends, and the maximum value of the energy was obtained under the occlusal condition of Angle Class I and consisting of rigid interdigitation. In conclusion, our results demonstrated that occlusal conditions can be evaluated using the energy level as an index.

[The availability of personality traits in the hierarchical structure: an exploration of the "basic level"].

Personality traits have a structure that is hierarchically organized in terms of trait abstractness. Which level of the hierarchy is most available to the person perceiver? We started out with four levels, and tried to determine which was most available and therefore became the "basic level", as in the Rosch, Mervis, Gray, Johnson, and Boyes-Braem's natural categories (1976). Two methods were employed. First, rating of trait descriptiveness showed that information effectiveness was relatively high at the second level from the top. Second, subjects preferred the same level when they described target persons. These results suggested that a "basic level" indeed existed in the hierarchy of personality traits. However, social desirability of traits and who the target person was also affected the results. Implications are discussed about theories of cognitive style, especially cognitive complexity, which assume the generality of our cognitive system and have been in confusion with contradictory findings.

[A study of hierarchical structure in personality traits: asymmetry judgments in category breadth and class inclusion].

Many personality theorists postulate a hierarchical structure in trait words. However, most evidences are indirect, mainly because the theorists rely on factor-analytic methods. Assuming a global structure, the factor approach is not necessarily adequate to investigate concrete relationship among trait words. In this study, we used two direct measures to study the hierarchical structure: direct comparison of breadth and asymmetry class-inclusion judgment on trait concepts. Results of three experiments in general confirmed robustness of the hierarchical structure in the domain of personality traits. Traits were organized in the structure at several different levels of abstractness. But the structure was fuzzy in nature, unlike the taxonomy in biology. It was also found that inter-relations among traits could vary considerably from individual to individual. Cognitive complexity may be one of the variables that explain such an individual difference.