Nail-patella syndrome with nephropathy in a de novo LMX1B mutation: triangular lunula of the thumb and lack of finger creases as clues.

Nail-patella syndrome (NPS) is an autosomal dominant disease caused mostly by mutations in the LMX1B gene and is characterized by hypoplastic nails, hypoplastic patella, elbow deformities, glaucoma, and nephropathy, sometimes leading to kidney failure. The combination and the severity of symptoms vary greatly from patient to patient. Because a kidney biopsy may show nonspecific findings, patients with nephropathy alone may not be diagnosed without undergoing genetic testing. We examined the case of a 6-year-old girl with persistent high proteinuria who was not diagnosed by kidney biopsy but had a diagnosis of a de novo mutation in the LMX1B gene following genetic testing. Retrospectively, only the thumbs showed triangular lunulae, while the third and fourth fingers lacked skin creases over the distal interphalangeal joints, which is subtle but characteristic of NPS. Notifying pediatric nephrologists of these findings can help avoid unnecessary kidney biopsies and lead to early detection of the disease.

Development of nephropathy in an adult patient after Fontan palliation for cyanotic congenital heart disease.

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

One-month-old boy with group B streptococcal meningitis, subdural effusion, and high levels of interleukin-6.

Meningitis is associated with elevated levels of inflammatory cytokines in the blood, cerebrospinal fluid (CSF), and subdural fluid. Subdural effusion prolongs fever in patients with meningitis. However, the reason for this remains unclear. A healthy one-month-old boy was admitted after presenting with bacterial meningitis. He was administered meropenem, cefotaxime, and dexamethasone intravenously. On the 3rd day, blood and CSF cultures revealed the presence of Group B Streptococcus from samples collected on day 1. Subsequently, ampicillin and gentamicin replaced the previous combination of antimicrobials used. On the 4th day, brain magnetic resonance imaging with contrast showed bilateral cerebral ventriculitis and left subdural effusion. On the 11th day, since the subdural effusion had worsened, we performed a subdural puncture from the anterior fontanelle. Owing to the prolonged fever, he was intravenously injected immunoglobulin on day 13. He was afebrile on day 23. Antimicrobials were administered for 28 days. Levels of interleukin-6 (IL-6) in the serum and CSF were the highest on the 1st day at 20,600 pg/mL and 170,000 pg/mL, respectively, and decreased upon treatment. IL-6 concentration in the subdural fluid (30,000 pg/mL) was much higher than that in the serum (9 pg/mL) and CSF (2600 pg/mL). To the best of our knowledge, this is the first report on the cytokines in subdural fluid in patients with group B Streptococcal meningitis. Subdural effusion maintained high levels of IL-6 even after the levels in the blood and CSF decreased dramatically. This could explain why subdural effusion prolongs fever in patients with meningitis.

Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1.

Shwachman-Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman-Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183-184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS-specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183-184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood-derived mRNA to demonstrate that the results were compatible with those obtained using SBDS-specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183-184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA-seq is recommended to circumvent this problem.

Clinical Features of Febrile Urinary Tract Infection Caused by Extended-spectrum Beta-lactamase-producing Escherichia Coli in Children.

The global prevalence of infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli has been increasing. In children, ESBL-producing E. coli manifest mostly as febrile urinary tract infections (fUTIs). This study aimed to elucidate the clinical features of fUTI resulting from ESBL-producing E. coli in Japanese patients. The clinical features of children with E. coli-related fUTI were retrospectively examined. These children underwent treatment at the National Hospital Organization Saitama Hospital, Japan, between May 2010 and April 2018. Urine specimens were obtained by either bladder catheterization or the clean-catch method. All children having positive urine cultures (≥104 colony-forming unit/mL for catheter specimens and ≥105 colony forming unit/mL for clean-catch specimens) and a fever of ≥38°C were considered to have fUTI. During the study period, 171 patients were diagnosed with E. coli-related fUTI. Among these, 17 (9.9%) fUTI cases were caused by ESBL-producing E. coli. A significant difference was noted in the median age of the populations having ESBL-producing E. coli and non-ESBL-producing E. coli infections (2 and 5 months, respectively); other characteristics were not significantly different between the two patient groups. ESBL-producing E. coli infections markedly increased in our hospital between 2013 and 2018. In the present study, young age was the only risk factor for fUTI caused by ESBL-producing E. coli identified in Japanese children.

Combination therapy of an iNKT cell ligand and CD40-CD154 blockade establishes islet allograft acceptance in nonmyeloablative bone marrow transplant recipients.

AIMS: Islet transplantation is an effective therapeutic option for type 1 diabetes. Although maintenance immunosuppression therapy is required to prevent allogeneic rejection and recurrence of autoimmunity, long-term allograft survival has not yet been achieved partly because of its adverse effects. The induction of donor-specific immunotolerance is a promising approach for long-term allograft survival without maintenance immunosuppression therapy. We previously reported that combination therapy using a liposomal ligand for invariant natural killer T cells, RGI-2001, and anti-CD154 antibody established mixed hematopoietic chimerism for the induction of donor-specific immunotolerance. This study investigated whether the protocol could promote islet allograft acceptance in experimental diabetes. METHODS: Streptozotocin-induced diabetic BALB/c mice were transplanted with bone marrow cells from C57BL/6 donors and received combination therapy of RGI-2001 and anti-CD154 antibody after 3-Gy total body irradiation. 3 Weeks after bone marrow transplantation, islets isolated from C57BL/6 donors were transplanted under the kidney capsule. RESULTS: Mixed chimerism was established in diabetic mice receiving the tolerance induction protocol. After islet transplantation, blood glucose levels improved and normoglycemia persisted for over 100 days. Hyperglycemia recurred after islet grafts were removed. Histopathological examinations showed insulin-positive staining and absence of cellular infiltration in the islet grafts. T cells of recipients showed donor-specific hyporesponsiveness, and anti-donor antibodies were not detected. CONCLUSIONS: The tolerance induction protocol with combination therapy of RGI-2001 and anti-CD154 antibody promoted islet allograft acceptance in a mouse diabetic model. This protocol may be clinically applied to islet transplantation for type 1 diabetes mellitus.

Evaluation of the impact of conventional immunosuppressant on the establishment of murine transplantation tolerance - an experimental study.

Regulatory T cells (Tregs) play a significant role in immune tolerance. Since Treg function deeply depends on Interleukin-2 signaling, calcineurin inhibitors could affect their suppressive potentials, whereas mammalian target of rapamycin (mTOR) inhibitors may have less impact, as mTOR signaling is not fundamental to Treg proliferation. We previously reported a novel mixed hematopoietic chimerism induction regimen that promotes Treg proliferation by stimulating invariant natural killer T cells under CD40 blockade. Here, we use a mouse model to show the impact of tacrolimus (TAC) or everolimus (EVL) on the establishment of chimerism and Treg proliferation in the regimen. In the immunosuppressive drug-dosing phase, peripheral blood chimerism was comparably enhanced by both TAC and EVL. After dosing was discontinued, TAC-treated mice showed gradual graft rejection, whereas EVL-treated mice sustained long-term robust chimerism. Tregs of TAC-treated mice showed lower expression of both Ki67 and cytotoxic T lymphocyte antigen-4 (CTLA-4), and lower suppressive activity in vitro than those of EVL-treated mice, indicating that TAC negatively impacted the regimen by interfering with Treg proliferation and activation. Our results suggest that the usage of calcineurin inhibitors should be avoided if utilizing the regimen to induce Tregs in vivo for the establishment of mixed hematopoietic chimerism.

Impact of activated invariant natural killer T cells on the expansion of regulatory T cell precursors in murine thymocytes in vitro.

Tolerance induction is a goal of clinical transplantation to prevent graft rejection without the lifelong use of immunosuppressive drugs. In a series of mouse studies, we previously reported that the establishment of mixed chimerism by treatment with a ligand for invariant natural killer T (iNKT) cells with CD40 signal blockade makes it possible to prevent allograft rejection without immunosuppressants, and this approach fails in thymectomized recipient mice. In this study, we showed that iNKT cells in murine thymocyte cultures are indispensable for the expansion of CD4+CD25+Foxp3+ regulatory T (Treg) cells as well as CD4+CD25+Foxp3- cells, which contained precursor Tregs (preTregs). After the culture of BALB/c mouse-derived thymocytes in the presence of α-galactosylceramide (α-GalCer), a representative ligand for iNKT cells, the ratio of CD4+CD25+Foxp3- preTregs to total CD4+CD8- T cells was much higher than that of CD4+CD25+Foxp3+ Treg cells, regardless of anti-CD40 L mAb treatment. The proliferation of CD4+CD25+Foxp3- cells, but not Treg cells, was significantly augmented, and the stability of Treg cells was not affected by α-GalCer. The expansion of thymocyte-derived Tregs was not inhibited by cytokine neutralization. However, in vitro thymus-derived CD4+CD25+Foxp3- cells expressed Foxp3 after IL-2 stimulation in a dose-dependent manner. These results collectively suggest that in vitro thymus-derived Treg cell expansion by α-GalCer treatment was caused by the proliferation of CD4+CD25+Foxp3- preTregs but not existing Treg cells.

Transitional B Cells Predominantly Reconstituted After a Desensitization Therapy Using Rituximab Before Kidney Transplantation.

The role of B cells in graft rejection and tolerance has aroused great interest. We previously reported that rituximab (RIT) induction prior to kidney transplantation (KTx) reduced the incidence rate of chronic rejection. Here, we performed a cross sectional investigation to determine the characteristics of B cells after RIT induction for KTx. We sampled blood from 29 patients with (N = 16) and without (N = 13) RIT induction 3 to 18 months after KTx. In the RIT group, the majority of repopulating B cells was the transitional type, while memory B cells were scarce. Although transitional B cells are believed to have immune-regulatory functions by producing IL-10, transcriptional levels of IL-10 in the peripheral blood mononuclear cells were similar in both groups. In contrast, transcription levels of BAFF-receptor relatively increased in patients with RIT induction. In conclusion, BAFF-receptor expressing highly proliferating transitional B cell was the major subset after RIT induction for KTx.

Serum and cerebrospinal fluid S100B, neuron-specific enolase, and total tau protein in acute encephalopathy with biphasic seizures and late reduced diffusion: a diagnostic validity.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized clinically by biphasic seizures and late magnetic resonance imaging abnormalities, such as reduced subcortical diffusion from day 3 onwards, often accompanied with some neurological sequelae. In the early stages of the disease, AESD closely resembles its far more prevalent and relatively benign counterpart, febrile seizure (FS). METHODS: We measured and compared the serum or cerebrospinal fluid (CSF) levels of S100B, neuron-specific enolase (NSE), and total tau protein in 43 patients with FS and 18 patients with AESD, at any point during the disease. To assess early diagnostic validity, we compared these biomarkers in 43 FS and eight AESD patients, with whom the day 0-2 samples were available. We used the receiver-operator characteristic curve to evaluate the diagnostic values of these markers. RESULTS: The levels of all biomarkers were significantly higher in AESD than FS patients. When only day 0-2 samples from AESD patients were used, the levels of all the measured biomarkers, except serum NSE, were still significantly higher in patients with AESD than in FS, suggesting that AESD could damage astrocytes, neurons, and axons, even in the early stages of the disease. According to the receiver-operator characteristic curve analyses, CSF S100B (cut-off value, 100 pg/mL) and CSF total tau protein (cut-off value, 100 pg/mL) were better predictors of AESD than other biomarkers. CONCLUSION: The combination of CSF S100B and CSF total tau protein resulted in a positive predictive value of AESD 83.3%, which could be helpful for early diagnosis, facilitating early therapeutic interventions.