Dynamics of immature subsets of dendritic cells during antiviral therapy in HLA-A24–positive chronic hepatitis C patients

Background The cellular immune response is important in chronic hepatitis C (CHC). To better understand its mechanism, we examined dendritic cells (DCs) and hepatitis C virus (HCV)-specific cytotoxic T cells (CTLs), which are thought to contribute to liver injury and viral clearance. Methods CHC patients received 24 weeks of interferon-α-based antiviral therapy. We analyzed time-sequential frequencies of peripheral DCs, classified as myeloid DCs (mDCs) or plasmacytoid DCs (pDCs), together with peptide major histocompatibility class I tetramers, epitope specific for HCV core 129–137 (t*24/c129) or HCV NS3 1296–1304 (t*24/ns1294), directly ex vivo. Results The mDC and pDC populations changed in parallel (P < 0.05), showing a significant transient decrease at weeks 12 and 16 during the therapy, and then recovering. However, neither of the tetramer results showed a direct correlation with the kinetics of peripheral DCs. Conclusions There is an apparent effect of antiviral therapy or a subsequent reduction of HCV on host immunity, but the effect may not include the induction of CTLs in CHC.     

Molecular analysis of the CLCNKB gene in Japanese patients with classic Bartter syndrome

Deletions or mutations in the gene encoding the basolateral chloride channel CLC-Kb (CLCNKB) cause classic Bartter syndrome (MIM 602023), which is characterized by hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism and hypercalciura. These patients are usually diagnosed during infancy or childhood due to failure to thrive and growth retardation. The purpose of this study was to investigate the underlying mutations in Japanese patients with classic Bartter syndrome. Seven Japanese patients from seven different families diagnosed as having classic Bartter syndrome were studied. Analysis of CLCNKB demonstrated a large deletion in two patients, a partial deletion in one patient and two mutations (DeltaL130 in exon 4 and W610X in exon 16) in the remaining four patients. DeltaL130 is a novel mutation, but W610X was previously reported in three unrelated Japanese patients. Six out of the seven patients were diagnosed due to typical characteristics of classic Bartter syndrome such as failure to thrive and poor weight gain however, one patient was asymptomatic with mild hypokalemia. In conclusion, we identified a novel mutation of the CLCNKB gene, DeltaL130. We did not determine whether the W610X mutation in our patients was from a common ancestor or if this mutation is frequent in Japan.     

Late-Onset Fatal Epstein-Barr Virus—Associated Hemophagocytic Syndrome Following Cord Blood Cell Transplantation for Adult Acute Lymphoblastic Leukemia

A 43-year-old Japanese woman underwent unrelated cord blood transplantation (CBT) during remission for acute lymphoblastic leukemia with t(4; 11)(q21;q23). Tacrolimus was given for prophylaxis of graft-versus-host disease. The posttransplantation clinical course was mostly uneventful, and the leukemia remained in remission. Fourteen months after CBT, the patient developed pancytopenia and hepatic dysfunction with persistent high-grade fever. The bone marrow was hypocellular with increased numbers of macrophages and hemophagocytes. The numbers of Epstein-Barr virus (EBV) copies in peripheral blood samples were remarkably high. Although the patient showed complete donor-type hematopoiesis, the titer of viral capsid antigen immunoglobulin G was low, and the results of a test for EBV nuclear antigen were negative. There was no clinical response to the reduction of immunosuppressive therapy or to the administration of high-dose methylprednisolone, human immunoglobulin, or acyclovir. The patient died 466 days after CBT of massive gastrointestinal hemorrhage due to bone marrow and hepatic failures. This case demonstrates that fatal EBV-associated hemophagocytic syndrome (HPS) can occur more than 1 year after CBT. This report is the first of a case of late-onset EBV-associated HPS following CBT.     

Prophylactic indomethacin in extremely premature infants between 23 and 24 weeks gestation

Background: In extremely premature infants, the presence of a left‐to‐right shunt through a patent ductus arteriosus (PDA) increases the risks of pulmonary hemorrhage, intraventricular hemorrhage, necrotizing enterocolitis, renal failure, and chronic lung disease. Conservative management induces spontaneous ductus closure in <20% of extremely premature infants (infants born at <25 weeks of gestation). The aim of the present study was to determine the efficacy and safety of prophylactic indomethacin (INDO) administration for PDA closure in extremely premature infants born between 23 and 24 weeks of gestation. Methods: A historical case–control study of 30 infants born between 23 and 24 weeks of gestation was carried out. In the prophylactic INDO group, a 12 h‐long, 0.01 mg/kg per h dose of INDO was administered within 6 h of life. During the historical control period, only infants with symptomatic PDA were treated with INDO for 1 h. The incidence of symptomatic PDA, mortality and early neonatal morbidity was compared between the two groups on Fisher's exact test and Mann–Whitney rank–sum test. Results: None of the infants in the prophylactic INDO group had symptomatic PDA, while 11 of the 15 infants in the control group showed symptomatic PDA (P < 0.001). There were no significant differences between the mortality rates and the early neonatal morbidities in the two groups. Conclusions: Prophylactic INDO administration to extremely premature infants born between 23 and 24 weeks of gestation decreased the incidence of symptomatic PDA without increasing the incidence of adverse effects.     

Effect of parathyroid hormone administration in a patient with severe hypoparathyroidism caused by gain-of-function mutation of calcium-sensing receptor

Hypoparathyroidism caused by gain-of-function mutations of the calcium-sensing receptor (CaR) in the transmembrane domain is usually severe and difficult to manage. A patient with severe hypoparathyroidism, caused by CaR activating mutation F821L, was treated for 3 days (Day 1 to Day 3) with synthetic human parathyroid hormone 1-34 (teriparatide, PTH). An Ellsworth-Howard test of the patient revealed normal responses of urine phosphate and cyclic AMP excretion, indicating that the patient's renal tubules normally responded to extrinsic PTH. On Day 1 to Day 3, 0.9 microg/kg/day of PTH was administered subcutaneously twice daily at 0800 and 2000. On Day 1, the serum calcium level that was 1.8 mmol/l before PTH administration increased to 2.1 mmol/l at 1200, and gradually decreased to 1.8 mmol/l at 2000. On Days 2 and 3, the maximum calcium levels were 2.5 and 2.4 mmol/l, respectively, at 1200. At 2000, they returned to or below basal levels at 0800. On Day 4 without PTH administration, the calcium levels were maintained at the basal levels at Day 0. The urine calcium/creatinine (Ca/Cr) ratio that was high (>0.4) before PTH injection decreased after PTH administration (0.4>). Changes in the ionized calcium levels were almost parallel with the total calcium levels. The serum inorganic phosphate (IP) level decreased to 2.4 mmol/l at 1000, but gradually increased before the second PTH injection to the level at 0800 on Day 1. The minimum IP level on Days 2 and 3 was 2.1 mmol/l and 2.0 mmol/l, respectively. In contrast to the remarkable changes in the serum calcium level by PTH treatment, the serum magnesium levels showed few changes. These results indicate that PTH therapy could be effective in correcting serum and urine calcium and the phosphate levels in hypoparathyroidism caused by activating mutation of CaR.     

Active cerebral perfusion during carotid endarterectomy

A patient with critical stenoses in the bilateral internal carotid arteries (ICA) required multivessel coronary revascularization. The diameter of the left ICA was far greater than the right, which strongly suggested that the cerebral circulation was highly dependent on the left. During left ICA endarterectomy, active cerebral perfusion of 300 mL x min(-1) at 23 degrees C using an extracorporeal circulation was employed through the ICA under repair. Subsequently, coronary bypass was performed on-pump with the heart beating. The postoperative course was very good.     

Nkx2.2 expression in differentiation of oligodendrocyte precursor cells and inhibitory factors for differentiation of oligodendrocytes after traumatic spinal cord injury

Because successful remyelination does not occur following traumatic spinal cord injury, patients suffer from long tract dysfunction. However, demyelination is followed by remyelination in early multiple sclerosis. Oligodendrocyte precursor cells constitute a large cell population in the adult mammalian central nervous system. We demonstrated the proliferation, migration, and differentiation of oligodendrocyte precursor cells in chemically induced demyelination, a model for multiple sclerosis, and reported that Nkx2.2 expression may regulate oligodendrocyte precursor cell differentiation, making it a key factor in the differentiation. To investigate what factors disturb remyelination in spinal cord injury, we examined the oligodendrocyte precursor cell proliferation and differentiation, and the expression of Nkx2.2 using contusive injury in rats as a model for traumatic spinal cord injury. This study showed that oligodendrocyte precursor cells proliferated after contusive injury but did not subsequently differentiate. The number of Nkx2.2-positive oligodendrocyte precursor cells did not significantly change in the tissue surrounding the lesion. Within the demyelinating lesion, the peak of Nkx2.2-positive oligodendrocyte precursor cell was delayed, and its level was lower than in the chemical models. No clearly recognizable oligodendrocytes were found in the demyelinating lesion throughout the observation period. To assess whether environmental changes differ between these two models, mRNA expressions of various cytokines were evaluated and compared. IL-1beta and IL-6 mRNA significantly increased in the contusion-induced injury model, 6 h after the injury. These results suggest that environmental factors such as cytokines may affect Nkx2.2 expression or oligodendrocyte precursor cell differentiation in the contusion-induced spinal cord injury model.