Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1.

BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

High-dose Cepharanthin for pediatric chronic immune thrombocytopenia in Japan.

BACKGROUND: A nationwide, multicenter and observational study was retrospectively conducted to evaluate the clinical utility of Cepharanthin (CEP) for pediatric patients with chronic immune thrombocytopenia (ITP). METHODS: Clinical and laboratory data for 46 Japanese patients aged <16 years who were diagnosed as having chronic ITP in 14 hospitals during 2001-2011, and were treated with CEP for >12 months, were analyzed. RESULTS: Median daily CEP dose was 1 mg/kg (range, 0.12-2 mg/kg). Median platelet count prior to CEP was 20.5 × 109 /L (IQR, 8.3-53.0 × 109 /L), and then significantly increased to 58.5 × 109 /L (IQR, 22.8-115.0 × 109 /L) and 69.0 × 109 /L (IQR, 23.0-134.0 × 109 /L) at 12 and 24 months of treatment, respectively. No life-threatening bleeds or moderate-severe adverse events were reported. Of 38 patients who received both corticosteroids (CS) and CEP, 17 patients (45%) were weaned from CS, and 15 patients (39%) attained the reduced dose of CS. The duration from the start of CEP to the stopping of CS was a median of 413 days (range, 49-1734 days) in patients who were weaned from CS. CONCLUSIONS: CEP alone or combined with CS was useful for the management of pediatric chronic ITPs.

Mild forms of toxic shock syndrome toxin-1-mediated exanthematous disease related to Staphylococcus aureus infection.

The present report describes three patients with toxic shock syndrome toxin (TSST)-1-associated exanthematous disease. In all patients, fever and systemic erythema without hemodynamic disturbance occurred following cellulitis of the lower limbs. At the site of infection, TSST-1 producing Methicillin-susceptible Staphylococcus aureus was detected. They defervesced and erythema resolved in response to administration of an antimicrobial drug, thereby avoiding severe illness. These patients did not meet the criteria for a clinical diagnosis of toxic shock syndrome. Measurement of T-cell receptor Vß2-positive T cells in the peripheral blood early after onset of symptoms was useful for diagnosis.

Bladder leiomyosarcoma in a boy.

Leiomyosarcoma of the urinary bladder in childhood is uncommon. We reported bladder leiomyosarcoma in a 10-year-old boy. He had underwent the extirpation of the tumor and performed adjuvant chemotherapy in combination with radiotherapy according to the Intergroup Rhabdomyosarcoma Study-4 regimens. He had no evidence of recurrence of disease after 3 years.

Experience with the use of salazosulfapyridine for intractable diarrhea after hematopoietic stem cell transplantation.

We encountered 2 children with intractable diarrhea after allogeneic hematopoietic stem cell transplantation (SCT). In both cases, salazosulfapyridine (SASP) was administered to treat the diarrhea. One patient was a 14-year-old male with acute myelogenous leukemia who received SCT from a related HLA-identical donor. The leukemia recurred early, and a second SCT from the same donor was performed approximately half a year later. Because intestinal graft-versus-host disease (GVHD) was observed, steroids and octreotide were administered, but the symptoms were not improved. Thereafter, SASP was administered, and the symptoms remitted 9 days later. The other patient was a 12-year-old male with chronic myelogenous leukemia who received SCT from an unrelated HLA-identical donor. Diarrhea and abdominal pain developed early after engraftment and did not respond to either steroids or tacrolimus. Oral administration of SASP was initiated on day 236, and the diarrhea remitted 4 days later without recurrence thereafter. SASP may be effective in children for the digestive system symptoms of chronic GVHD.

[Systemic lupus erythematosus with bilateral salivary gland swelling and clouding of consciousness accompanied by hemophagocytic syndrome--a study of serial determination of serum cytokines].

We investigated changes in various serum cytokines in a case of systemic lupus erythematosus (SLE) accompanied by hemophagocytic syndrome (HPS). The patient, a 15-year-old male, presented in December 1998 with bilateral salivary gland swelling and a history of fever continuing for more than 10 days. After admission, cerebellar ataxia and clouding of consciousness developed. Laboratory examinations revealed leukopenia, thrombocytopenia, high serum LDH and ferritin, hypercytokinemia, and prominent hemophagocytosis in the bone marrow. Given these findings and positive titers of antinuclear antibody, hypocomplementemia, proteinuria and pericarditis, a diagnosis of HPS with associated SLE was made. The patient was treated with high dose methylprednisolone followed by oral prednisolone and cyclosporine. The patient's clinical symptoms, abnormal blood and urine laboratory data consequently improved, and no recurrence of the symptoms has been documented. However, hemophagocytosis in bone marrow recurred with concomitantly increased serum levels of IL-6 and IL-1 beta. This case indicated that aberrant production of these inflammatory cytokines might be involved in HPS in autoimmune disease.

The effect of Lactobacillus brevis KB290 against irritable bowel syndrome: a placebo-controlled double-blind crossover trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional disorder of the digestive tract that causes chronic abdominal symptoms. We evaluated the effects of Lactobacillus brevis KB290 (KB290), which has been demonstrated to be effective at improving bowel movements and the composition of intestinal microflora, on IBS symptoms. METHODS: We performed a placebo control double-blind cross matched trial. Thirty-five males and females (aged 6 years and above) who had been diagnosed with IBS according to the Rome III criteria were divided into 2 groups, and after a 4-week pre-trial observation period, they were administered test capsules containing KB290 or placebo for 4 weeks (consumption period I). Then, the capsule administration was suspended for 4 weeks in both groups (washout period), before the opposite capsules were administered for a further 4 weeks (consumption period II). Fecal samples were collected on the first day of the pre-consumption observation period, the last day of consumption period I, the last day of the washout period, and the last day of consumption period II. In addition, the subjects' IBS symptoms and quality of life (QOL) and any adverse events that they experienced were evaluated. RESULTS: No significant difference in IBS symptoms was noted among the various periods. However, the mean QOL scores were improved during the test capsule consumption.The frequencies of watery and mushy feces were significantly lower in the test capsule consumption period than during the pre-consumption observation period, and the frequency of abdominal pain was significantly reduced in the test capsule consumption period compared with the other periods.The frequency of the genus Bifidobacterium was significantly higher, and that of the genus Clostridium was significantly lower, after the test capsule consumption than after the placebo consumption. The frequencies of the genera Lactobacillus, Bacteroides, and Enterococcus were also investigated, but no differences in their frequencies were detected between the placebo and test capsule consumption periods. CONCLUSIONS: Probiotics, the safety of which has been established, are used widely in various foods and can now be purchased readily. The results of the present study suggest that KB290 is useful for early intervention in IBS.

Outbreak of CTX-M-3-type extended-spectrum beta-lactamase-producing Enterobacter cloacae in a pediatric ward.

A first resistant strain of Enterobacter cloacae was isolated from a blood specimen in a pediatric patient with immature teratoma-developed sepsis after combination chemotherapy. The strain produced extended-spectrum beta-lactamase (ESBL), and the same ESBL-producing strains were detected in urine samples from other patients in the pediatric ward. All strains harbored genes for bla (CTX-M-3) by polymerase chain reaction (PCR) and sequencing analysis. Analysis of pulsed-field gel electrophoresis revealed that all strains were the same clonal type. These results suggest that ESBL-producing strains might be transmitted in the ward via contact among patients or medical staff.

Granulocyte functions and changes in ability with age in newborns; Report no. 1: flow cytometric analysis of granulocyte functions in whole blood.

BACKGROUND: Serious bacterial infections occur with higher frequency in the first weeks of life than in other age groups and this may be, in part, related to functional impairment of neonatal granulocytes. The purpose of the present study was to estimate the characteristics of granulocyte function during the neonatal period. METHODS: The expression of adhesive molecules on the surface of granulocytes present in umbilical cord blood and peripheral blood obtained at 5 days and 1 month after birth, H(2)O(2) production and protease activity in granulocytes were studied by comparison with adult blood. RESULTS: Although there were no significant differences observed with respect to the expression of CD11b on the surface of granulocytes between each age group and adults, l-selectin was significantly lower in cord blood as compared with adult blood. Production of H(2)O(2) by granulocytes was significantly lower for cord blood than peripheral blood from 1 month old infants or that from adults in the presence of either phorbol myristate acetate or N-formyl-methionyl-leucyl-phenylalanine stimulation. The intracellular activity of elastase and collagenase within granulocytes exhibited a higher tendency for cord blood as compared with adult blood. CONCLUSIONS: Decreased functions of part of the phagocyte system during early infancy were clearly observed.

Granulocyte functions and changes in ability with age in newborns; Report no. 2: activation of granulocyte functions by cytokines.

BACKGROUND: The aim of the present study was to examine the function of granulocytes in newborns from the perspective of granulocyte activation by cytokines. METHODS: Granulocytes were stimulated with tumor necrosis factor-alpha, granulocyte-macrophage colony stimulating factor (GM-CSF) or granulocyte colony stimulating factor, and the reactivity of granulocytes to these substances was then compared between newborns (umbilical cord blood, peripheral blood obtained at age 5 days and at age 1 month) and peripheral blood obtained from adults. In addition, the expression of cytokine receptors on the surface of granulocytes was measured for each age group. RESULTS: The amplification of CD11b expression on the surface of granulocytes and suppression of l-selectin expression were weaker for cord blood regardless of which cytokine was added. In addition, the increases in the activity of intracellular elastase when stimulated with tumor necrosis factor-alpha or GM-CSF were significantly lower for cord blood. Moreover, the expression of GM-CSF receptors and granulocyte colony stimulating factor receptors on the surface of granulocytes was lower for cord blood, and this expression approached the level found in adults as age increased. CONCLUSION: Granulocytes during early infancy exhibit low reactivity to inflammatory cytokines, and this was considered to be one of the factors contributing to the higher incidence of serious bacterial infections in infants.