Hypersensitivity of megakaryocyte progenitors to thrombopoietin in essential thrombocythemia.

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by an elevation of platelets in peripheral blood and excessive proliferation of megakaryocytes in bone marrow. The pathological mechanisms for the elevation of megakaryocytes and platelets in ET remain unclear. To study the hypersensitivity of megakaryocyte progenitors to thrombopoietin (TPO), a 9-year-old girl, diagnosed with ET, underwent dose-response experiments with recombinant human TPO, using her bone marrow non-adherent mononuclear cells and CD34 positive cells. Spontaneous colony-forming unit-megakaryocytes (CFU-Meg) were observed in serum-deprived cultures of non-adherent mononuclear cells, whereas they disappeared in cultures of CD34 positive cells. The patient's CFU-Meg showed maximal growth at concentrations of TPO lower than those for normal children. Dose-response curves demonstrated a 50-80 fold increase in sensitivity of the patient's CFU-Meg to TPO. We observed hypersensitivity of megakaryocyte progenitors to TPO in a child with ET. Our results suggest that spontaneous CFU-Meg formation in patients with ET may be due to hypersensitivity to TPO.

Cloning of translocation breakpoints associated with Shwachman syndrome and identification of a candidate gene.

Shwachman syndrome is an autosomal-recessive disorder characterized by exocrine pancreatic insufficiency, bone-marrow dysfunction, and metaphyseal chondrodysplasia. A de novo balanced translocation was recently documented in a patient with this disease. Toward isolating the gene(s) responsible for Shwachman syndrome, we cloned and sequenced the translocation breakpoints in the DNA of this patient. The nucleotide sequences around the breakpoints contained neither repetitive elements nor motifs reported to be implicated in recombination events, although we did detect gains or losses of oligonucleotides at the translocation junctions. By large-scale genomic sequencing and in silico gene trapping, we identified two novel transcripts in the vicinity of the breakpoints that might represent candidate genes for Shwachman syndrome, one on chromosome 6 and the other on chromosome 12. The gene on chromosome 12 was actually disrupted by the translocation.

Heterogeneity of immune markers in hemophagocytic lymphohistiocytosis: comparative study of 9 familial and 14 familial inheritance-unproved cases.

PURPOSE: Although immune dysfunction is suspected in patients with hemophagocytic lymphohistiocytosis (HLH), the difference between immune dysfunction in patients with familial erythrophagocytic lymphohistiocytosis (FEL) and familial inheritance-unproved lymphohistiocytosis (FIU) remains unknown. The aim of this study was to determine useful markers to distinguish patients with FEL from those with FIU. PATIENTS AND METHODS: Clinical features and laboratory findings, especially natural killer (NK) cell activity and the relative frequencies of peripheral blood mononuclear cell (PBMC) subsets, and serum levels of interferon-gamma and soluble interleukin-2 receptor were compared in 9 patients with FEL and 14 age-matched patients with FIU. Twenty-seven healthy infants served as controls. The treatment and outcome were also compared for patients with FEL and FIU. RESULTS: Comparison between patients with FEL and FIU revealed significantly lower NK activity in those with FEL (p = 0.03) but failed to show any significant differences in PBMC subsets, except that the percentage of CD3+ T cells was higher in patients with FEL (p = 0.02). CD4- and CD8-dominant phenotypes were characteristic findings in both groups of patients, although increased CD19+ B cells were restricted to patients with FIU. NK activity was deficient (< 5%) in four of the seven patients with FEL tested but in only one of eight patients with FIU. By comparison to values for age-matched controls, the percentages of CD3+, CD3+DR+ and CD45RO+ PBMCs in patients with FEL were significantly high (p < 0.05) and those of CD19+ and CD45RA+ subsets were lower than normal. Among patients with FIU, PBMC subsets included significantly reduced CD3+, CD4+, CD45RA+, and CD4+CD45RA+. In this small series, the outcome of patients with FEL and FIU treated with chemotherapy was not significantly different at the time of evaluation. CONCLUSIONS: These results indicate considerable immune heterogeneity among patients with HLH younger than 2 years. Although NK activity was useful but not diagnostic, determination of PBMC subsets and patterns of cytokine expression was not helpful in distinguishing patients with FEL from those with FIU, suggesting that the immune responses characteristic of these diseases may reflect different triggering factors, including viruses. The impact of this immune heterogeneity on patients' outcome remains to be determined.

Multiple hepatoblastomas associated with trisomy 18 in a 3-year-old girl.

A very rare case of full trisomy 18 associated with multiple hepatoblastomas is reported. The patient also had ventricular septal defect and patent ductus arteriosus, which were repaired at 6 months of age. After the cardiac surgery, she was noted to have an abdominal mass and an elevated serum alpha-fetoprotein level. A partial hepatic lobectomy was performed at 7 months of age, and the resected tumor was diagnosed as a fetal-type hepatoblastoma. At 2 years and 4 months of age, a chest radiography disclosed an elevated left diaphragm, and abdominal ultrasonography demonstrated a tumor in the left hepatic lobe. The resected tumor was also diagnosed as a fetal-type hepatoblastoma. Chromosomal analysis demonstrated that the karyotypes of peripheral blood and hepatic tumor cell obtained on two occasions were both 47,XX, +18. She has no evidence of recurrence at 3 years of age without specific therapy.

Disseminated infection with Trichosporon asahii.

Trichosporon fungaemia and disseminated, purpuric, papular skin lesions developed on the head, trunk and extremities of a 5-year-old female with acute lymphocytic leukaemia. Histopathologically, the skin lesions demonstrated dermal budding yeasts. She died despite treatment with antifungal drugs. The isolate from the blood was further identified morphologically and physiologically as Trichosporon asahii, based on the revision of the genus Trichosporon by Guého et al. (1992). According to the new revision, T. asahii is the only taxon regularly involved in systemic mycoses, so that most of the isolates previously reported as T. beigelii (formerly, T. cutaneum) in human deep mycoses are now thought to belong to T. asahii.

Cartilage-hair hypoplasia associated with IgG2 deficiency.

We report on a 1 year old boy with cartilage-hair hypoplasia (CHH). He suffered from recurrent upper respiratory infections and short-limbed dwarfism. As with most patients with CHH, he had impaired cellular immunity as determined by lymphocyte reactivity. In addition, he had a selective IgG2 deficiency. This combination of immunodeficiencies has not previously been reported for patients with CHH. His recurrent upper respiratory infections were likely to be associated with cellular immunodeficiency and IgG2 deficiency.

[A case of primary mediastinal teratocarcinoma in a young girl].

Primary malignant germ cell tumors of the mediastinum are rare neoplasm, almost always occurring in young adult males. This report described embryonal carcinoma in a 13-year-old girl. The patient was checked up at chest X-ray examination of middle-school pupils on June 1989, and was referred to us because of rapid enlargement of the shadow on October 1989. Chest rentogenograms on admission showed a large mass at the anterior mediastinum, and MRI also revealed a multicystic one extending to the right hemithorax and pressing the superior vena cava and the right atrium. Her serum AFP level was high at 211.1 ng/ml. At operation, on November 6, 1989, a large tumor (110 x 95 x 75 mm) was removed completely through median sternotomy. Histological study of the lesion revealed a wide spread of cystic mature teratoma containing some foci of embryonal carcinoma. Positive immunochemical reaction indicated the presence of AFP in these carcinoma cells. She was treated with 13 courses of anti-cancer chemotherapy by various combinations of CDDP, THP-ADR, VP-16, VCR, ACD, CPM, CBDCA, for one postoperative year. She showed clinical improvement and has continued to be free from recurrence now at 52 months after surgery.

Decreased CD4+CD29+ (memory T) cells in patients with chronic granulomatous disease.

By the use of flow cytometry, 17 patients with chronic granulomatous disease (CGD) were examined for lymphocyte subsets. CD4+CD29+ cell (memory T cell) and CD8+CD11b+ cell (suppressor T cell) subsets in CGD were significantly decreased and remained practically unchanged throughout the period examined except in those < 6 months of age, although in controls both subsets gradually increased with age. These data indicate a certain abnormality in the maturation process of CGD T lymphocytes. Memory T cells are known to secrete a large amount of interferon-gamma (IFN-gamma). Recently, administration of IFN-gamma to CGD patients has become an effective treatment that reduces the frequency of serious bacterial infections. Decreased memory T cells may clarify the mechanism of therapeutic effectiveness, which remains unknown.

[Clinical evaluation of a new oral cephalosporin, cefprozil, in pediatrics].

Cefprozil (CFPZ, BMY-28100), a new oral cephalosporin, was evaluated for its antibacterial activity and clinical efficacy. Thirty-four patients were treated with 7.7-36.2 mg/kg per day of CFPZ divided into 3 times. A total of 33 patients including 3 with acute pneumonia, 2 with acute bronchitis, 17 with acute upper respiratory tract infections, 4 with urinary tract infections, 1 with suppurative lymphadenitis and 6 with other soft tissue infections were evaluated for clinical efficacy except for 1 patient whose general conditions were too serious to continue to be treated with orally medication. Clinical effects were excellent in 8 patients and good in 23 but 2 cases were excluded because they were suspected for viral infections, hence the overall efficacy rate was 100%. Bacteriological responses were confirmed on 6 (66.7%) strains which were eradicated by the treatment out of 9 strains identified. CFPZ showed stronger antibacterial activities than those of cefaclor. Side effects or abnormal laboratory test results were observed in 2 patients; nausea and pallor of face in 1 patient and an increase of eosinophil in 1. The above findings suggest that CFPZ is a safe and useful antibiotics for the treatment of bacterial infections in pediatric patients.

[Pharmacokinetic and clinical study of cefpirome in children].

Pharmacokinetic and clinical studies of cefpirome (CPR) in children were carried out, and the following results were obtained. 1. Peak serum levels were obtained at the end of drip infusion of 20.0, 17.5 and 6.8 mg/kg for 30 minutes and the half-lives were 1.93, 1.91 and 0.48 hours, respectively. 2. Urinary excretion rates in 6 hours were 40.0-96.2%. 3. Thirty-two patients including 17 with respiratory infections, 7 with urinary tract infections and 8 with skin and soft tissue infections were treated with CPR at 52.2-92 mg/kg per day by intravenous administration. Clinical effects were excellent in 12 cases, good in 13 cases, fair in 3 cases and unknown in 4 cases, and the overall efficacy rate was 89.3% (25 cases/28 cases). 4. Bacterial eradication rate was 93.8% (15 strains/16 strains). 5. Rash and diarrhea were found in 1 case each, and abnormal laboratory test values were found in 7 cases.