Hypoxic-ischemic encephalopathy with cystic brain stem necroses and thalamic calcifications in a preterm twin.

A severe and rare ischemic brain lesion in a preterm twin boy is reported. The boy was born after two weeks of anhydramnios and amnionic infection at 24 weeks of gestation. Following a difficult Caesarean section and prolonged umbilical cord compression he developed prenatal acidosis with an umbilical cord pH of 6.96. At the age of 7 h, heart rate variability narrowed due to severely disturbed brain stem function and the patient developed clinical signs of hypoxic-ischemic encephalopathy. Sonography demonstrated extensive symmetrical brain stem and basal ganglia lesions. After a prolonged comatose and apneic state, death occurred at the age of 25 days. Autopsy confirmed columnar bilateral cavitation of basal ganglia, diencephalon, brain stem and spinal gray matter, as well as focal calcifications in the palladium, thalamus, and brain stem. The findings highly resemble those observed after experimental or clinical cardiac arrest.

Thrombopoietin concentration in umbilical cord blood of healthy term newborns is higher than in adult controls.

Thrombopoietin (TPO) concentrations were determined in umbilical cord plasma of 121 healthy term newborns. The lower detection limit of the enzyme immunoassay employed was 32.5 pg/ml. Median cord plasma TPO concentration was 78 (interquartile range 55-107) pg/ml. 95th percentile was 255 pg/ml. In only 8% (10/121), TPO was below the detection limit compared to 81% of healthy adults (25/31). In cord blood and adult controls, there were no significant correlations of TPO with platelet count or mass.

A point mutation leads to an unpaired cysteine residue and a molecular weight polymorphism of a functional platelet beta 3 integrin subunit. The Sra alloantigen system of GPIIIa.

Recently, we described a low frequency platelet alloantigen on human platelet membrane glycoprotein (GP) IIIa, termed Sra, that was involved in neonatal alloimmune thrombocytopenia. To identify the molecular nature of the Sra alloantigen, we analyzed the nucleotide sequence of polymerase chain reaction-amplified GPIIIa mRNA, and found a C2004-->T substitution in seven Sra positive individuals which results in an Arg636-->Cys polymorphism within the cysteine-rich region of GPIIIa. Analysis of allele-specific recombinant forms of GPIIIa that differed only at amino acid residue 636 showed that anti-Sra alloantibodies reacted with the Cys636, but not the Arg636, recombinant form of GPIIIa. Interestingly, under reducing conditions, the Cys636 form of GPIIIa migrated with a slightly increased apparent molecular weight compared with the Arg636 form. Following treatment with Endoglycosidase H, both allelic forms of GPIIIa exhibited the same mobility, however the Sra epitope was lost. Sra positive platelets express the same number of GPIIb-IIIa complexes on their surface as wild-type Sra negative platelets, and also aggregate normally in response to a variety of platelet agonists. Based upon these results, we conclude that 1) GPIIIa residue 636 specifically controls the formation and expression of the Sra alloantigenic determinant, and 2) an unpaired cysteine residue alters the N-linked glycosylation pattern of the extracellular domain of GPIIIa, but affects neither the degree of surface expression nor the adhesive function of the GPIIb-IIIa complex.

[Complete remission of a highly malignant, progressive under therapy Wilm's tumor using the combination carboplatin and etoposide (VP 16)]. / Vollremission eines unter Therapie progredienten Wilms-Tumors hohen Malignitätsgrades durch die Kombination von Carboplatin und Etoposid (VP 16).

A Wilms' tumor in a 4 year old girl did not diminish under preoperative chemotherapy following SIOP 9/GPO study guidelines. Surgery revealed an anaplastic (high grade) nephroblastoma infiltrating pancreas, transverse colon, and diaphragm. During postoperative treatment with ifosfamide, vincristine, actinomycin D, and doxorubicin, there was massive tumor growth per continuitatem in chest and abdomen within 6 weeks. Following a French study for relapsed Wilms' tumor, we gave 160 mg/m2 carboplatin and 100 mg/m2 etoposide on 5 consecutive days. After only one cycle, the tumor showed already remarkable regress. We applied six cycles of carboplatin/etoposide and a abdominal radiation. At the end of therapy, the patient was in complete remission. Side effects of chemotherapy were severe bone marrow aplasia and a moderate and reversible decrease of creatinine clearance. The combination of carboplatin and etoposide is a promising therapy in Wilms' tumor resistant to classic nephroblastoma drugs like vincristine, doxorubicin, and actinomycin D.

Vitamin D dependent rickets type II with myelofibrosis and immune dysfunction.

We present a new patient with vitamin D dependent rickets type II. A 20-month-old Arabian boy whose parents are first cousins showed florid rickets, myelofibrosis and recurrent septicaemia. In addition to absent specific binding for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 25-Hydroxyvitamin D3-24-hydroxylase activity could not be induced in cultured fibroblasts. The patient did not respond to 99 micrograms 1,25(OH)2D3 per day, but skeletal and haematological abnormalities improved with daily infusion of 100 mg/kg calcium, as serum parathyroid hormone levels fell to normal values. At the age of 7 years, he died from pneumonia. The improvement of haematological abnormalities with calcium infusions but not with 1.25(OH)2D3 suggests a pathogenetic relationship of myelofibrosis and hyperparathyroidism. Having anti-lipid A IgM antibody titres up to 1:10.000 after Gram negative septicaemias, the patient never produced corresponding IgG antibodies. His neutrophil chemotaxis was persistently reduced to 57% +/- 3% of age-matched controls (P less than 0.028). The patient showed two pathological immune functions considered to contribute to the well-known susceptibility to infection in rickets.

Lymphocyte cell lines from vitamin D-dependent rickets type II show functional defects in the 1 alpha,25-dihydroxyvitamin D3 receptor.

Lymphocyte cell lines were established from five patients with vitamin D-dependent rickets, type II (VDDR-II). These lines were established by infection with human T-lymphotrophic virus type I (HTLV-I). Binding of [3H]1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) to its receptor in these cell lines was compared to binding studies using a T-lymphocyte cell line (S-LB1) from a normal individual. The 1,25(OH)2D3 receptor of S-LB1 was comparable to the well-characterized chick intestinal 1,25(OH)2D3 receptor in terms of its ligand binding affinity and capacity, its mobility on 5-20% sucrose gradients, and its adsorption to and elution properties from DNA-cellulose. Three cell lines established from patients with VDDR-II (Rh-VDR, Sh-VDR, and Ab-VDR) showed no specific binding of 1,25(OH)2D3 to a receptor and treatment of the cultured cells with 1,25(OH)2D3 did not stimulate production of 24,25-dihydroxy-vitamin D3 (24,25(OH)2D3), a response which is diagnostic of the presence of a functional 1,25(OH)2D3 receptor. In a fourth cell line, A1-VDR, the receptor for 1,25(OH)2D3 had a low binding capacity and 25(OH)D3-24-hydroxylase activity was not detectable. Induction of 24,25-(OH)2D3 synthesis by 1,25(OH)2D3 was observed in the fifth cell line, designated Ro-VDR, although the sensitivity to hormone treatment was lower than in the control cell line from a normal donor. The capacity of the receptor for 1,25(OH)2D3 was low in Ro-VDR. In all cell lines where 1,25(OH)2D3 binding to a receptor was detectable, the receptor had the typical sedimentation coefficient of 3.7 S on sucrose density gradient analysis. Binding and elution properties to DNA-cellulose, however, differed from normal in both Ro-VDR and A1-VDR cells where elution from DNA-cellulose occurred at a lower salt concentration than is typical of the 1,25(OH)2D3 receptor. While Ro-VDR cells showed typical nuclear localization of the unoccupied 1,25(OH)2D3 receptor, neither the unoccupied nor the occupied receptor from A1-VDR cells was completely localized in the nucleus. In a series of functional studies we found that modulation of the level of the mRNAs coding for both the c-myc oncogene and the growth factor known as granulocyte-monocyte colony stimulating activity by 1,25(OH)2D3 correlated with the 1,25(OH)2D3 receptor status of these cells. Use of these cell lines will facilitate further study of the molecular defect(s) in the receptor for 1,25(OH)2D3 in vitamin D-dependent rickets type II and will allow a correlation with impairment of cellular functions.