Recombinant human nerve growth factor is biologically active and labels novel high-affinity binding sites in rat brain.

Iodinated recombinant human nerve growth factor (125I-rhNGF) stimulated neurite formation in PC12 cell cultures with a half-maximal potency of 35-49 pg/ml, compared with 39-52 pg/ml for rhNGF. In quantitative ligand autoradiography, the in vitro equilibrium binding of 125I-rhNGF to brain sections showed a 10-fold regional variation in density and was saturable, reversible, and specifically displaced by up to 74% with rhNGF or murine NGF (muNGF). At equilibrium, 125I-rhNGF bound to these sites with high affinity (Kd 52-85 pM) and low capacity (Bmax less than or equal to 13.2 fmol/mg of protein). Calculation of 125I-rhNGF binding affinity by kinetic methods gave average Kd values of 24 and 31 pM. Computer-generated maps revealed binding in brain regions not identified previously with 125I-muNGF, including hippocampus; dentate gyrus; amygdala; paraventricular thalamus; frontal, parietal, occipital, and cingulate cortices; nucleus accumbens; olfactory tubercle; subiculum; pineal gland; and medial geniculate nucleus. NGF binding sites were distributed in a 2-fold increasing medial-lateral gradient in the caudate-putamen and a 2-fold lateral-medial gradient in the nucleus accumbens. 125I-rhNGF binding sites were also found in most areas labeled by 125I-muNGF, including the interpedunucular nucleus, cerebellum, forebrain cholinergic nuclei, caudoventral caudate-putamen, and trigeminal nerve nucleus. 125I-rhNGF binding sites were absent from areas replete with low-affinity NGF binding sites, including circumventricular organs, myelinated fiber bundles, and choroid plexus. The present analysis provides an anatomical differentiation of high-affinity 125I-rhNGF binding sites and greatly expands the number of brain structures that may respond to endogenous NGF or exogenously administered rhNGF.     

Granulocytic sarcoma of the brain: a case report and review of the literature

Granulocytic sarcoma (chloroma), a rare tumor usually associated with myelogenous leukemia, is capable of invading the meninges or brain parenchyma. Radiologic findings in a case of granulocytic sarcoma of the brain, as well as those in 11 previously reported cases of intracranial leukemic masses, are interpreted. On computed tomographic scans, the lesions can appear isodense or hyperdense, edema and necrosis are variable, and there is uniform enhancement following intravenous administration of contrast material. There may be some affinity for the posterior fossa.     

The nature of the autoimmune antibody repertoire in human immunodeficiency virus type 1 infection.

Human immunodeficiency virus type 1 (HIV-1) seropositive donors typically have high serum antibody titers to a range of autoantigens, and the corresponding autoantibodies have been suggested to be of importance in the pathogenesis of HIV-1 infection. We have prepared 38 IgG human monoclonal autoantibodies from asymptomatic HIV-1 seropositive donors with elevated serum titers to autoantigens by construction of Fab combinatorial libraries on the surface of phage and affinity selection using a range of autoantigens, including double-stranded DNA, major histocompatibility complex class II, CD14, epidermal growth factor receptor, and ganglioside GD2. The autoantibodies are shown to be of moderate affinity and exhibit marked cross-reactivity with a range of antigens. This contrasts with the specific high-affinity antibodies selected (i) against infectious agents using the same libraries and (ii) against one of the autoantigens using a library from a donor with established autoimmune disease. The results lend no support to the presence of specific autoantibodies in HIV-1 infection and instead suggest attention should be focused on the pathological significance of high serum levels of antibodies capable of interacting with multiple molecular species.     

Immunogenic and Antigenic Epitopes of Immunoglobulins Binding of Human Monoclonal Anti-D Antibodies to FcRI on the Monocyte-Like U937 Cell Line

Seventeen human monoclonal IgG1- or IgG3 anti-D-secreting clones have been examined for their ability to sensitise O+ red cells for Fc-receptor-mediated rosette formation with U937 cells. IgG3 but not IgG1 anti-D antibodies were able to mediate stable rosette formation with unstimulated U937 cells via interaction with the FcRI receptor. Decreasing FcRI density by incubating U937 cells with di-butyryl cAMP almost completely abolished rosette formation, whilst increasing FcRI density by incubating U937 cells with interferon-gamma increased the percentage of cells forming rosettes with IgG3- and IgG1-sensitised red cells. These data suggest that rosette formation between IgG anti-D-sensitised red cells and FcRI-expressing cells is dependent upon the density of IgG3 on the red cell surface, the density of FcRI on the effector cell, multiple FcRI/IgG interactions are required for stable rosette formation and that more FcRI/IgG1 than FcRI/IgG3 interactions are required.     

Wheeze in preschool children and its relation with doctor diagnosed asthma.

OBJECTIVE--To describe the characteristics of wheeze and its relation with doctor diagnosed asthma in children aged 5 years and under. DESIGN--Questionnaire survey of population based random sample of children registered on Leicestershire Health Authority's child health index for immunisation; questionnaire completed by parents. SUBJECTS--1650 white children born in 1985 to 1989 who were surveyed in 1990. MAIN OUTCOME MEASURES--Age distribution, severity, precipitants, seasonal characteristics, and diurnal variation of wheeze, family history of asthma/atopy, and their association(s) with doctor diagnosed asthma. RESULTS--There were 1422 replies (86.2%). Two hundred and twenty two (15.6%) were reported to have wheezed and of these 121 (8.6%) had formally been diagnosed as having asthma. More than 80% of the former had recurrences of wheeze and 40% (72) had three or more episodes in the preceding 12 months. Age, number of episodes per year, the severity of shortness of breath with attacks, and precipitants other than colds were the major factors determining the probability that a wheezy child will be diagnosed as having asthma. The data also suggest that despite the strong association of symptom based criteria with the label asthma, asthma was not diagnosed by these same severity criteria in one quarter of cases. CONCLUSIONS--Clinical and physiological follow up studies of children identified as asthmatic by the above criteria during the preschool years should validate or refute the predictive value of these measures of wheeze severity.     

Change in waist-hip ratio with weight loss and its association with change in cardiovascular risk factors.

We investigated whether weight loss decreases the waist-hip ratio (WHR) in overweight men and women, and whether changes in WHR relates to change in cardiovascular risk factors, independent of change in weight. Weight loss correlated significantly with decreases in the circumference of the waist and hips, and decreases in WHR in men and women. At comparable levels of weight loss, men had greater decreases in the waist, and smaller decreases in the hips than women, resulting in greater decreases in WHR. Cardiovascular risk factors improved significantly with weight loss. However, after controlling for weight loss, there was no evidence that change in WHR or change in circumference measures were related to change in risk factors. These data suggest that WHR is modifiable by weight loss, especially in men, but that change in WHR may not be independently related to changes in cardiovascular risk factors.     

Biochemical composition of amniotic fluid and extraembryonic coelomic fluid in the first trimester of pregnancy.

OBJECTIVE: To determine the biochemical composition of amniotic fluid and extraembryonic coelomic fluid between 8 and 12 weeks gestation. DESIGN: Prospective observational study. SUBJECTS: 40 women with a normal pregnancy between 7 and 12 weeks gestation having termination of pregnancy. INTERVENTIONS: Before termination the women had a transvaginal ultrasound guided amniocentesis. Pure samples of amniotic fluid and extraembryonic coelomic fluid were obtained from each woman and standard biochemical variables were measured in each fluid sample immediately after collection. RESULTS: Levels of sodium, potassium and bicarbonate were significantly higher in amniotic fluid whilst chloride, urea, bilirubin, protein, albumin, glucose, creatinine, calcium and phosphate were present in higher concentrations in extraembryonic coelomic fluid. All differences in concentration were significant (P less than 0.05; unpaired t-test). No relation was demonstrated between electrolyte concentrations in amniotic fluid or coelomic fluid and stage of gestation. CONCLUSIONS: Amniotic fluid and extraembryonic coelomic fluid have a widely differing biochemical composition. The biological significance of these differences remains unexplained.