Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: clinical and in vitro studies

Two anemic patients with rheumatoid arthritis were treated with recombinant human erythropoietin (EPO) for 5 months. Both patients showed significant increases in hematocrit, red cell volumes, and marrow erythroid and megakaryocyte progenitor cells. No significant toxic effects from EPO were observed. These data indicate that EPO may be effective in overcoming the pathogenetic factors that limit erythropoiesis in rheumatoid arthritis.     

Polycythemia vera. II. Hypersensitivity of bone marrow erythroid, granulocyte-macrophage, and megakaryocyte progenitor cells to interleukin-3 and granulocyte-macrophage colony-stimulating factor.

Polycythemia vera (PV) is a clonal disease of the hematopoietic stem cell characterized by a hyperplasia of marrow erythropoiesis, granulocytopoiesis, and megakaryocytopoiesis. We previously reported that highly purified PV blood burst-forming units-erythroid (BFU-E) are hypersensitive to recombinant human interleukin-3 (rIL-3). Because these cells may be only a subset, and not representative of marrow progenitors, we have now studied partially purified marrow hematopoietic progenitor cells. Dose-response experiments with PV marrow BFU-E showed a 38-fold increase in sensitivity to rIL-3 and a 4.3-fold increase in sensitivity to recombinant human erythropoietin (rEpo) compared with normal marrow BFU-E. In addition, PV marrow colony-forming units-granulocyte-macrophage (CFU-GM) and CFU-megakaryocyte (CFU-MK) also showed a marked hypersensitivity to rIL-3 and to human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Dose-response curves with rGM-CSF and blood BFU-E showed a 48-fold increase in sensitivity. No effect of rIL-4, rIL-6, human recombinant granulocyte-CSF (rG-CSF), or macrophage-CSF (rM-CSF) was evident, nor was there any effect of PV cell-conditioned medium on normal BFU-E, when compared with normal cell-conditioned medium. Autoradiography with 125I-rEpo showed an increase in Epo receptors after maturation of PV BFU-E to CFU-E similar to that shown with normal BFU-E, but no increase of specific binding of 125I-rIL-3 by PV CD34+ cells was seen compared with normal CD34+ cells. These studies show that PV marrow hematopoietic progenitor cells are hypersensitive to rIL-3 and rGM-CSF, similar to PV blood BFU-E. While the mechanism does not appear to be due to enhanced binding of rIL-3, the hypersensitivity of PV progenitor cells to IL-3 and GM-CSF may be a key factor in the pathogenesis of PV.     

The effect of temporal adverbials on past tense production by children with specific language impairment.

PURPOSE: Children with specific language impairment (SLI) often fail to produce past tense forms in obligatory contexts, although the factors affecting such inconsistency are not well understood. This study examined the influence of accompanying temporal adverbials (e.g., just, already) on the past tense production of these children. METHOD: Fifteen preschool-aged children with SLI, 15 typically developing children matched for age (TD-A) and 15 younger typically developing children matched for mean length of utterance (TD-MLU) participated in the study. The children responded to probes that obligated the use of past tense forms. The verbal context provided by the experimenter for half of the items included a temporal adverbial. RESULTS: Overall, the SLI and TD-MLU groups produced past tense less frequently than the children in the TD-A group, and there were no significant differences between the SLI and the TD-MLU groups. However, both the SLI and the TD-MLU participants produced past tense forms less frequently when temporal adverbials were included than when they were absent. CONCLUSIONS: These findings suggest that the tendency to use past tense by the children with SLI and their younger MLU-matched peers may not have been independent of other types of temporal information.     

Increasing incidence of coeliac disease in Sweden.

Changes in the incidence of coelic disease was studied among children born in Göteborg, Sweden, between 1970 and 1988. A total of 188 patients with coeliac disease were found. Of these, 83% were less than 2 years old at the time of their first duodenal biopsy and 74% of them have so far been verified according to the criteria of the European Society for Gastroenterology and Nutrition (ESPGAN). The cumulative incidence at 2 years of age/1000 liveborn infants increased significantly from 0.31 in the first birth cohort to 2.93 in the last. This increase could only partly be explained by improvements in detection. Weight for age at diagnosis was generally considerably below the reference value, but was slightly less affected towards the end of the period. The increase in incidence of coeliac disease is the first reported since the middle 1970s and makes the disease one of the most common chronic diseases among Swedish children.     

Serum antibody response to filamentous hemagglutinin in patients with clinical pertussis measured by an enzyme-linked immunosorbent assay

Titers of antibodies to filamentous hemagglutinin (FHA) were determined by enzymelinked immunosorbent assay in acute and convalescent phase serum samples from 158 patients with clinical symptoms typical of whooping-cough. In 96 of the patients the diagnosis was verified by culture. Significant changes in serum levels of IgG, IgM and/or IgA antibodies against FHA were demonstrated in 126 patients (80%). Thus, demonstration of significant changes in FHA antibody titers in serum can be used for serological diagnosis of pertussis. The results also show that high levels of IgG, IgM and/or IgA antibodies in a single serum sample suggest current pertussis infection, but if the diagnosis is based on determinations of FHA antibody titers in a single serum sample the sensitivity is low. The levels of antibody to FHA were compared with previously determined levels of antibodies to pertussis toxin. A significant antibody response against both FHA and pertussis toxin was seen in 111 patients (70 %) while 147 patients (93 %) developed a significant increase in antibodies against one or both antigens.     

Comparative effects of two beta-blockers on cardiovascular reactivity and type A behavior in hypertensives

This study compared the effects of beta-blockers differing in degree of central nervous system penetration on Type A behavior and cardiovascular reactivity to mental stress. Forty-six male hypertensives were assigned randomly to receive either highly lipophilic and nonselective propranolol, hydrophilic and cardioselective atenolol, the diuretic hydrochlorothiazide, or placebo. Subjects were administered parallel forms of the Structured Interview (SI) and performed mental arithmetic and a cognitive task prior to and after 6 weeks of therapy. Results indicated that diuretic and placebo subjects (subsequently combined into a single control group) did not differ and that both beta-blockers reduced heart rate but not blood pressure reactivity to mental stress (p less than 0.02), an effect that was strongest during the mental arithmetic test. Analysis of SI components indicated a reduction only in explosive speech for beta-blockers versus controls (p less than 0.05). For global SI classifications, seven out of 12 subjects (58%) receiving propranolol, three of 12 (25%) receiving atenolol, and four of 22 control subjects (18%) became less Type A (p less than 0.05). These data do not replicate results of a prior study obtained with atenolol and suggest that only a subset of hypertensive individuals show reduced Type A behavior with propranolol. Central nervous system mechanisms may be important in producing these effects.     

Pyrosequencing for detection of mutations in the connexin 26 (GJB2) and mitochondrial 12S RNA (MTRNR1) genes associated with hereditary hearing loss

Hereditary hearing loss (HHL) is one of the most common congenital disorders and is highly heterogeneous. Mutations in the connexin 26 (CX26) gene (GJB2) account for about 20% of all cases of childhood deafness, and approach 50% in documented recessive cases of non-syndromic hearing loss. In addition, a single mitochondrial DNA mutation, mt1555A>G, in the 12S rRNA gene (MTRNR1), is associated with familial cases of progressive deafness. Effective screening of populations for HHL necessitates rapid assessment of several of these potential mutation sites. Pyrosequencing links a DNA synthesis protocol for determining sequence to an enzyme cascade that generates light whenever pyrophosphate is released during primer strand elongation. We assessed the ability of Pyrosequencing to detect common mutations causing HHL. Detection of the most common CX26 mutations in individuals of Caucasian (35delG), Ashkenazi (167delT), and Asian (235delC, V37I) descent was confirmed by Pyrosequencing. A total of 41 different mutations in the CX26 gene and the mitochondrial mt1555A>G mutation were confirmed. Genotyping of up to six different adjacent mutations was achieved, including simultaneous detection of 35delG and 167delT. Accurate and reproducible results were achieved taking advantage of assay flexibility and experimental conditions easily optimized for a high degree of standardization and cost-effectiveness. The standardized sample preparation steps, including target amplification by PCR and preparation of single-stranded template combined with automated sequence reaction and automated genotype scoring, positions this approach as a potentially high throughput platform for SNP/mutation genotyping in a clinical laboratory setting. .