Immune hemolytic anemia associated with teicoplanin

BACKGROUND: Several drugs can cause immune hemolytic anemia. Here a patient who developed hemolytic anemia after treatment with teicoplanin is described. CASE REPORT: Owing to a two-vessel disease, a 68-year-old white man underwent coronary artery bypass grafting. He was readmitted for superficial sternal wound infection and sternal instability. Rewiring was required and worsening anemia characterized the course after the reoperation. Drugs used in the second admission were gentamycin, teicoplanin, paracetamol, and codeine. They were considered as a possible cause of drug-induced hemolytic anemia. RESULTS: The DAT was positive for complement and IgG. Autoanti-e was identified in the patient's undiluted serum sample. The eluate was reactive with all RBCs tested only after adding teicoplanin; when diluted 1:4, anti-e specificity was observed in the presence of teicoplanin. CONCLUSION: To our knowledge, this is the first report of immune hemolytic anemia owing to teicoplanin.     

Inhibition by CāINH of Hageman Factor Fragment Activation of Coagulation, Fibrinolysis, and Kinin Generation

Highly purified inhibitor of the first component of complement (CāINH) was shown to inhibit the capacity of active Hageman factor fragments to initiate kinin generation, fibrinolysis, and coagulation. The inhibition of prealbumin Hageman factor fragments observed was dependent upon the time of interaction of the fragments with CāINH and not to an effect upon kallikrein or plasmin generated. The inhibition of the coagulant activity of the intermediate sized Hageman factor fragment by CāINH was not due to an effect on PTA or other clotting factors. The inhibition by CāINH of both the prealbumin and intermediate sized Hageman factor fragments occurred in a dose response fashion. The CāINH did not appear to be consumed when the activity of the Hageman factor fragments was blocked, although the fragments themselves could no longer be recovered functionally or as a protein on alkaline disc gel electrophoretic analysis. These results suggest that the CāINH may have an enzymatic effect on the fragments or that an additional site on CāINH is involved in Cā inactivation.     

Pharmacokinetics of cephalosporin antibiotics: protein-binding considerations

The therapeutic activity of antibiotics depends on several factors including absorption, elimination kinetics, distribution in the body, minimal inhibitory concentrations (MIC), stability against enzymes, and plasma-protein binding. Some of these factors are interrelated, for example, the extent of protein binding of an antibiotic influences its elimination kinetics, distribution into tissues, MIC, and antibacterial activity. To evaluate the potential efficacy of an antibiotic, it is important to know the extent of its binding to plasma proteins especially since the protein-bound fraction of the antibiotic is devoid of antibacterial activity. Cephalosporins are a new class of broad-spectrum antibiotics that bind to plasma proteins in different degrees. Reported values for protein binding range from 6% for cephradine to 92% for cefazolin. The effects of protein binding of some of the commonly used cephalosporins on antibacterial activity and several pharmacokinetic parameters are discussed in this communication.     

The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways.

Cystic fibrosis (CF) airway cells, besides their well-known defect in cAMP-dependent Cl- conductance, are characterized by an enhanced Na+ conductance. In this study we have examined the Na+ conductance in human respiratory tract by measuring transepithelial voltage and resistance (Vte, Rte) and by assessing membrane voltages (Vm) of freshly isolated airway epithelial cells from CF and non-CF patients. Basal amiloride inhibitable (10 micromol/liter) equivalent short circuit current (Isc = Vte/Rte) was significantly increased in CF compared with non-CF tissues. After stimulation by forskolin (10 micromol/liter) a significant depolarization of Vm corresponding to the cAMP-dependent activation of a Cl- conductance was observed in non-CF but not in CF airway cells. In non-CF tissue but not in CF tissue the effects of amiloride and N-methyl-D-glucamine on Vm were attenuated in the presence of forskolin. Also the amiloride-inhibitable Isc was significantly reduced by forskolin (1 micromol/liter) and isobutylmethylxanthine (IBMX; 100 micromol/liter) only in non-CF tissue. We conclude that cystic fibrosis transmembrane conductance regulator acts as a downregulator of epithelial Na+ channels in human airways. This downregulation of epithelial Na+ channels is absent in CF airways, leading to hyperabsorption and to the characteristic increase in mucus viscosity.     

Interaction of endothelial cell growth factor with heparin: characterization by receptor and antibody recognition.

Endothelial cell growth factor (ECGF) binds specifically in vitro to membrane receptors present on the surface of several cell types, including murine and human endothelial cells and fibroblasts. Monoclonal antibodies prepared against ECGF that inhibit the mitogenic activity of the growth factor prevent receptor occupancy by the ligand. Heparin interacts structurally with ECGF [Maciag, T., Mehlman, T., Friesel, R. & Schreiber, A. B. (1984) Science 225, 932-935], potentiates the mitogenic activity of the polypeptide, restores the biological activity to inactivate ECGF, enhances the affinity of the ligand to cell surface receptors, and modifies antibody recognition of ECGF. These data suggest that the association between heparin and ECGF induces a conformational change in the polypeptide that increases or stabilizes the biological activity of the mitogen.     

Investigation of HLA-DPA1 genotypes as predictors of inflammatory bowel disease in the German,South African,and South Korean populations

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a polygenic disorder, as demonstrated by epidemiological evidence, genetic linkage, and the identification of the first susceptibility gene, NOD2. Genetic linkage analysis has identified and replicated several genomic regions as locations for susceptibility genes, including chromosome 6p (termed IBD3). The HLA-DP genes play an important role in antigen presentation and are located within the chromosome 6p linkage region. PATIENTS AND METHODS: We investigated HLA-DPA1 as a positional and functional candidate gene for IBD using 249 German multiplex IBD families, 174 unrelated German controls, 48 monoplex families from a mixed South African population, 87 IBD patients, and 71 controls from a South Korean sample. Polymorphisms in exon 2 at amino acid positions 31, 37-38 and 50 were genotyped using direct sequencing. Analyses were performed using chi(2) statistics, multipoint transmission disequilibrium test and nonparametric linkage analysis. RESULTS: A marginally significant association for Crohn's disease was detected in the German family cohort for DPA1*02021. This finding was not replicated in ulcerative colitis or any of the other populations. CONCLUSION: HLA-DPA1 is not a major determinant of IBD risk in any of the three populations. The transmission distortion observed in the German cohort may indicate an extended haplotype, suggesting another disease relevant gene in the vicinity of HLA-DPA.     

Three proteins define a class of human histone deacetylases related to yeast Hda1p

Gene expression is in part controlled by chromatin remodeling factors and the acetylation state of nucleosomal histones. The latter process is regulated by histone acetyltransferases and histone deacetylases (HDACs). Previously, three human and five yeast HDAC enzymes had been identified. These can be categorized into two classes: the first class represented by yeast Rpd3-like proteins and the second by yeast Hda1-like proteins. Human HDAC1, HDAC2, and HDAC3 proteins are members of the first class, whereas no class II human HDAC proteins had been identified. The amino acid sequence of Hda1p was used to search the GenBank/expressed sequence tag databases to identify partial sequences from three putative class II human HDAC proteins. The corresponding full-length cDNAs were cloned and defined as HDAC4, HDAC5, and HDAC6. These proteins possess certain features present in the conserved catalytic domains of class I human HDACs, but also contain additional sequence domains. Interestingly, HDAC6 contains an internal duplication of two catalytic domains, which appear to function independently of each other. These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A. Coimmunoprecipitation experiments indicate that these HDAC proteins are not components of the previously identified HDAC1 and HDAC2 NRD and mSin3A complexes. However, HDAC4 and HDAC5 associate with HDAC3 in vivo. This finding suggests that the human class II HDAC enzymes may function in cellular processes distinct from those of HDAC1 and HDAC2.     

A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: short- and long-term efficacy and safety results

OBJECTIVE: In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA). METHODS: Children ages 2-16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups. RESULTS: Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups. CONCLUSION: The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.