Erythropoietin structure-function relationships: high degree of sequence homology among mammals

To investigate structure-function relationships of erythropoietin (Epo), we have obtained cDNA sequences that encode the mature Epo protein of a variety of mammals. A first set of primers, corresponding to conserved nucleotide sequences between mouse and human DNAs, allowed us to amplify by polymerase chain reaction (PCR) intron 1/exon 2 fragments from genomic DNA of the hamster, cat, lion, dog, horse, sheep, dolphin, and pig. Sequencing of these fragments permitted the design of a second generation of species-specific primers. RNA was prepared from anemic kidneys and reverse-transcribed. Using our battery of species-specific 5' primers, we were able to successfully PCR-amplify Epo cDNA from Rhesus monkey, rat, sheep, dog, cat, and pig. Deduced amino acid sequences of mature Epo proteins from these animals, in combination with known sequences for human, Cynomolgus monkey, and mouse, showed a high degree of homology, which explains the biologic and immunological cross-reactivity that has been observed in a number of species. Human Epo is 91% identical to monkey Epo, 85% to cat and dog Epo, and 80% to 82% to pig, sheep, mouse, and rat Epos. There was full conservation of (1) the disulfide bridge linking the NH2 and COOH termini; (2) N-glycosylation sites; and (3) predicted amphipathic alpha-helices. In contrast, the short disulfide bridge (C29/C33 in humans) is not invariant. Cys33 was replaced by a Pro in rodents. Most of the amino acid replacements were conservative. The C-terminal part of the loop between the C and D helices showed the most variation, with several amino acid substitutions, deletions, and/or insertions. Calculations of maximum parsimony for intron 1/exon 2 sequences as well as coding sequences enabled the construction of cladograms that are in good agreement with known phylogenetic relationships.     

Apnea threshold and breathing rhythmicity in newborn lambs

This study was designed to determine the effect of the removal of chemical stimuli on breathing rhythmicity in awake newborn lambs; it was also designed to define the chemical threshold below which breathing would stop [arterial PCO2 (PaCO2) apnea threshold]. We used a technique of graded extracorporeal CO2 removal with apneic oxygenation in three groups of animals according to age and carotid body (CB) integrity: < 2 days, CB intact (n = 5); 12 days, CB intact (n = 7); and 12 days, CB denervated (CBD; n = 5). In all animals, whatever their age and CB status, suppression of the chemical drive resulted in sustained apnea. The study, performed at four constant levels of oxygenation (hyperoxia, normoxia, moderate hypoxia, and severe hypoxia), allowed precise determination of the PaCO2 apnea threshold. We found that this PaCO2 apnea threshold depended on the degree of postnatal maturation (it was higher in the younger lambs), the level of arterial oxygenation (it was lowered by hypoxia), and CB status (it was higher in CBD animals). Moreover, we found that the 12-day-old CBD lambs breathe at a level of PaCO2 set close to the point of apnea.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mental status and fragile X expression in relation to FMR-1 gene mutation

The fragile X mental retardation syndrome is caused by unstable expansion of a CGG repeat in the FMR-1 gene. Clinical expression is associated with a large expansion of the CGG repeat. The mutation in the FMR-1 gene and the cytogenetic expression of the fragile site at Xq27.3 have been studied in 52 fragile X male patients. The percentage of the cytogenetic expression of the fragile site at Xq27.3 positively correlates with the mean size of the full mutation in the FMR-1 gene (p < 0.0001) irrespective of the presence of additional premutation alleles. We noted a less frequent occurrence of additional premutation alleles in adult patients compared with juveniles, suggesting a continued mitotic instability in life. Additionally, the level of mental retardation has been ascertained in 35 patients using the Stanford-Binet or Terman-Merrill test of general intelligence. The presence of a full mutation in the FMR-1 gene seemed decisive for the occurrence of mental impairment in the patient. No correlation is observed between the degree of mental retardation and the size of the full mutation. The degree of mental retardation seemed not to be influenced by the presence of premutation alleles in part of the cells in addition to a full mutation. One patient is described with the 'Prader-Willi-like' subphenotype of the fragile X syndrome, showing a deletion in the FMR-1 gene in a part of his cells in addition to a full mutation.     

Focal epithelial hyperplasia: human-papillomavirus-induced disease with a genetic predisposition in a Venezuelan family

A study on the presence of human papillomavirus (HPV) DNA sequences and focal epithelial hyperplasia (FEH) in a family of Venezuelan ancestry has revealed that FEH is an HPV-induced disease presenting familial aggregation. The genealogical evidence indicates a genetic predisposition to the disease.     

Neutropenia in a newborn secondary to sulfamethoxazole-trimethoprim administered to the mother

As Markowitz et al. explain, the atypical antipsychotics should become the first-line agents for the treatment of schizophrenia. There is much to be learned about these drugs, but their displacement of the conventional antipsychotics will be a continuous process. The loss of the older drugs will not be mourned.     

Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis

Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important issues for the pathogenesis and treatment of multiple sclerosis.