Cell generated rfEPO was utilized in the treatment of cats with nonregenerative anemia attributed

As explained below, the Reversine results here indicate that light-related variability in the form of shadows might become less visible in ageing & AD, rather than more visible as we originally suggested. However, any such changes appear not to arise from changes to lighting-specific processing mechanisms. Our data suggest that in older people and AD patients, such mechanisms appear robust, and such people efficiently utilise the same assumptions about the behaviour of light as normal young observers. The glycoprotein hormone erythropoietin, made by the peritubular cells of the renal cortex, stimulates the production of red blood cells. Erythropoietin-responsive anemia is a common cause of morbidity in cats affecting 32–65% of cats with chronic renal failure. Injection of exogenous recombinant human erythropoietin in these cats often results in the resolution of anemia, improvement in appetite, weight gain, energy level, alertness, playfulness, physical strength and attitude. Multiple rHuEPO products are currently available including epoetin alfa, epoetin beta and darbepoetin alfa. These products all have the same humanspecific primary amino acid sequence but differ in the degree of glycosylation, which affects renal clearance, thus influencing the frequency of administration. Multiple adverse effects have been reported to be associated with the use of rHuEPO in cats, including refractory anemia, systemic hypertension, polycythemia, seizures, vomiting, iron deficiency, injection discomfort, cellulitis, cutaneous/mucocutaneous reactions, and arthralgia. Because the amino acid sequence of rHuEPO is only 81.3% homologous to that of feline EPO, antibodies directed against rHuEPO can develop when it is administered to cats. These antibodies are believed to block rHuEPO bioactivity and potentially cross-neutralize endogenous feline EPO leading to the development of life threatening red cell aplasia. Antibodies usually develop within the first few months of rHuEPO administration and a clinically significant immunologic reaction has been reported in 20% to 70% of feline patients receiving rHuEPO. Several therapeutic strategies utilizing species-specific recombinant EPO have been attempted to address the issue of rHuEPO immunogenicity in cats. In an in vitro recombinant feline erythropoietin strategy, Chinese hamster ovary cells were transfected with a construct resulting in the production of biologically active, glycosylated rfEPO protein. In a subsequent in vivo experiment by a different research group, CHO to CRF. In treated cats, the hematocrit increased significantly during the first 3 weeks of treatment. However, some of the cats that initially responded appropriately developed red cell aplasia that was refractory to additional treatments. Importantly, the reported cDNA sequence of the rfEPO utilized in this in vivo study had a single nucleotide substitution in the 44th codon, which resulted in the misincorporation of the glycine amino acid in lieu of glutamic acid. In an analysis of the EPO cDNA sequence of multiple mammalian species, the 44th codon of the EPO gene, GAG, encodes the glutamic amino acid, manifesting for the existence of strong evolutionary pressure at this locus. It is conceivable that glycine misincorporation in the rfEPO could lead to immunogenicity in treated cats. Adeno-associated viral vectors expressing recombinant feline erythropoietin have been developed. A rAAV-rfEPO vector, when administered intramuscularly to normal healthy cats, resulted in an increase in hematocrit over a 7 week period.