The objectives of this study were to determine the effects of far-off and close-up diets on prepartum metabolism, postpartum metabolism, and postpartum performance of multiparous Holstein cows. From dry-off to -25 d relative to expected parturition (far-off dry period), cows were fed a control diet to meet National Research Council (NRC) recommendations for net energy for lactation (NE(L)) at ad libitum intake (100NRC; n = 25) or a higher nutrient density diet, which was fed for either ad libitum intake to provide at least 150% of calculated NE(L) requirement (150NRC; n = 25) or at restricted intake to provide 80% of calculated NE(L) requirements (80NRC; n = 24). From -24 d relative to expected parturition until parturition (close-up period), cows were fed a diet that met or exceeded NRC nutrient recommendations at either ad libitum intake (n = 38) or restricted intake (n = 36) to provide 80% of the calculated NE(L) requirement. After parturition, all cows were fed a lactation diet and measurements were made through 56 d in milk (DIM). Prepartum metabolism was consistent with the plane of nutrition. During the first 10 DIM, far-off treatments had significant carryover effects on dry matter intake, energy balance, serum nonesterified fatty acid (NEFA) concentration, and serum beta-hydroxybutyrate concentration. Cows with the lower energy balance during the far-off period (100NRC and 80NRC) had higher dry matter intake and energy balance and lower serum NEFA and beta-hydroxybutyrate during the first 10 DIM. There were no effects of close-up diet and no interactions of far-off and close-up treatments. During the first 56 DIM, there were no residual effects of far-off or close-up diets on dry matter intake, milk yield or composition, body weight, body condition score, serum glucose and insulin concentrations, or muscle lipid concentration. Serum NEFA was higher for 150NRC than 80NRC; 100NRC was intermediate. Thus, the effects of far-off and close-up treatments on postpartum variables diminished as lactation progressed. Overfeeding during the far-off period had a greater negative impact on peripartum metabolism than did differences in close-up period nutrition.

Dairy cows undergo tremendous metabolic and physiological adaptations around parturition to support lactation. The liver 

is central to many of these processes, including gluconeogenesis and metabolism of fatty acids mobilized from adipose tis- 

sue. Fat accumulation may impair normal functions of the liver and increase ketogenesis, which in turn may predispose cows 

to other metabolic abnormalities. Several aspects of dietary management and body condition may alter these adaptations, 

affect dry matter intake, and increase or decrease susceptibility to periparturient health problems. Overfeeding energy dur- 

ing the dry period is a prominent risk factor. Considerable progress has been made in recent years in describing the adap- 

tive changes in the liver and other organs in normal and abnormal states, but this knowledge has not yet identified unequiv- 

ocally the key steps that might be compromised during development of metabolic disorders. The potential role of signaling 

compounds, such as the inflammatory cytokines released in response to environmental stressors, infectious challenge, and 

oxidative stress, in the pathogenesis of periparturient disease is under investigation. New techniques such as functional 

genomics, using cDNA or oligonucleotide microarrays, as well as proteomics and metabolomics, provide additional high- 

throughput tools to determine the effects of nutrition, management, or stressors on tissue function in development of dis- 

ease. Integrative approaches should be fruitful in unraveling the complex interactions of metabol...

Successful therapy for many inherited disorders could be improved if the intervention were initiated early. This is especially true for lysosomal storage disorders. Earlier intervention may allow metabolic correction to occur before lipid buildup has irreversible consequences and͞or before the immune system mounts limiting responses. We have been developing gene therapy to treat lysosomal storage disorders, especially Fabry disease. We describe studies directed toward metabolic correction in neonatal animals mediated by recombinant lentiviral vectors. To develop this method, we first injected a marking lentiviral vector that engineers expression of luciferase into the temporal vein of recipient neonatal animals. The use of a cooled charged-coupled device camera allowed us to track transgene expression over time in live animals. We observed intense luciferase expression in many tissues, including the brain, that did not diminish over 24 weeks. Next, we injected neonatal Fabry mice a single time with a therapeutic lentiviral vector engineered to express human ␣-galactosidase A. The injection procedure was well tolerated. We observed increased plasma levels of ␣-galactosidase A activity starting at our first plasma collection point (4 weeks). Levels of ␣-galactosidase A activity were found to be significantly elevated in many tissues even after 28 weeks. No immune response was observed against the corrective transgene product. Increased levels of enzyme activity also led to significant reduction of globotriaosylceramide in the liver, spleen, and heart. This approach provides a method to treat lysosomal storage disorders and other disorders before destructive manifestations occur.gene therapy ͉ lentivirus ͉ luciferase marking ͉ lysosomal storage disorder