Chronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1α subunit increases exponentially as O 2 concentration is decreased. Hif1a -/-mouse embryos with complete deficiency of HIF-1α due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a +/-heterozygotes develop normally and are indistinguishable from Hif1a +/+ wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a +/-and Hif1a +/+ mice exposed to 10% O 2 for one to six weeks were analyzed. Hif1a +/-mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1α deficiency has significant effects on multiple systemic responses to chronic hypoxia.

Rationale: Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the diseasecausing gene, indicating that other factors determine severity of lung disease. Objectives: To quantify the contribution of modifier genes to variation in CF lung disease severity. Methods: Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV 1 within the last year was used for cross-sectional analysis. FEV 1 measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins ‫ف(‬ 100% gene sharing) with that of dizygous (DZ) twins/siblings ‫ف(‬ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects. Measurements and Main Results

ROTECTION OF HUMAN SUBjects in research is an evolving process. The current system of institutional review board (IRB) assessment of human subjects protection was established in 1974 in response to highly publicized human research scandals in the 1960s and early 1970s. 1,2 Federal regulation of research conduct and IRB function was implemented in 1979. When IRBs were created, the common paradigm for human subjects research consisted of a single investigator at one institution enrolling local participants, with the major emphasis of regulation on the review of clinical trials. Over the past 25 years, research strategies and technologies have changed, often bringing together investigators from multiple institutions to enroll geographically diverse pools of participants into epidemiological studies. However, IRB procedures and their federal underpinnings have not correspondingly kept pace. 2,3 Because of the focus of IRBs on clinical trials, others have asserted that IRBs "often have little insight into the needs of epidemiology." 4 Indeed, it is worth noting that one infamous human subjects re

Background & Aims-Neonatal intestinal obstruction (meconium ileus or MI) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and non-genetic modifiers to the development of this major complication of CF.