Copper serves as an essential cofactor for a variety of proteins in all living organisms. Previously, we described a human gene (CTR1;SLC31A1) that encodes a high-affinity copper-uptake protein and hypothesized that this protein is required for copper delivery to mammalian cells. Here, we test this hypothesis by inactivating the Ctr1 gene in mice by targeted mutagenesis. We observe early embryonic lethality in homozygous mutant embryos and a deficiency in copper uptake in the brains of heterozygous animals. Ctr1 ؊/؊ embryos can be recovered at E8.5 but are severely developmentally retarded and morphologically abnormal. Histological analysis reveals discontinuities and variable thickness in the basement membrane of the embryonic region and an imperfect Reichert's membrane, features that are likely due to lack of activity in the collagen cross-linking cupro-enzyme lysyl oxidase. A collapsed embryonic cavity, the absence of an allantois, retarded mesodermal migration, and increased cell death are also apparent. In the brains of heterozygous adult mice, which at 16 months are phenotypically normal, copper is reduced to approximately half compared with control littermates, implicating CTR1 as the required port for copper entry into at least this organ. A study of the spatial and temporal expression pattern of Ctr1 during mouse development and adulthood further shows that CTR1 is ubiquitously transcribed with highest expression observed in the specialized epithelia of the choroid plexus and renal tubules and in connective tissues of the eye, ovary, and testes. We conclude that CTR1 is the primary avenue for copper uptake in mammalian cells.

The diagnosis of methemoglobinemia should be considered in patients presenting with cyanosis and hypoxia. A variety of frequently used medications are capable of inducing methemoglobinemia, with dapsone and benzocaine being common culprits. Unique features, such as a saturation gap and chocolate-brown-colored blood, can raise suspicion for methemoglobinemia. Typically, symptoms correlate with the methemoglobin level, and treatment with methylene blue is reserved for patients with significantly elevated methemoglobin levels. In the presence of comorbid conditions that impair oxygen transport, however, low-grade methemoglobinemia can become symptomatic and may warrant treatment.

Predictors of successful virologic, immunologic, and clinical response with combined antiretroviral therapy (cART) containing a boosted protease inhibitor or a nonnucleoside reverse transcriptase inhibitor were analyzed among an antiretroviral naive (ARV-naive) urban cohort. Measures of success included virologic suppression [HIV-1 viral load (VL) <400 copies/ml], an increase in CD4(+) T cells from baseline of >100 cells/microl, and lack of development of an AIDS-defining illness at 24 and 48 weeks after cART initiation. Two hundred and eighty-seven ARV-naive patients were included in this cohort, of which 76.7% were male and 86.8% were nonwhite. At the time of cART initiation their median age was 39 years, the geometric mean CD4(+) count was 42 cells/microl, and the mean viral load was 5.3 log(10) copies/ml. At 48 weeks, 72% of patients achieved virologic suppression, with> or =90% adherence and high school graduation predicting viral undetectability at 48 weeks. Baseline VL < or =100,000 copies/ml and a CD4(+) cell count >100 cells/microl were associated with viral suppression at 24 weeks [OR (95% CI) = 3.55 (1.29-9.81) and 3.96 (1.19-13.15), respectively]; female gender was associated with a greater increase in CD4(+) cell counts [OR (95% CI) = 7.41 (2.48-22.1)]. CDC stage A1-C2 at baseline predicted lack of clinical progression at 48 weeks. The results of this analysis of an ARV-naive cohort comprised predominantly of indigent, minority patients suggest that men who did not have a high school education and who had advanced HIV infection are less likely to have therapeutic success after cART initiation.

BACKGROUND: Coaching has been shown to improve resident well-being; however, not all benefit equally. OBJECTIVE: Assess predictors of changes in resident physician well-being and burnout in a multisite implementation of a Professional Development Coaching Program. DESIGN: Pre-and post-implementation surveys administered to participant cohorts at implementation sites in their intern year. Effect size was calculated comparing pre-and post-intervention paired data. PARTICIPANTS: In total, 272 residents in their intern year at five internal medicine residency programs (Boston