Control of Systemic Iron Homeostasis by the 3' Iron-Responsive Element of Divalent Metal Transporter 1 in Mice.

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Involving religious leaders in HIV care and treatment at a university-affiliated hospital in Ethiopia: Application of formative inquiry.

In sub-Saharan Africa, religious views strongly influence how people relate to illness, health, and healing. Belief in the curative power of religion, including for HIV, persists in many communities. As such, many funding agencies and organisations working in the field of HIV have incorporated religious institutions into their programmes in various capacities. Yet, debate continues regarding the benefits and drawbacks of including sectarian organisations in the fight against HIV. In the current study, we sought to explore whether patients with HIV would be amenable to receiving HIV-related psychosocial support from religious leaders. We interviewed 48 Ethiopian Orthodox Church followers who presented for routine HIV care at Gondar University Hospital ART (antiretroviral treatment) clinic. Although almost half (46%) of participants self-identified as 'very religious', the majority of them (73%) had not disclosed their HIV status to a religious leader. Study participants highlighted multiple factors that could potentially affect their willingness to involve religious leaders in their HIV care. We discuss these findings in relation to religion and HIV in the African context. Our findings support the use of formative qualitative work prior to developing and implementing programmes that integrate faith and medical communities.

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice.

Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.

A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart.

Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure.

Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis.

Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through receptor-mediated endocytosis of iron-loaded transferrin. It is expressed in the intestinal epithelium but not involved in dietary iron absorption. To investigate its role, we inactivated the Tfr1 gene selectively in murine intestinal epithelial cells. The mutant mice had severe disruption of the epithelial barrier and early death. There was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell markers, and striking induction of many genes associated with epithelial-to-mesenchymal transition. Administration of parenteral iron did not improve the phenotype. Surprisingly, however, enforced expression of a mutant allele of Tfr1 that is unable to serve as a receptor for iron-loaded transferrin appeared to fully rescue most animals. Our results implicate Tfr1 in homeostatic maintenance of the intestinal epithelium, acting through a role that is independent of its iron-uptake function.

Hungry irony.

Iron-deficient individuals experience a loss of appetite that can be restored with iron supplementation. It has been proposed that iron influences the satiety hormone leptin; however, a direct link between iron and leptin has remained elusive. In this issue of the JCI, Gao and colleagues demonstrate an inverse relationship between adipocyte iron and leptin that is mediated by iron-dependent activation of cAMP-responsive element binding protein (CREB), the transcription factor that represses leptin transcription. Together, the results of this study provide a mechanistic connection between dietary iron and the appetite-regulating hormone leptin.

Research in academic medical centers: two threats to sustainable support.

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.

Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle.

Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that iron assimilation via Tfr1 was critical for skeletal muscle metabolism, and that iron deficiency in muscle led to dramatic changes, not only in muscle, but also in adipose tissue and liver. Inactivation of Tfr1 incapacitated normal energy production in muscle, leading to growth arrest and a muted attempt to switch to fatty acid ß oxidation, using up fat stores. Starvation signals stimulated gluconeogenesis in the liver, but amino acid substrates became limiting and hypoglycemia ensued. Surprisingly, the liver was also iron deficient, and production of the iron regulatory hormone hepcidin was depressed. Our observations reveal a complex interaction between iron homeostasis and metabolism that has implications for metabolic and iron disorders.

Stigma in Ethiopia: association with depressive symptoms in people with HIV.

Rates of depression among people living with HIV can be as high as 50%. In many settings, HIV-related stigma has been associated with depressive symptoms which may lead to poor engagement in care and ultimately, poorer health outcomes. Stigma is a major issue in Ethiopia but data examining the relationship between stigma and depression in Ethiopia are lacking. We performed a mixed-methods cross-sectional study to examine the relationship between stigma of HIV/AIDS and depressive symptoms in Gondar, Ethiopia. We interviewed patients who presented for routine HIV care at Gondar University Hospital during the study period, examining depressive symptoms and HIV/AIDS-related stigma using standardized measures. Multiple-regression was used to assess the relationship between depressive symptoms, stigma, and gender. Of 55 patients included in this analysis, 63.6% were female and most participants had limited formal education (69%, less than 12th grade education). The majority reported experiencing both stigma (78%) and depressive symptoms (60%) ranging in severity from mild to moderately severe. Higher levels of HIV-related stigma were significantly associated with higher levels of depressive symptoms (ß = 0.464, p ≤ 0.001). Although gender was associated with stigma, it was not associated with depressive symptoms (ß = -0.027, p > 0.05). Results suggest the importance of psychosocial issues in the lives of people with HIV in Ethiopia.

Iron and copper in mitochondrial diseases.

Transition metals are frequently used as cofactors for enzymes and oxygen-carrying proteins that take advantage of their propensity to gain and lose single electrons. Metals are particularly important in mitochondria, where they play essential roles in the production of ATP and detoxification of reactive oxygen species. At the same time, transition metals (particularly Fe and Cu) can promote the formation of harmful radicals, necessitating meticulous control of metal concentration and subcellular compartmentalization. We summarize our current understanding of Fe and Cu in mammalian mitochondrial biology and discuss human diseases associated with aberrations in mitochondrial metal homeostasis.

The ELDER expansion project: building cultural competence among long term home care workers.

This study aimed to improve communication and care provision in five home or long term care settings by raising staff awareness about health beliefs and patterns among varied cultures. Lack of cultural competence is linked to ethnocentric attitudes that can lead to inappropriate communication and ineffective interventions. Understanding the culturally imbedded belief systems of patients and providers is an integral part of effective communication skills that are foundational to optimal team functioning. Participants included five home or long term care agencies in an underserved region of New England. Seventy-four nurses, aids and allied health professionals participated in 10-12 small group interactive sessions. Comparison of pre and post cultural self efficacy scores revealed that participant confidence regarding their knowledge and skills when interacting with other cultures improved interactions with patients and co-workers. Journal exemplars supported the ability of attendees to apply content to the workplace.

Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic ß cell fate in response to cytokines.

Reactive oxygen species (ROS) contribute to target-cell damage in inflammatory and iron-overload diseases. Little is known about iron transport regulation during inflammatory attack. Through a combination of in vitro and in vivo studies, we show that the proinflammatory cytokine IL-1ß induces divalent metal transporter 1 (DMT1) expression correlating with increased ß cell iron content and ROS production. Iron chelation and siRNA and genetic knockdown of DMT1 expression reduce cytokine-induced ROS formation and cell death. Glucose-stimulated insulin secretion in the absence of cytokines in Dmt1 knockout islets is defective, highlighting a physiological role of iron and ROS in the regulation of insulin secretion. Dmt1 knockout mice are protected against multiple low-dose streptozotocin and high-fat diet-induced glucose intolerance, models of type 1 and type 2 diabetes, respectively. Thus, ß cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications.

Late stage erythroid precursor production is impaired in mice with chronic inflammation.

BACKGROUND: We and others have shown previously that over-expression of hepcidin antimicrobial peptide, independently of inflammation, induces several features of anemia of inflammation and chronic disease, including hypoferremia, sequestration of iron stores and iron-restricted erythropoiesis. Because the iron-restricted erythropoiesis evident in hepcidin transgenic mice differs from the normocytic, normochromic anemia most often observed in anemia of inflammation, we tested the hypothesis that chronic inflammation may contribute additional features to anemia of inflammation which continue to impair erythropoiesis following the acute phase of inflammation in which hepcidin is active. DESIGN AND METHODS: We compared erythropoiesis and iron handling in mice with turpentine-induced sterile abscesses with erythropoiesis and iron handling in hepcidin transgenic mice. We compared erythrocyte indices, expression of genes in the hepcidin regulatory pathway, tissue iron distribution, expression of heme and iron transport genes in splenic macrophages, the phenotype of erythroid maturation and chloromethyl dichlorodihydrofluorescein diacetate, acetyl ester fluorescence. RESULTS: Mice with sterile abscesses exhibited an intense, acute inflammatory phase followed by a mild to moderate chronic inflammatory phase. We found that erythrocytes in mice with sterile abscesses were normocytic and normochromic in contrast to those in hepcidin transgenic mice. We also observed that although hypoferremia resolved in the late phases of inflammation, erythropoiesis remained suppressed, with evidence of inefficient maturation of erythroid precursors in the bone marrow of mice with sterile abscesses. Finally, we observed increased oxidative stress in erythroid progenitors and circulating erythrocytes of mice with sterile abscesses which was not evident in hepcidin transgenic mice. CONCLUSIONS: Our results suggest that chronic inflammation inhibits late stages of erythroid production in the turpentine-induced sterile abscess model and induces features of impaired erythropoiesis which are distinct from those in hepcidin transgenic mice.

Mutation of Rubie, a novel long non-coding RNA located upstream of Bmp4, causes vestibular malformation in mice.

BACKGROUND: The vestibular apparatus of the vertebrate inner ear uses three fluid-filled semicircular canals to sense angular acceleration of the head. Malformation of these canals disrupts the sense of balance and frequently causes circling behavior in mice. The Epistatic circler (Ecl) is a complex mutant derived from wildtype SWR/J and C57L/J mice. Ecl circling has been shown to result from the epistatic interaction of an SWR-derived locus on chromosome 14 and a C57L-derived locus on chromosome 4, but the causative genes have not been previously identified. METHODOLOGY/PRINCIPAL FINDINGS: We developed a mouse chromosome substitution strain (CSS-14) that carries an SWR/J chromosome 14 on a C57BL/10J genetic background and, like Ecl, exhibits circling behavior due to lateral semicircular canal malformation. We utilized CSS-14 to identify the chromosome 14 Ecl gene by positional cloning. Our candidate interval is located upstream of bone morphogenetic protein 4 (Bmp4) and contains an inner ear-specific, long non-coding RNA that we have designated Rubie (RNA upstream of Bmp4 expressed in inner ear). Rubie is spliced and polyadenylated, and is expressed in developing semicircular canals. However, we discovered that the SWR/J allele of Rubie is disrupted by an intronic endogenous retrovirus that causes aberrant splicing and premature polyadenylation of the transcript. Rubie lies in the conserved gene desert upstream of Bmp4, within a region previously shown to be important for inner ear expression of Bmp4. We found that the expression patterns of Bmp4 and Rubie are nearly identical in developing inner ears. CONCLUSIONS/SIGNIFICANCE: Based on these results and previous studies showing that Bmp4 is essential for proper vestibular development, we propose that Rubie is the gene mutated in Ecl mice, that it is involved in regulating inner ear expression of Bmp4, and that aberrant Bmp4 expression contributes to the Ecl phenotype.

The channel kinase, TRPM7, is required for early embryonic development.

Global disruption of transient receptor potential-melastatin-like 7 (Trpm7) in mice results in embryonic lethality before embryonic day 7. Using tamoxifen-inducible disruption of Trpm7 and multiple Cre recombinase lines, we show that Trpm7 deletion before and during organogenesis results in severe tissue-specific developmental defects. We find that Trpm7 is essential for kidney development from metanephric mesenchyme but not ureteric bud. Disruption of neural crest Trpm7 at early stages results in loss of pigment cells and dorsal root ganglion neurons. In contrast, late disruption of brain-specific Trpm7 after embryonic day 10.5 does not alter normal brain development. We developed induced pluripotent stem cells and neural stem (NS) cells in which Trpm7 disruption could be induced. Trpm7(-/-) NS cells retained the capacities of self-renewal and differentiation into neurons and astrocytes. During in vitro differentiation of induced pluripotent stem cells to NS cells, Trpm7 disruption prevents the formation of the NS cell monolayer. The in vivo and in vitro results demonstrate a temporal requirement for the Trpm7 channel kinase during embryogenesis.

Partnerships among community development, public health, and health care could improve the well-being of low-income people.

Safe, vibrant neighborhoods are vital to health. The community development "industry"-a network of nonprofit service providers, real estate developers, financial institutions, foundations, and government-draws on public subsidies and other financing to transform impoverished neighborhoods into better-functioning communities. Although such activity positively affects the "upstream" causes of poor health, the community development industry rarely collaborates with the health sector or even considers health effects in its work. Examples of initiatives-such as the creation of affordable housing that avoids nursing home placement-suggest a strong potential for cross-sector collaborations to reduce health disparities and slow the growth of health care spending, while at the same time improving economic and social well-being in America's most disadvantaged communities. We propose a four-point plan to help ensure that these collaborations achieve positive outcomes and sustainable progress for residents and investors alike.