Effectiveness of a rural longitudinal integrated clerkship in preparing medical students for internship.

BACKGROUND: We interviewed graduates from the first two cohorts of a postgraduate medical program that had a senior year longitudinal integrated clerkship (LIC) in a practice setting in rural New South Wales, Australia to determine how well their training prepared them to be junior doctors (3-4 years after graduation), and what aspects of that training they thought were particularly useful. METHODS: In-depth interviews. RESULTS: Fourteen junior doctors were interviewed. Participants reported feeling well prepared in ability to develop close relationships with clinical supervisors, good clinical and procedural skills, ability to work autonomously and work in teams, knowledge of health systems, ability to ensure self-care, and professionalism. Consensus view was that a rural placement was an excellent way to learn medicine for a variety of reasons including relationships with clinicians, less competition for access to patients, and opportunities to extend their clinical skills and act up to intern level. CONCLUSION: The advantages we found in the training these junior doctors received which prepared them well for internship were integral both to the longitudinal, unstructured placement, and to the fact that it was carried out in a rural area. The two aspects of these placements appear to act synergistically, reinforcing the learning experience.

Time Isn't of the Essence: Activating Goals Rather Than Imposing Delays Improves Inhibitory Control in Children.

Is it easier to inhibit inappropriate behaviors if one pauses before acting? An important finding for theory and intervention is that children's inhibitory control improves if an adult imposes a delay before they can act. Such findings have suggested that the passage of time allows impulsive urges to dissipate passively. However, in prior studies with imposed delays, children were also reminded about what they should be doing, which may have aided their activation of goal-relevant information. We tested this possibility by independently manipulating delays and task reminders, and measuring 3-year-olds' abilities to inhibit opening boxes in a go/no-go box-search task. Task reminders, but not adult-imposed delays, improved children's response inhibition. However, as in prior work, children who spontaneously delayed their action longer on go trials exhibited better response inhibition on no-go trials. These results pose a challenge to the view that the passage of time plays a causal role, suggest that spontaneous delays index other processes that improve inhibitory control, and highlight the importance of goal activation in developing inhibitory control.

Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells.

The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors. A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia. Using a positional cloning strategy, we identified a gene, six-transmembrane epithelial antigen of the prostate 3 (Steap3), responsible for the iron deficiency anemia in the mouse mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake. Steap3 shares homology with F(420)H(2):NADP(+) oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.

Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors.

Microcephaly affects approximately 1% of the population and is associated with mental retardation, motor defects and, in some cases, seizures. We analyzed the mechanisms underlying brain size determination in a mouse model of human microcephaly. The Hertwig's anemia (an) mutant shows peripheral blood cytopenias, spontaneous aneuploidy and a predisposition to hematopoietic tumors. We found that the an mutation is a genomic inversion of exon 4 of Cdk5rap2, resulting in an in-frame deletion of exon 4 from the mRNA. The finding that CDK5RAP2 human mutations cause microcephaly prompted further analysis of Cdk5rap2(an/an) mice and we demonstrated that these mice exhibit microcephaly comparable to that of the human disease, resulting from striking neurogenic defects that include proliferative and survival defects in neuronal progenitors. Cdk5rap2(an/an) neuronal precursors exit the cell cycle prematurely and many undergo apoptosis. These defects are associated with impaired mitotic progression coupled with abnormal mitotic spindle pole number and mitotic orientation. Our findings suggest that the reduction in brain size observed in humans with mutations in CDK5RAP2 is associated with impaired centrosomal function and with changes in mitotic spindle orientation during progenitor proliferation.

Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent.

Deficient suppression of T cell responses to allergen by CD4+CD25+ regulatory T cells has been observed in patients with allergic disease. Our current experiments used a mouse model of airway inflammation to examine the suppressive activity of allergen-specific CD4+CD25+ T cells in vivo. Transfer of ovalbumin (OVA) peptide-specific CD4+CD25+ T cells to OVA-sensitized mice reduced airway hyperreactivity (AHR), recruitment of eosinophils, and T helper type 2 (Th2) cytokine expression in the lung after allergen challenge. This suppression was dependent on interleukin (IL) 10 because increased lung expression of IL-10 was detected after transfer of CD4+CD25+ T cells, and regulation was reversed by anti-IL-10R antibody. However, suppression of AHR, airway inflammation, and increased expression of IL-10 were still observed when CD4+CD25+ T cells from IL-10 gene-deficient mice were transferred. Intracellular cytokine staining confirmed that transfer of CD4+CD25+ T cells induced IL-10 expression in recipient CD4+ T cells, but no increase in IL-10 expression was detected in airway macrophages, dendritic cells, or B cells. These data suggest that CD4+CD25+ T cells can suppress the Th2 cell-driven response to allergen in vivo by an IL-10-dependent mechanism but that IL-10 production by the regulatory T cells themselves is not required for such suppression.

Lower general executive function is primarily associated with trait worry: A latent variable analysis of negative thought/affect measures.

This exploratory latent-variable study sought to identify common sources of variance between two multifaceted sets of constructs: executive functions (EFs) and negative thoughts/affect. One-hundred ninety-two college students completed nine tasks representing three types of EFs (inhibition, updating, and shifting) and a set of questionnaires assessing four facets of negative thought/affect (anxiety symptoms, depression symptoms, worry, and rumination). Results indicated that, although the four negative thought/affect constructs were substantially correlated with one another, trait worry was the construct uniquely associated with EFs. Specifically, worry was associated with general EF abilities underlying all three subtypes of EFs (common EF), but was not associated with specific EF abilities (i.e., shifting-specific and updating-specific). These findings highlight the importance of partitioning common and specific variances in both EFs and negative thought/affect when examining the associations between these two research domains. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Mobile phone applications and their use in the self-management of Type 2 Diabetes Mellitus: a qualitative study among app users and non-app users.

BACKGROUND: Mobile phone applications (apps) have been shown to successfully facilitate the self-management of chronic disease. This study aims to evaluate firstly the experiences, barriers and facilitators to app usage among people with Type 2 Diabetes Mellitus (T2DM) and secondly determine recommendations to improve usage of diabetes apps. METHODS: Participants were aged ≥ 18 years with a diagnosis of T2DM for ≥ 6 months. Semi-structured phone-interviews were conducted with 16 app and 14 non-app users. Interviews were based on the Technology Acceptance Model, Health Information Technology Acceptance Model (HITAM) and the Mobile Application Rating Scale. Data were analysed using deductive content analysis. RESULTS: Most app-users found apps improved their T2DM self-management and health. The recommendation of apps by health professionals, as well as positive interactions with them, improved satisfaction; however, only a minority of patients had practitioners involved in their app use. All non-app users had never had the concept discussed with them by a health professional. Facilitators to app use included the visual representation of trends, intuitive navigation and convenience (for example, discretion and portability). Barriers to app use were participant's lack of knowledge and awareness of apps as healthcare tools, perceptions of disease severity, technological and health literacy or practical limitations such as rural connectivity. Factors contributing to app use were classified into a framework based on the Health Belief Model and HITAM. Recommendations for future app design centred on educational features, which were currently lacking (e.g. diabetes complications, including organ damage and hypoglycaemic episodes), monitoring and tracking features (e.g. blood glucose level monitoring with trends and dynamic tips and comorbidities) and nutritional features (e.g. carbohydrate counters). Medication reminders were not used by participants. Lastly, participants felt that receiving weekly text-messaging relating to their self-management would be appropriate. CONCLUSIONS: The incorporation of user-centred features, which engage T2DM consumers in self-management tasks, can improve health outcomes. The findings may guide app developers and entrepreneurs in improving app design and usability. Given self-management is a significant factor in glycaemic control, these findings are significant for GPs, nurse practitioners and allied health professionals who may integrate apps into a holistic management plan which considers strategies outside the clinical environment.

A prospective longitudinal study of cosmetic outcome in immediate latissimus dorsi breast reconstruction and the influence of radiotherapy.

BACKGROUND: Immediate breast reconstruction may result in superior cosmetic outcomes as a result of the preservation of the skin envelope. The impact of implant use and radiotherapy (RT) on the cosmetic outcome of latissimus dorsi (LD) breast reconstruction, however, has never been prospectively evaluated with adequate long-term follow-up. METHODS: Women undergoing immediate LD breast reconstruction from January 2000 to February 2007 underwent photographic assessment and clinical evaluation for breast retraction analysis (BRA) at 3, 6 and 12 months postoperatively and on the anniversary of their surgery. The resulting photographs were subject to panel cosmetic assessment. A patient-reported cosmetic outcome questionnaire and the body image scale (BIS) were administered to each woman at a single time point to coincide with the anniversary of their surgery. Multilevel linear regression modelling was used to analyse the results. RESULTS: Seventy-three women underwent 53 implant-assisted LD breast reconstructions and 20 autologous procedures with a mean follow-up of 2.71 years. The incidence of radiotherapy in this cohort was 43%. RT over time adversely influenced overall cosmetic outcome as assessed by the panel (P = 0.0002), and BRA (P = 0.033), both of which were significantly worse in the implant-assisted group (P = 0.020). Patient reporting of overall cosmetic outcome and BIS, however, did not differ significantly between the LD groups or following RT. CONCLUSION: Radiotherapy may adversely affect the cosmetic outcome of latissimus dorsi breast reconstruction, particularly if an implant is used, but this is not universal. Patient assessment of their cosmetic outcome may, however, differ significantly from the clinician's view.

The relationship between undernutrition and humoral immune status in children with pneumonia in Papua New Guinea.

Malnutrition is a significant risk factor for childhood infectious diseases in developing countries, including Papua New Guinea (PNG). Whilst the mechanisms are not fully understood there is little doubt that impairment of immune function is a major contributing factor in enhancing disease susceptibility in malnourished children. This susceptibility has been clearly shown for pneumonia in PNG. The aim of this study was to examine the effect of undernutrition on the humoral immune profile in children less than 60 months of age with pneumonia. The study was cross-sectional with measurements of nutritional status and parameters of the immune response being assessed simultaneously. The children were grouped according to age for the purpose of comparative analysis. The children were from the Goroka region of the Eastern Highlands Province of PNG and had been admitted to hospital with moderate-severe pneumonia. They were classified as undernourished (less than 80% weight for age) or nourished (greater than or equal to 80% weight for age). Serum albumin, IgG, IgA and IgM and salivary albumin and IgA were measured. Antibodies to nontypeable Haemophilus influenzae outer membrane protein and Escherichia coli O antigen were also determined in serum and saliva. Undernourished children aged less than 49 months had lower levels of serum albumin than nourished children throughout this age range. Lower values of salivary IgA were observed in infants (less than 13 months of age) than in older children, with a larger proportion of younger children having no detectable IgA. The age-related immunological profile was similar in undernourished and nourished children. At different age intervals the concentration of immunoglobulins in serum and saliva from undernourished children was generally found to be less than or the same as that from nourished children. In most cases undernourished children had lower levels of specific antibodies than nourished children but for some antibodies in some age groups the levels in the undernourished were higher. In conclusion, undernutrition was associated with hypoalbuminaemia and reduced humoral immune responses in children with pneumonia but its immunological effects varied with age in an unpredictable way.

Getting ready to use control: Advances in the measurement of young children's use of proactive control.

A key developmental transition in executive function is in the temporal dynamics of its engagement: children shift from reactively calling to mind task-relevant information as needed, to being able to proactively maintain information across time in anticipation of upcoming demands. This transition is important for understanding individual differences and developmental changes in executive function; however, methods targeting its assessment are limited. We tested the possibility that Track-It, a paradigm developed to measure selective sustained attention, also indexes proactive control. In this task children must track a target shape as it moves unpredictably among moving distractors, and identify where it disappears, which may require proactively maintaining information about the target or goal. In two experiments (5-6 year-olds, Ns = 33, 64), children's performance on Track-It predicted proactive control across two established paradigms. These findings suggest Track-It measures proactive control in children. Theoretical possibilities regarding how proactive control and selective sustained attention may be related are also discussed.

High incidence, early onset of histiocytic sarcomas in mice with Hertwig's anemia.

OBJECTIVE: Histiocytic sarcoma (HS) is a rare, rapidly disseminated, usually lethal tumor in humans. Treatment specific for HS has not been developed primarily due to deficiencies of appropriate animal models with high incidence/early onset. Mice with Hertwig's anemia (an/an) provide a potential model. METHODS: Here, we compare HS susceptibility in an/an and unaffected control mice maintained on three genetic backgrounds. As a potential therapeutic measure, genetically marked bone marrow is transplanted between high and low susceptibility animals. RESULTS: HS is detected earlier and the overall incidence is 15-fold higher in WBB6F1(F1)-an/an than in F1-+/?, B6-an/an and -+/? mice. Neither WB-an/an nor their normal WB-+/? littermates present with HS. Liver myelopoiesis and aneuploidy coexist with HS but the former is also rampant (33.7% incidence) in HS-free +/? and an/an mice. Marrow transplantation experiments provide evidence that (1) myelopoiesis is associated with HS and (2) early-onset/high-incidence HS is blocked by using late-onset F1-+/+ mice, as either donor or recipient. CONCLUSIONS: Homozygosity for an on an F1 genetic background is essential for high-incidence/early-onset HS; myelopoiesis and HS coexist; and therapeutic transplantation may be feasible.

No Evidence of the Ego-Depletion Effect across Task Characteristics and Individual Differences: A Pre-Registered Study.

Ego-depletion, a psychological phenomenon in which participants are less able to engage in self-control after prior exertion of self-control, has become widely popular in the scientific community as well as in the media. However, considerable debate exists among researchers as to the nature of the ego-depletion effect, and growing evidence suggests the effect may not be as strong or robust as the extant literature suggests. We examined the robustness of the ego-depletion effect and aimed to maximize the likelihood of detecting the effect by using one of the most widely used depletion tasks (video-viewing attention control task) and by considering task characteristics and individual differences that potentially moderate the effect. We also sought to make our research plan transparent by pre-registering our hypotheses, procedure, and planned analyses prior to data collection. Contrary to the ego-depletion hypothesis, participants in the depletion condition did not perform worse than control participants on the subsequent self-control task, even after considering moderator variables. These findings add to a growing body of evidence suggesting ego-depletion is not a reliable phenomenon, though more research is needed that uses large sample sizes, considers moderator variables, and pre-registers prior to data collection.

Delayed administration of carrier marrow can decrease competition on donor stem cells during engraftment and maintain radioprotection of the host.

OBJECTIVE: The goal of this study was to determine if competitive pressure was placed on hematopoietic stem cells (HSC) by a coinjected "carrier" population that maintains short-term survival of the host. Our hypothesis was that delayed introduction of "carrier" cells would increase engraftment of donor HSC. MATERIALS AND METHODS: Competitive repopulation assays were performed using genetically distinguishable whole bone marrow (BM) populations. Donor BM was competed against carrier BM that was coinjected or injected 3 or 4 days later. Radioprotection with delayed carrier injection also was examined by performing the initial HSC transplantation with Hoechst(lo) side population (SP) cells. SP HSC incubated with cytokines and BM stroma to stimulate cell cycling before transplantation also were tested using coinjection or delayed carrier administration. RESULTS: Delayed introduction of carrier whole BM increased peripheral expansion of donor whole BM, freshly isolated HSC, or cytokine-stimulated HSC compared to coinjection with carrier cells. A 3-day delay in carrier administration maintained radioprotection in 100% of lethally irradiated recipients of highly enriched HSC, whereas a 4-day delay did not rescue these recipients from death. When recipients are rescued, recovering host marrow can compete against donor HSC unless sufficient donor cells are injected. CONCLUSIONS: Delayed introduction of carrier BM significantly increases donor HSC engraftment and peripheral expansion by reducing competition in the host. Competition by a coinjected carrier cell population or recovery of host marrow significantly reduces the therapeutic efficacy of normal or in vitro manipulated donor HSC.

Donor cell expansion is delayed following nonablative in utero transplantation to treat murine mucopolysaccharidosis type VII.

To block development of progressive childhood diseases, in utero transplantation (IUTx) requires immediate and significant donor peripheral blood (PB) cell amplification. To date, negligible and nontherapeutic donor PB cell levels have been observed postnatally, except in patients with immunodeficiency diseases. Donor cell fate in utero still is not clear. Ease of identifying and quantifying beta-glucuronidase (GUSB)-expressing donor cells in GUSB-null mucopolysaccharidosis type VII (MPSVII) mouse recipients allowed us to evaluate temporal donor cell engraftment and amplification post-IUTx. Like humans, MPSVII mice are unable to catabolize lysosomal glycosaminoglycans and progressively develop severe storage disease unless they are treated early in life.IUTx recipients were nonablated MPSVII fetuses and genetically stem cell-deficient, and hence myeloablated, W(41)/W(41) MPSVII fetuses. Donor GUSB+ cells were identified and counted in histochemical tissue sections. Quantitative results were confirmed by flow cytometry, enzyme analysis, and histopathology. Whereas GUSB+ cells engraft in most tissues in utero, significant amplification does not occur until the first postnatal week in the nonablated MPSVII hosts. In contrast, genetically myeloablated MPSVII recipients display widely distributed donor cell replacement accompanied by extensive amplification in utero. In both models, storage is alleviated in adult tissues with significant donor cell repopulation. To become therapeutic, IUTx must overcome the limitations of donor cell expansion in the highly competitive fetal environment. Fortunately, nonablative mechanisms to amplify cells in utero are coming on line.

Normoblastosis, a murine model for ankyrin-deficient hemolytic anemia, is caused by a hypomorphic mutation in the erythroid ankyrin gene Ank1.

Ankyrin deficiency is one of the most common causes of hereditary spherocytosis in humans. A spontaneous mutation, normoblastosis (Ank1nb), discovered in 1969 in a mouse stock maintained at the Jackson Laboratory, provides an important animal model for these human ankyrin-deficient anemias. Study of this model has led to the finding of multiple isoforms of Ank1 as well as Ank1nb-related pathology in nonerythroid tissues. To enhance the usefulness of this model, we have identified the Ank1nb mutation as the deletion of a guanosine residue in exon 36 of the erythroid ankyrin gene (Ank1). This results in a frame shift that introduces a stop 13 codons downstream and predicts a 157 kDa nb-ankyrin lacking the regulatory domain but including intact membrane- and spectrin-binding domains. By epitope scanning on immunoblots, we show that a previously reported protein (p150) found in nb reticulocytes is the predicted nb-ankyrin. Existing evidence indicates that this protein is functional, making the normoblastosis mutation a hypomorph rather than a null as originally thought. The nb-ankyrin provides an explanation for the milder phenotype displayed by nb/nb animals relative to the murine spectrin-deficient anemias, spherocytosis (Spna1(sph), Spna1(sph-1J), Spna1(sph-2BC), Spna1(sph-DEM)) and jaundiced (Spnb1(ja)), and suggests that truncated ankyrins could be useful in gene replacement therapy.

Less-structured time in children's daily lives predicts self-directed executive functioning.

Executive functions (EFs) in childhood predict important life outcomes. Thus, there is great interest in attempts to improve EFs early in life. Many interventions are led by trained adults, including structured training activities in the lab, and less-structured activities implemented in schools. Such programs have yielded gains in children's externally-driven executive functioning, where they are instructed on what goal-directed actions to carry out and when. However, it is less clear how children's experiences relate to their development of self-directed executive functioning, where they must determine on their own what goal-directed actions to carry out and when. We hypothesized that time spent in less-structured activities would give children opportunities to practice self-directed executive functioning, and lead to benefits. To investigate this possibility, we collected information from parents about their 6-7 year-old children's daily, annual, and typical schedules. We categorized children's activities as "structured" or "less-structured" based on categorization schemes from prior studies on child leisure time use. We assessed children's self-directed executive functioning using a well-established verbal fluency task, in which children generate members of a category and can decide on their own when to switch from one subcategory to another. The more time that children spent in less-structured activities, the better their self-directed executive functioning. The opposite was true of structured activities, which predicted poorer self-directed executive functioning. These relationships were robust (holding across increasingly strict classifications of structured and less-structured time) and specific (time use did not predict externally-driven executive functioning). We discuss implications, caveats, and ways in which potential interpretations can be distinguished in future work, to advance an understanding of this fundamental aspect of growing up.

Chemotactic action of prostaglandin E2 on mouse mast cells acting via the PGE2 receptor 3.

Mast cells are long-lived cells that are principally recognized for their effector function in helminth infections and allergic reactions. These cells are derived from pluripotential hematopoietic stem cells in the bone marrow that give rise to committed mast cell progenitors in the blood and are recruited to tissues, where they mature. Little is known about the chemotactic signals responsible for recruitment of progenitors and localization of mature mast cells. A mouse model was set up to identify possible mast cell progenitor chemoattractants produced during repeated allergen challenge in vivo. After the final challenge, the nasal mucosa was removed to produce conditioned medium, which was tested in chemotaxis assays against 2-wk murine bone marrow-derived c-kit+ mast cells (BMMC). A single peak of chemotactic activity was seen on reverse-phase HPLC with a retention time and electrospray mass spectrum consistent with prostaglandin E2 (PGE2). This lipid was found to be a highly potent chemoattractant for immature (2-wk) and also mature (10-wk) BMMC in vitro. Fluorescently labeled 2-wk c-kit+ BMMC, when injected intravenously, accumulated in response to intradermally injected PGE2. Analysis using TaqMan showed mRNA expression of the PGE2 receptors 3 (EP3) and 4 (EP4) on 2- and 10-wk BMMC. Chemotaxis induced by PGE2 was mimicked by EP3 agonists, blocked by an EP3 receptor antagonist, and partially inhibited by a MAPKK inhibitor. These results show an unexpected function for PGE2 in the chemotaxis of mast cells.

Early onset of lysosomal storage disease in a murine model of mucopolysaccharidosis type VII: undegraded substrate accumulates in many tissues in the fetus and very young MPS VII mouse.

Lysosomal storage diseases (LSDs), due to deficiency of a lysosomal enzyme, are inherited, progressive disorders that are often fatal during childhood. The mucopolysaccharidoses (MPS) are LSDs caused by deficiency of a lysosomal enzyme needed for the stepwise degradation of glycosaminoglycans. A murine model of MPS VII shares many clinical, biochemical, and pathologic features with human MPS and has proved valuable for the study of the pathophysiology of MPS and for evaluation of therapies for LSDs. Early therapy of MPS VII mice, initiated in the first weeks of life, is much more effective in decreasing clinical and morphologic evidence of disease than treatment begun in mature animals. Whether such early therapy decreases existing storage or prevents its accumulation is incompletely investigated. We performed an analysis of storage in very young MPS VII mice to define the extent of disease at and before the time of initiation of early treatments. MPS VII pups from 12 days postcoitus (dpc) to 31 days postnatal (dpn) were studied. Storage accumulated in fixed tissue macrophages in the liver and cartilage as soon as 12 dpc and was present in central nervous system glia, leptomeninges, and perivascular cells by 15 dpc. Osteoblast and primitive neocortical cell storage was apparent at 18 to 19 dpc. At 2 dpn, lysosomal distention appeared in circulating leukocytes. Abundant lysosomal storage was present in many sites by 14 dpn. Secondary accumulation of beta-hexosaminidase paralleled increasing glycosaminoglycan storage. These results confirm the presence of widespread storage even in utero and in the very young MPS VII mouse and highlight the importance of early treatment to prevent storage accumulation.

nm1054: a spontaneous, recessive, hypochromic, microcytic anemia mutation in the mouse.

Hypochromic, microcytic anemias are typically the result of inadequate hemoglobin production because of globin defects or iron deficiency. Here, we describe the phenotypic characteristics and pathogenesis of a new recessive, hypochromic, microcytic anemia mouse mutant, nm1054. Although the mutation nm1054 is pleiotropic, also resulting in sparse hair, male infertility, failure to thrive, and hydrocephaly, the anemia is the focus of this study. Hematologic analysis reveals a moderately severe, congenital, hypochromic, microcytic anemia, with an elevated red cell zinc protoporphyrin, consistent with functional erythroid iron deficiency. However, serum and tissue iron analyses show that nm1054 animals are not systemically iron deficient. From hematopoietic stem cell transplantation and iron uptake studies in nm1054 reticulocytes, we provide evidence that the nm1054 anemia is due to an intrinsic hematopoietic defect resulting in inefficient transferrin-dependent iron uptake by erythroid precursors. Linkage studies demonstrate that nm1054 maps to a genetic locus not previously implicated in microcytic anemia or iron phenotypes.