PBRM1 bromodomains associate with RNA to facilitate chromatin association.

PBRM1 is a subunit of the PBAF chromatin remodeling complex, which is mutated in 40-50% of clear cell renal cell carcinoma patients. It is thought to largely function as a chromatin binding subunit of the PBAF complex, but the molecular mechanism underlying this activity is not fully known. PBRM1 contains six tandem bromodomains which are known to cooperate in binding of nucleosomes acetylated at histone H3 lysine 14 (H3K14ac). Here, we demonstrate that the second and fourth bromodomains from PBRM1 also bind nucleic acids, selectively associating with double stranded RNA elements. Disruption of the RNA binding pocket is found to compromise PBRM1 chromatin binding and inhibit PBRM1-mediated cellular growth effects.

Successful Treatment of Prolonged, Severe Coronavirus Disease 2019 Lower Respiratory Tract Disease in a B cell Acute Lymphoblastic Leukemia Patient With an Extended Course of Remdesivir and Nirmatrelvir/Ritonavir.

A patient with B-cell acute lymphoblastic leukemia (ALL) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had persistent, progressive pneumonia with viremia after 5 months of infection despite monoclonal antibodies, intravenous (IV) remdesivir and prolonged oral steroids. Twenty days of nirmatrelvir/ritonavir and 10 days of IV remdesivir led to full recovery.

A Potent Inhibitor of Aminopeptidase P2 Reduces Reperfusion Injury in Models of Myocardial Infarction and Stroke.

During a myocardial infarction or ischemic stroke, blood flow to the heart or brain is partially blocked. This results in reduced delivery of oxygen and nutrients and, ultimately, tissue damage. Initial treatment involves removing the clot and restoring blood flow (reperfusion). However, this treatment is not as effective as one would hope because the reperfusion process itself can cause a different type of damage (reperfusion injury) that contributes up to 50% of the total damage. Bradykinin is an autocoid that is released from blood vessel endothelial cells during ischemia and reperfusion and has the potential to prevent reperfusion injury. However, bradykinin is rapidly inactivated by enzymes on endothelial cells, limiting its beneficial effects. One of these enzymes is aminopeptidase P2. We designed a potent and specific inhibitor of aminopeptidase P2 called ST-115, [(S)-2-mercapto-4-methylpentanoyl]-4(S)-fluoro-Pro-Pro-3(R)-beta-Pro. When ST-115 is administered intravenously at the start of reperfusion, it reduces bradykinin degradation. This increases bradykinin's concentration in the capillaries and enhances its protective effects. We tested ST-115 in a mouse model of myocardial infarction and found that the damaged area of the heart was reduced by 58% compared with mice given saline. In a rat model of ischemic stroke, ST-115 reduced functional deficits in a skilled walking test by 60% and reduced brain edema by 51%. It reduced brain infarct size by 48% in a major subset of rats with small strokes. The results indicate that ST-115 can ameliorate reperfusion injury and can ultimately serve as a therapeutic for acute myocardial infarction and ischemic stroke. SIGNIFICANCE STATEMENT: We have shown that our aminopeptidase P2 inhibitor, ST-115, can reduce tissue injury caused by episodes of ischemia followed by reperfusion. It was successful in rodent models of myocardial infarction and stroke. The clinical use would involve the intravenous administration of ST-115 at the induction of reperfusion. In the case of stroke, the successful technique of thrombectomy could be combined with ST-115 administration to simultaneously reduce both ischemic and reperfusion injury.

A Quantitative Assessment of Mucosal Eosinophils in the Gastrointestinal Tract of Children Without Detectable Organic Disease.

BACKGROUND: Accurate measurements of mucosal eosinophil concentrations in gastrointestinal tracts of healthy children are necessary to differentiate health and disease states in general, and better define eosinophilic gastrointestinal diseases. STUDY: We retrospectively reviewed gastrointestinal biopsies from children with macroscopically normal endoscopies, who, after a minimal follow-up of one year, were not diagnosed with any organic disease. Peak eosinophil concentrations and distributions were assessed from each segment of the gastrointestinal tract. RESULTS: Three centers (Italy, United Kingdom, and Israel) contributed 202 patients (median age 13 years IQR 9.5-15.5, range 1-18 years). Median (IQR, range) eosinophil concentrations (eos/mm2) were: esophagus 0 (0-0, 0-84), stomach 0 (0-4, 0-84), duodenal bulb 20 (13-30, 7-67), second part of duodenum 20 (13-29, 0-105), terminal ileum 29 (14-51, 0-247), cecum 53 (37-89, 10-232), ascending colon 55 (25-84, 0-236), transverse colon 38 (21-67, 4-181), descending colon 29 (17-59, 0-114), sigmoid colon 25 (13-40, 0-215) and rectum 13 (4-28, 0-152). Significant geographical variance was present, however, no differences in eosinophil concentrations were identified between children with resolving symptoms vs. those with functional diagnoses, nor across age groups. CONCLUSIONS: Standardized eosinophil concentrations from the gastrointestinal tracts of children without organic disease will serve to better define both health and disease states. No differences were found between resolved symptoms vs. functional diagnoses nor between age groups in this pediatric cohort.

Development of Wastewater Pooled Surveillance of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from Congregate Living Settings.

Wastewater-based monitoring for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the individual building level could be an efficient, passive means of early detection of new cases in congregate living settings, but this approach has not been validated. Preliminary samples were collected from a hospital and a local municipal wastewater treatment plant. Molecular diagnostic methods were compared side by side to assess feasibility, performance, and sensitivity. Refined sample collection and processing protocols were then used to monitor two occupied dormitory complexes (n = 105 and 66) over 8 weeks. Wastewater results were validated using known case counts from external clinical testing of building occupants. Results confirm that ultracentrifugation from a 24-h composite collection had a sensitivity of 96.2% and a specificity of 100%. However, the method could not distinguish new infectious cases from persistent convalescent shedding of SARS-CoV-2 RNA. If the detection of convalescent shedding is considered a false positive, then the sensitivity is 100% and specificity drops to 45%. It was determined that the proposed approach constitutes a highly sensitive wastewater surveillance method for detecting SARS-CoV-2, but it could not distinguish new infectious cases from persistent convalescent shedding. Future work must focus on approaches to distinguish new infections from convalescent shedding to fully realize the potential of building wastewater as a surveillance tool for congregate living. IMPORTANCE Some of the most severe outbreaks of COVID-19 have taken place in places where persons live together, such as nursing homes. Wastewater testing from individual buildings could be used for frequent pooled surveillance of virus from all occupants, including those who are contagious, with or without symptoms. This work provides a sensitive practical method for detecting infected individuals, as validated in two building complexes housing occupants who underwent frequent clinical testing performed by external entities. Although this sensitive method could be deployed now for pooled surveillance as an early warning system to limit outbreaks, the study shows that the approach will require further refinement to differentiate contagious, newly infected individuals from persons who have persistent viral fragments shedding in their stool outside the contagious period.

The Gendered Effects of Local Immigration Enforcement: Latinas' Social Isolation in Chicago, Houston, Los Angeles, and Phoenix.

The 2017 revitalization of the controversial Security Communities program, which requires local law enforcement to cooperate with federal immigration officials in the United States, has made it urgent to better understand such enforcement programs' effects on the well-being of Latinas/os, especially the foreign-born. Social isolation from increased immigration enforcement can have significant impacts on economic, social, and health outcomes among Latina/o immigrants and non-immigrants. This article analyzes the gendered impacts of different levels of increased local involvement in immigration enforcement on social isolation, using a survey of over 2000 Latinas/os in four large US cities, all considered to be traditional destinations. Unsurprisingly, respondents reported increased social isolation resulting from local law enforcement's involvement in immigration enforcement. In contrast to results from previous research, our analysis found that women and men were equally likely to feel socially isolated and that having children led to more social isolation for both women and men. Personal and vicarious experiences with immigration enforcement, as well as living in Phoenix and Houston - two urban areas with the strictest enforcement regimes - were strongly related to social isolation. Our results indicate that local authorities' increased involvement in immigration enforcement can lead to more social isolation for Latina immigrants, particularly those who have children, aligning their experiences with men's and, thus, undermining Latinas' previously recognized role as bridges between their families and social institutions and as community builders.

Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC-subtype diffuse large B-cell lymphoma.

The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Identification of novel nuclear targets of human thioredoxin 1.

The dysregulation of protein oxidative post-translational modifications has been implicated in stress-related diseases. Trx1 is a key reductase that reduces specific disulfide bonds and other cysteine post-translational modifications. Although commonly in the cytoplasm, Trx1 can also modulate transcription in the nucleus. However, few Trx1 nuclear targets have been identified because of the low Trx1 abundance in the nucleus. Here, we report the large-scale proteomics identification of nuclear Trx1 targets in human neuroblastoma cells using an affinity capture strategy wherein a Trx1C35S mutant is expressed. The wild-type Trx1 contains a conserved C32XXC35 motif, and the C32 thiol initiates the reduction of a target disulfide bond by forming an intermolecular disulfide with one of the oxidized target cysteines, resulting in a transient Trx1-target protein complex. The reduction is rapidly consummated by the donation of a C35 proton to the target molecule, forming a Trx1 C32-C35 disulfide, and results in the concurrent release of the target protein containing reduced thiols. By introducing a point mutation (C35 to S35) in Trx1, we ablated the rapid dissociation of Trx1 from its reduction targets, thereby allowing the identification of 45 putative nuclear Trx1 targets. Unexpectedly, we found that PSIP1, also known as LEDGF, was sensitive to both oxidation and Trx1 reduction at Cys 204. LEDGF is a transcription activator that is vital for regulating cell survival during HIV-1 infection. Overall, this study suggests that Trx1 may play a broader role than previously believed that might include regulating transcription, RNA processing, and nuclear pore function in human cells.

Antibiotic prescribing patterns for bacterial superinfection of mpox: A retrospective cohort study in an urban center.

Bacterial superinfection and antibiotic prescribing in the setting of the current mpox outbreak are not well described in the literature. This retrospective observational study revealed low prevalence (11%) of outpatient antibiotic prescribing for bacterial superinfection of mpox lesions; at least 3 prescriptions (23%) were unnecessary.

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension.

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.

Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target.

Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma

Evaluation of human enamel surfaces treated with theobromine: a pilot study.

PURPOSE: The objectives of this in-vitro study were to investigate the effect of theobromine, which is the principle xanthine species in Theobroma cacao, at two concentrations on the surface hardness and topography of human enamel. MATERIALS AND METHODS: Twenty-four freshly extracted human third molars were collected and stored in distilled water with 0.1% thymol solution at room temperature prior to the experiments. The enamel specimens were treated with one coat of theobromine at two concentrations (100 mg/l or 200 mg/l in distilled water) for 5 min. Enamel surfaces in the control group received no theobromine. They were then kept in distilled water for 1 week and subjected to SEM analysis. The specimens were demineralised by storing them in acidic hydroxyethylcellulose for three days. After baseline microhardness measurements, they were incubated either in 100 or 200 mg/l theobromine for 5 min. The control group was kept in distilled water. After washing the specimens under distilled water, they were kept in a remineralising solution for 18 h. Microhardness of the enamel surface was initially determined for each specimen before artificial demineralisation. After demineralisation, the experimental groups were incubated in 100 mg or 200 mg theobromine and control-group specimens were placed in remineralising solution. RESULTS: Enamel surfaces of the untreated control group presented a generally smooth and slightly hummocky surface with small lines of pits. Specimens treated with theobromine showed differences between the two concentrations. The group treated with 200 mg/l solution for 5 min showed a greater quantity of globules on enamel than did specimens treated with 100 mg/l solution. CONCLUSION: As shown by the microhardness values, a consistent and remarkable protection of the enamel surface was found with the application of theobromine.

Maternal sepsis caused by Listeria monocytogenes with a fatal fetal outcome.

Improving maternal and child health is a global priority. Although infection with Listeria monocytogenes (LM), a small facultative anaerobic, gram-positive motile bacillus is rare, when it infects the maternal-fetoplacental unit, it can result in adverse fetal sequelae such as chorioamnionitis, preterm labour, neonatal sepsis, meningitis and neonatal death. Pregnancy-associated listeriosis may present with a plethora of diverse, non-specific symptoms such as fever, influenza-like or gastrointestinal symptoms, premature contractions and preterm labour. It has a predilection for the second and third trimester of pregnancy, occurring sporadically or as part of an outbreak, most of which have involved unpasteurised dairy products, long shelf life products, contaminated ready-to-eat food, deli meats and soft cheeses. Strains belonging to the clonal complexes 1, 4 and 6 are hypervigilant and are commonly associated with maternal-neonatal infections. Maternal listeriosis occurs as a direct consequence of LM-specific placental tropism, which is mediated by the conjugated action of internalin A and internalin B at the placental barrier. The diagnosis is established from placental culture. Penicillin, ampicillin and amoxicillin are the antimicrobials of choice. It has a high fetal morbidity of up to 30%. The authors present the case of a multiparous woman in her early 20s presenting with sepsis and preterm premature rupture of her membranes at 21 weeks gestation. A live baby was delivered spontaneously and died shortly after birth. Placental cultures and postmortem examination were consistent with the diagnosis of disseminated Listeria infection. Due to the increased susceptibility of pregnant women for LM, a high index of clinical suspicion is required to establish the diagnosis and initiate appropriate antimicrobial therapy to reduce adverse fetal outcomes.

Integration of a Community Radiology Division into a Subspecialty-Focused Academic Radiology Department.

INTRODUCTION: Assimilate a general radiology division into a subspecialty-focused radiology department at an academic medical center. METHODS: This Institutional Review Board-approved quality improvement initiative was performed at an academic medical centers' subspecialty-focused academic radiology department, aiming to assimilate a general radiology division providing interpretive services for a distributed set of community ambulatory practices. An Oversight Committee charged by the department chair created a charter with unambiguous goal, timelines, clear decision-making, and conflict resolution processes. The Committee assessed the resources and clinical capabilities of the general radiologists, and the anticipated shift in exam volume from the community into subspecialty divisions. Primary outcome, percentage of targeted organ systems-specific interpretations by general radiologists based on assigned subspecialty division, and secondary outcome of report turnaround time (TAT) for all ambulatory exams, were compared before and after sub-specialization. RESULTS: Among 10 general radiologists, 4.5 were assigned to subspecialty divisions; 5.5 continued to cover an independent general radiology practice in a for-profit delivery network. In the 5 months' post-transition, a total 86.6% (11,668/13,477) of reports by the integrated general radiologists were within designated subspecialty divisions vs 23.9% (2,586/10,829) pre-transition (P < 0.01). There was no change in ambulatory radiology report TAT for non-urgent care center (UCC) or UCC exams pre- vs post-integration. DISCUSSION: A quality improvement initiative with unambiguous decision-making and conflict resolution processes incorporated a general radiology practice (radiologists and exams) into a subspecialty-focused academic radiology practice without negatively impacting TAT metrics. Future studies would be needed to assess impact on quality of interpretations.

SARS-COV2 placentitis and pregnancy outcome: A multicentre experience during the Alpha and early Delta waves of coronavirus pandemic in England.

Background: Pregnant women with SARS-CoV-2 infection experience higher rates of stillbirth and preterm birth. A unique pattern of chronic histiocytic intervillositis (CHI) and/or massive perivillous fibrin deposition (MPFD) has emerged, coined as SARS-CoV-2 placentitis. Methods: The aim of this study was to describe a cohort of placentas diagnosed with SARS-CoV-2 placentitis during October 2020-March 2021. Cases with a histological diagnosis of SARS-CoV-2 placentitis and confirmatory immunohistochemistry were reported. Maternal demographic data, pregnancy outcomes and placental findings were collected. Findings: 59 mothers delivered 61 infants with SARS-CoV-2 placentitis. The gestational age ranged from 19 to 41 weeks with most cases (78.6%) being third trimester. 30 infants (49.1%) were stillborn or late miscarriages. Obese mothers had higher rates of pregnancy loss when compared with those with a BMI <30 [67% (10/15) versus 41% (14/34)]. 47/59 (79.7%) mothers had a positive SARS-CoV-2 PCR test either at the time of labour or in the months before, of which 12 (25.5%) were reported to be asymptomatic. Ten reported only CHI, two cases showed MPFD only and in 48 placentas both CHI and MPFD was described. Interpretation: SARS-CoV2 placentitis is a distinct entity associated with increased risk of pregnancy loss, particularly in the third trimester. Women can be completely asymptomatic and still experience severe placentitis. Unlike 'classical' MPFD, placentas with SARS-CoV-2 are generally normal in size with adequate fetoplacental weight ratios. Further work should establish the significance of the timing of maternal SARS-CoV-2 infection and placentitis, the significance of SARS-CoV2 variants, and rates of vertical transmission associated with this pattern of placental inflammation. Funding: There was not funding associated with this study.

The sustainability-peace nexus in crisis contexts: how the Rohingya escaped the ethnic violence in Myanmar, but are trapped into environmental challenges in Bangladesh.

Because of ethnic and cultural violence in Myanmar, approximately a million Rohingya fled to neighboring Bangladesh starting from August 2017, in what the UN has called a "textbook example of ethnic cleansing". Those arriving in Bangladesh were able to escape decade-long ethnic violence in Myanmar, but the Rohingya's immediate destination, Cox's Bazar district is one of the most climate-vulnerable and disaster-prone areas in Bangladesh. Currently, they have been subjected to extreme rainfalls, landslides, and flashfloods. With the COVID-19 pandemic, they continue to face fear and further marginalization in resource-constrained Bangladesh, as well as increased vulnerability due to tropical cyclones, flashfloods, and landslides. The Rohingya in southeast Bangladesh are now at the epicenter of a humanitarian and sustainability crisis. However, their situation is not entirely unique. Millions of displaced, stateless or refugees around the world are facing multi-dimensional crises in various complex geopolitical, and climatic situations. Using the theoretical lens of political ecology and critical development studies, this paper analyzes the sustainability-peace nexus for millions of Rohingya in Myanmar and in Bangladesh. This paper is based on information from various sources, including three ethnographic field visits in recent years, which helped to get local insights into the current sustainability challenges in this humanitarian context. The core arguments of this paper suggest that sustainability-peace nexus will especially be compromised in climate-vulnerable resource-constrained conditions. To overcome this challenge, decolonizing Rohingya solutions would be critical, by engaging the Rohingya in the process of development and meaningful change, which can affect their lives, livelihoods, and wellbeing. Even though this paper has a specific geographical focus, the insights are relevant in parts of the world facing similar social, economic, political, and environmental challenges.

Strengthening the clinical research workforce through a competency-based orientation program: Process outcomes and lessons learned across three academic health institutions.

Clinical research coordinators are increasingly tasked with a multitude of complex study activities critical to scientific rigor and participant safety, though more than half report not receiving appropriate training. To determine the reproducibility of an established clinical research workforce orientation program, collaborative partners across Clinical and Translational Science Award institutions seeded core principles and structure from Mayo Clinic's Clinical Research Orientation program within Penn State University and the University of Mississippi Medical Center from 2019 to 2021. Training concepts were established and tied to those domains deemed critical by the Joint Task Force for Clinical Trial Competency for the conduct of clinical research at the highest levels of safety and quality possible. Significant knowledge and confidence gains and high overall program satisfaction were reported across participants and partner sites, despite programs being required to pivot from traditional, in-person formats to entirely virtual platforms as a result of the COVID-19 pandemic. The successful standardization and translation of foundational clinical research training has important efficiency and efficacy implications for research enterprises across the USA.

Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema.

BACKGROUND: Angioedema is a rare adverse effect of angiotensin-converting enzyme (ACE) inhibitors, which occurs more commonly in women and black Americans. Angioedema is thought to result from decreased degradation of vasoactive peptides. During ACE inhibition, bradykinin is primarily inactivated by aminopeptidase P (APP). Earlier studies have provided conflicting data with regard to serum APP activity in patients with a history of ACE inhibitor-associated angioedema. A single nucleotide polymorphism, -2399C>A (rs3788853, C-2399A), in XPNPEP2, the X-linked gene that encodes membranous APP, has been reported to associate with APP activity. OBJECTIVE: To test the hypothesis that the relationship between XPNPEP2 C-2399A genotype and APP activity or ACE inhibitor-associated angioedema is sex-dependent and race-dependent. METHODS: We compared C-2399A genotype frequencies in 169 cases with a history of ACE inhibitor-associated angioedema and 397 ACE inhibitor-exposed controls. Controls were prespecified to be 50% white, 50% black, and 50% women. Cases and controls were group matched for age and smoking. RESULTS: XPNPEP2 C-2399A genotype associated with serum APP activity in both men and women. Serum APP activity was lower in men than in women, independent of genotype. XPNPEP2 -2399 A/ genotype was associated with an increased risk of angioedema in men [odds ratio 2.17 (1.09-4.32), P=0.03] in multivariate analysis. The A/ genotype was associated with angioedema in black men (P=0.03) but not in white men. CONCLUSION: APP activity is lower in men and the XPNPEP2 C-2399A polymorphism associates with ACE inhibitor-associated angioedema in men but not women.

Normal Iron Homeostasis Requires the Transporter SLC48A1 for Efficient Heme-Iron Recycling in Mammals.

In mammals over 65% of the total body iron is located within erythrocytes in the heme moieties of hemoglobin. Iron homeostasis requires iron absorbed from the diet by the gut as well as recycling of iron after the destruction of senescent erythrocytes. Senescent erythrocytes are engulfed by reticuloendothelial system macrophages where hemoglobin is broken down in the lysosomes, releasing heme for iron recovery in the cytoplasm. We recently showed that the SLC48A1 protein is responsible for transporting heme from the lysosome to the cytoplasm. CRISPR generated SLC48A1-deficient mice accumulate heme in their reticuloendothelial system macrophages as hemozoin crystals. Here we describe additional features of SLC48A1-deficient mice. We show that visible hemozoin first appears in the reticuloendothelial system macrophages of SLC48A1-deficient mice at 8 days of age, indicating the onset of erythrocyte recycling. Evaluation of normal and SLC48A1-deficient mice on iron-controlled diets show that SLC48A1-mediated iron recycling is equivalent to at least 10 parts per million of dietary iron. We propose that mutations in human SLC48A1 could contribute to idiopathic iron disorders.