Hemoglobin Receptor Research Articles

Serum homocysteine and left ventricular hypertrophy in adults with chronic kidney disease: A case–control study

Hyperhomocysteinemia (serum homocysteine concentration > 15 μmol/L) is of high prevalence in chronic kidney disease (CKD). And myocardial hypertrophy is a common complication of CKD. Given that both hyperhomocysteinemia and cardiac hypertrophy have an association with CKD, we hypothesized that high level of plasma homocysteine (Hcy) is associated with a higher prevalence of ventricular hypertrophy(LVH) in adults with CKD. The registration number of the case-control study is ChiCTR2200064834. The information of inpatients with CKD including Echocardiograms and analysis of plasma Hcy concentrations were collected. We performed linear and logistic regression to investigate the association of plasma Hcy with left ventricular hypertrophy (LVH) (LVMI ≥ 95th percentile), adjusted for levels of hemoglobin, ferritin, cystatin C and β-adrenergic blocker therapy. Further, a stratified analysis of the relationship between plasma Hcy and LVH was carried out according to eGFR. The case records for 1068 inpatients with CKD were collected. After data soring and case-control matching, there were 374 samples screened for statistical analysis. Univariate logistic regression indicated a high level of serum Hcy had an association with LVH (OR, 1.16; 95% CI, 1.11–1.20). Finally, multivariable logistic regression suggested that hyperhomocysteinemia was independently associated with LVH (OR, 1.14; 95% CI, 1.10–1.19) after adjustment for hemoglobin, ferritin, cystatin C, and β-adrenergic receptor blocker therapy. We constructed a predicting model including the variable of Hcy for cardiac hypertrophy in CKD. The model had an area under the ROC curve (AUC) of 0.86 (95% CI: 0.82–0.89, P < .001). The decision curve analysis (DCA) showed a superior net clinical benefit of model with Hcy over model without Hcy. Elevated level of serum Hcy is closely associated with LVH in adults with CKD.

Physiologically based trimester-specific serum ferritin thresholds for iron deficiency in US pregnant women

AbstractSerum ferritin (SF) concentration is the most widely used indicator for iron deficiency (ID). During pregnancy, the World Health Organization recently recommended SF thresholds for ID of <15 μg/L for the first trimester of pregnancy, based on expert opinion, and made no recommendations for the second and third trimesters. We examined the relationship of SF with 2 independent indicators of the onset of iron-deficient erythropoiesis, hemoglobin and soluble transferrin receptor 1, in cross-sectional data from US National Health and Nutrition Examination Survey for 1999 to 2010 and 2015 to 2018. We included 1288 pregnant women aged 15 to 49 years and excluded women with inflammation or potential liver disease. We used restricted cubic spline (RCS) regression analysis to determine SF thresholds for iron-deficient erythropoiesis. SF decreased during pregnancy; geometric mean SF was higher during the first and lower during the second and third trimesters. Using RCS analysis, the SF thresholds identified during pregnancy were <25.8 μg/L (18.1-28.5) during first trimester, <18.3 μg/L (16.3-22.9) during second trimester, and <19.0 μg/L (14.4- 26.1) during third trimester. These SF threshold levels track concentrations of hepcidin, the iron-regulatory hormone controlling the mobilization of iron stores. An SF concentration of <15 μg/L as the criterion for ID may underestimate the true prevalence of ID throughout pregnancy. In our study, an additional 1 of every 10 pregnant women would be recognized as iron deficient by using the physiologically based thresholds at SF of ∼25 μg/L during the first and ∼20 μg/L during the second and third trimesters.

A Haemophilus ducreyi strain lacking the yfeABCD iron transport system is virulent in human volunteers.

Haemophilus ducreyi causes the genital ulcer disease chancroid and painful cutaneous ulcers in children who live in the tropics. To acquire heme from the host, H. ducreyi expresses a TonB-dependent hemoglobin receptor, HgbA, which is necessary and sufficient for H. ducreyi to progress to the pustular stage of disease in a controlled human infection model. HgbA transports hemoglobin across the outer membrane; how heme is transported across the cytoplasmic membrane is unclear. In previous studies, transcripts encoding the YfeABCD heme transporter were upregulated in experimental lesions caused by H. ducreyi in human volunteers, suggesting the latter may have a role in virulence. Here we constructed a double deletion mutant, 35000HPΔyfeABΔyfeCD, which exhibited growth defects relative to its parent 35000HP in media containing human hemoglobin as an iron source. Five human volunteers were inoculated at three sites on the skin overlying the deltoid with each strain. The results of the trial showed that papules formed at 100% (95% CI, 71.5, 100) at both 35000HP and 35000HPΔyfeABΔyfeCD-inoculated sites (P = 1.0). Pustules formed at 60% (95% CI, 25.9, 94.1) at parent-inoculated sites and 53% (95% CI, 18.3, 88.4) at mutant-inoculated sites (P = 0.79). Thus, the ABC transporter encoded by yfeAB and yfeCD was dispensable for H. ducreyi virulence in humans. In the absence of YfeABCD, H. ducreyi likely utilizes other periplasmic binding proteins and ABC-transporters such as HbpA, SapABCDF, and DppBCDF to shuttle heme from the periplasm into the cytoplasm, underscoring the importance of redundancy of such systems in gram-negative pathogens.

Выявление и профилактика железодефицитного состояния у доноров крови (компонентов крови)

The problem of iron deficiency among donors is relevant and directly affects the provision of hemocomponents to the blood service. Donors, being a risk group for the development of iron deficiency, are examined before donation, including a study of hemoglobin levels. However, there is no information about the state of iron stores, when depleted, iron deficiency anemia develops. In turn, anemia is a contraindication to donation and, therefore, leads to medical exemptions from donation. The purpose of the study was to evaluate the main indicators of iron metabolism in donors of blood and (or) blood components at risk of developing latent iron deficiency. The examination of 174 donors included a hemogram, assessment of the level of hemoglobin, serum ferritin (SF), transferrin, and soluble transferrin receptors. When assessing the intensity of changes in reserve and transport iron indicators, 228 deviations from the reference range were analyzed. The criterion for the risk of developing iron deficiency was hemoglobin values at the lower limit of normal (130–135 g/l in men and 120–125 g/l in women) and the threshold level of ferritin (30 μg/l in male donors and 20 μg/l in women). The risk group included 58.3% of young donors — women who donate blood 1–2 times during the year (p &lt; 0.01) and 66.6% (p &lt; 0.01) of donors — men who donate blood regularly throughout 4 and &gt; years. The average ferritin level in male donors was 27.37 μg/l (p &lt; 0.02) and lower than the reference values. It is concluded that it is advisable to assess the indicators of iron metabolism in donors in the case of borderline hemoglobin levels, in women of reproductive age after 2 blood donations and in men with the number of donations ≥ 10. To replenish the iron depot in the body, when iron deficiency is detected in donors, it is necessary to consider the issue of prevention.

Hemoglobin Receptor CD163 As a Potential Biomarker of Hemolysis Induced Hepatobiliary Injury in Sickle Cell Disease

Sickle cell disease (SCD) associated chronic hemolysis promotes oxidative stress, inflammation and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD related hepatobiliary injury has not been fully elucidated yet. Here, we show that chronic liver injury in SCD mice and patients is associated with elevated levels of hepatic CD163. Hemolysis and increase in hepatic heme, hemoglobin, iron and haptoglobin levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that HO-1 positively regulates CD163 expression and that HO-1 and NRF2 form a complex with CD163 in the SCD liver. Finally, we demonstrate that blocking CD163 activity promotes hemolysis induced liver injury in SCD. These findings indicate that CD163 is a mediator and a potential biomarker of SCD associated hepatobiliary injury. Understanding the role of HO-1 in CD163 regulation may help identify novel therapeutic targets for hemolysis induced chronic liver injury.

Modulation of TGF-β Superfamily Signaling By Ker-050 Demonstrated Potential to Treat Myelofibrosis and Mitigate Ruxolitinib-Associated Cytopenia

Background: Myelofibrosis (MF) is a disorder characterized by unrestrained proliferation of myeloid precursors and dysfunctional Janus kinase (JAK) signaling. Fibroblast proliferation, bone remodeling, and marrow fibrosis within the osteohematopoietic niche (OHN) result in ineffective and extramedullary hematopoiesis. Clinical manifestations include anemia, splenomegaly, and often disabling symptoms. JAK inhibitors, such as ruxolitinib, have been shown to improve spleen size and symptoms but are associated with dose-limiting cytopenia, reducing their utility for many patients. KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) to address ineffective hematopoiesis by promoting differentiation of erythroid and megakaryocytic precursors. Here, we present new data from an ongoing Phase 2 study (NCT05037760) evaluating KER-050 as a monotherapy and in combination with ruxolitinib in participants with MF. Methods: This ongoing Phase 2 study is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of KER-050 administered with or without ruxolitinib in participants with anemia and primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Part 1 involves parallel dose escalation arms (1A: monotherapy, 1B: combination with ruxolitinib) to identify the dose(s) of KER-050 to be evaluated in Part 2. Data are presented as of the data cutoff date of April 3, 2023. Results: A total of 24 participants were enrolled (n=12 in Arm 1A and n=12 in 1B). One participant recently enrolled in Arm 1B at dose level III (3.0 mg/kg) had limited exposure at the time of data cutoff and is not included in the PD findings reported below. All participants met the criteria for higher-risk disease by DIPSS and 41.7% met IWG 2013 transfusion-dependent (TD) criteria (Table 1). The median duration of KER-050 treatment was 116 days (range 26 to 474), with 62.5% of participants ongoing as of the cutoff date. Most participants (91.7%) had at least 1 treatment-emergent adverse event (TEAE). No dose-limiting toxicities and no treatment-related severe or serious TEAEs have been observed. Most frequently observed TEAEs in ≥15% of participants were fatigue (including asthenia) (37.5%), and diarrhea (20.8%). Mean increases in hemoglobin (Hgb), reticulocytes, and soluble transferrin receptor (sTfR) were observed over the first 12 weeks of treatment in non-TD (NTD) participants for whom changes in markers of erythropoiesis were less confounded by ongoing transfusions (Figure 1). Overall, 7 of 13 (53.8%) NTD participants achieved a mean Hgb increase of ≥1.0 g/dL over the first 12 weeks and 2 of 13 (15.4%) achieved an increase of ≥1.5 g/dL. Increases in Hgb were also observed among TD participants, with 3/10 (30%) having a Hgb increase ≥1 g/dL over the first 12 weeks and one participant achieving a transfusion reduction ≥50% over at least 12 weeks (data not shown). For this participant (dose level I, Arm 1B), transfusion burden decreased from 9 red blood cell (RBC) units/12 weeks at baseline to 2 RBC units/12 weeks. Another participant (dose level I, Arm 1B), who received 4 RBC units/12 weeks at baseline, achieved a 20-week transfusion-free period with concomitant increases in Hgb, sTfR and platelets. Across treatment arms, platelet values were generally maintained if not increased. Additionally, for one participant receiving KER-050 monotherapy (dose level I), spleen size decreased by 38% from 2569 cm 3 at baseline to 1592 cm 3 at 24 weeks, coinciding with a 55% reduction in MF-SAF-TSS score from 56 to 25. Summary: Preliminary data from this ongoing Phase 2 study suggest that KER-050 is generally well tolerated and support the potential of KER-050 to improve key aspects of MF, including cytopenia, spleen size, and symptoms. Despite data being limited thus far to the 2 lowest dose levels, encouraging increases in markers of hematopoiesis have been observed as well as an initial case of reduced spleen size in a participant receiving KER-050 monotherapy. Updated analyses available at the time of presentation will provide further insight into the potential of KER-050 to treat MF and mitigate ruxolitinib-associated cytopenia.

Iron metabolism disorders of patients with chronic paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is caused by Paracoccidioides spp.; during infection, some host mechanisms limit the availability of iron, thereby reducing its reproduction. However, Paracoccidioides spp. can evade the immune defense and, even under limited iron conditions, use this mineral for growth and dissemination. This study evaluated the iron metabolism of 39 patients who were diagnosed with chronic PCM from 2013 to 2021. The forms of iron before treatment and at the time of clinical cure were evaluated based on the following: serum ferritin levels (storage iron); total iron-binding capacity (TIBC) and transferrin saturation (TSAT) level (transport iron); red blood cell (RBC), hemoglobin (Hb), hematocrit (HCT), and soluble transferrin receptor (sTfR) levels; and sTfR/log ferritin ratio (functional iron). The mean age of the patients was 54.5 years (±6.7 years). Most patients were men (97.4%), rural workers (92.1%), and smokers (84.6%); furthermore, most had moderate disease severity (66.7%). After achieving clinical cure, we observed that serum ferritin levels decreased, and parameters of functional iron increased. The extent of alteration in these parameters were more pronounced in severe cases than in to mild or moderate cases. Furthermore, moderate correlations were observed between C-reactive protein and the Hb (r = -0.500; p = 0.002), RBC (r = -0.461; p = 0.005), HCT (r = -0.514; p = 0.001), and iron levels (r = -0.491; p = 0.002). However, it is possible to infer that PCM interferes with functional and storage iron because improvements in these parameters after treatment as well as associations with disease severity were observed. PCM can lead to anemia of inflammation, which can be differentiated from iron deficiency anemia by a careful investigation of the iron form parameters.

Targeting hemoglobin receptors IsdH and IsdB of Staphylococcus aureus with a single VHH antibody inhibits bacterial growth

Methicillin-resistant Staphylococcus aureus, or MRSA, is one of the major causative agents of hospital-acquired infections worldwide. Novel antimicrobial strategies efficient against antibiotic-resistant strains are necessary and not only against S.aureus. Among those, strategies that aim at blocking or dismantling proteins involved in the acquisition of essential nutrients, helping the bacteria to colonize the host, are intensively studied. A major route for S.aureus to acquire iron from the host organism is the Isd (iron surface determinant) system. In particular, the hemoglobin receptors IsdH and IsdB located on the surface of the bacterium are necessary to acquire the heme moiety containing iron, making them a plausible antibacterial target. Herein, we obtained an antibody of camelid origin that blocked heme acquisition. We determined that the antibody recognized the heme-binding pocket of both IsdH and IsdB with nanomolar order affinity through its second and third complementary-determining regions. The mechanism explaining the inhibition of acquisition of heme invitro could be described as a competitive process in which the complementary-determining region 3 from the antibody blocked the acquisition of heme by the bacterial receptor. Moreover, this antibody markedly reduced the growth of three different pathogenic strains of MRSA. Collectively, our results highlight a mechanism for inhibiting nutrient uptake as an antibacterial strategy against MRSA.

Prognostic value of lipid profile in adult hemophagocytic lymphohistiocytosis.

Adult secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare clinical syndrome with a high mortality rate. Currently, there are no feasible prognostic factors to clinically predict untreated sHLH patients' prognosis. Our objective was to characterize the lipid profile of adult sHLH patients and to determine the relationship with overall survival. We retrospectively analyzed 247 patients with newly diagnosed sHLH from January 2017 to January 2022 according to the HLH-2004 criteria. Multivariate Cox regression analyses and restricted cubic splines were conducted to evaluate the prognostic value of the lipid profile. The median age of all patients was 52 years, and the commonest cause of sHLH in our cohort was malignancy. During a median follow-up of 88 (interquartile ranges, 22-490) days, 154 deaths occurred. The univariate analysis confirmed total cholesterol (TC) ≤ 3 mmol/L, triglycerides (TG) > 3.08 mmol/L, high-density lipoprotein cholesterol (HDL-c) ≤ 0.52 mmol/L, and low-density lipoprotein cholesterol (LDL-c) ≤ 2.17 mmol/L were associated with an inferior survival. In a multivariate model, HDL-c, hemoglobin, platelet, fibrinogen, and soluble interleukin-2 receptor were considered as independent factors. Additionally, the restricted cubic spline analyses indicated an inverse linear association between HDL-c and the risk of mortality in sHLH. Lipid profiles, which were low-cost and readily available promising biomarkers, were strongly associated with the overall survival in adult sHLH patients.

Synthesis of 4-Amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)one-[1,2,3]triazolebenzenesulphonamide Bioactive Hybrids as Novel Therapeutic Agents

A novel 1H-pyrazol[1,2,3]triazole-benzenesulphonamide hybrids (7a-o) were synthesized with benzenesulfonamide and substituted aromatic azides/benzyl azides by Click reaction conditions using Cu(II) and aqueous sodium ascorbate as an inexpensive catalyst in the solvent ratio 1:1 H2O-tBu-OH around 12-14 h at room temperature with high yields (81-92%) under eco-friendly conditions. These newly designed hybrids were characterized by IR, 1H NMR and mass spectroscopic studies. These hybrids were also screened for in vitro antimicrobial activities and correlated with molecular docking studies. Among the derivatives, compound 7c was found to be a potent antibacterial and antifungal agents with minimum inhibition concentration (MIC) of in vitro values were compared with standard molecules. The docking studies of these derivatives revealed that compound 7c having greater binding affinity against the drug target haemoglobin receptor IsdB (3RTL) and it was confirmed by the in vitro screening.

Spatial distribution and identifying biochemical factors affecting haemoglobin levels among women of reproductive age for each province in Indonesia: A geospatial analysis.

Anaemia is still a public health problem in Indonesia. The iron supplement program, known as Tablet Tambah Darah (Blood Add Tablet) has not yet produced optimal results. This study aimed to identify the cause of anaemia and the factors that influence it. Biochemical indicator data are haemoglobin (Hb), C-reactive protein (CRP), ferritin and serum transferrin receptor (sTfR) from 9,463 women of reproduction age. Data from the Basic Health Research (Riskesdas) project of 2013 were used for the study. ANOVA as well as global and local regression approaches (classical regression and geo-weighted regression) were used to compare the mean Hb and CRP values between provinces and to determine the factors that influence Hb concentrations. The results showed that the distribution of anaemia in Indonesia is uneven and not always caused by iron deficiency. The lowest Hb mean coupled with the highest iron deficiency was found in Papua, where there are high rates of parasitic infections. In contrast, the highest mean Hb coupled with low iron deficiency, and also low infection rates, was found in North Sulawesi. The Hb concentrations were significantly associated by ferritin, CRP and sTfR and there were varying magnitudes between provinces. Although anaemia is mainly influenced by the iron concentration, CRP, ferritin and sTfR can also affect it through their association with inflammatory reactions. Identification of all causes of anaemia in each province needs to be done in the future, while blanket iron supplementation should be reviewed.

Levels of TNF-α and Soluble TNF Receptors in Normal-Weight, Overweight and Obese Patients with Dilated Non-Ischemic Cardiomyopathy: Does Anti-TNF Therapy Still Have Potential to Be Used in Heart Failure Depending on BMI?

We sought to measure the levels of adipokines, TNF-α and soluble receptors (sTNFr1, sTNFr2) in heart failure patients with reduced ejection fraction (HFrEF) due to non-ischemic cardiomyopathy (nDCM). A total of 123 patients with HFrEF due to nDCM were divided into three groups according to BMI: 34 (27.6%) normal weight, 56 (45.5%) overweight and 33 (26.8%) obese. A six-minute walk test, echocardiography and right heart catheterization were performed. Serum concentrations of adiponectin, leptin, NT-proBNP, blood hemoglobin, sodium, creatinine, ALAT, AspAT, bilirubin, CRP, lipids, TNF-α, sTNFr1 and sTNFr2 receptors were measured. Obese patients had the lowest NT-proBNP concentrations, significantly higher leptin levels and higher leptin/adiponectin ratios. The concentration of sTNFr1 was higher in normal-weight patients. In all groups, TNF-α concentrations correlated positively with sTNFr1 (p &lt; 0.001). Higher levels of sTNFr1 were associated with higher sTNFr2 (p &lt; 0.001) and CRP (p &lt; 0.001). Moreover, the concentration of sTNFr2 positively correlated with CRP (p &lt; 0.05) and adiponectin (p &lt; 0.001). Levels of TNF-α were not associated with elevated CRP. This study demonstrated that changes in the concentrations of TNF and its receptors differ between groups of patients with different BMI. These findings suggest that the effective use of anti-TNF therapy is dependent not only on BMI, but also on concentrations of TNF-α receptors and other laboratory parameters.

Formulation and Effect of Iron Fortified Instant Bose Corn on Addressing Anemia among Adolescent Girls in Kupang, Indonesia.

This study aimed to develop Fe-fortified instant Bose corn (IBC), a traditional Timorese food, as a strategy to address anemia among adolescent girls in Kupang, Indonesia. Instant corn and cowpea grits were made to shorten the preparation time with various times of soaking (IBC1=10 min; IBC2=15 min; IBC3=20 min) to select the best formula. The selected IBC was then fortified with NaFeEDTA·3H2O and nutrient content was evaluated. In the intervention study, a pre-post controlled trial was applied to 40 anemic adolescent girls aged 16∼19 years. Subjects with severe anemia (Hb=8.5∼10.4 g/dL) received the fortified selected IBC, whereas those with moderate anemia (Hb=10.5∼11.5 g/dL) received the unfortified selected IBC. A total of 100 g IBC were provided three times/week for 2 months. The hemoglobin and soluble transferrin receptor (sTfR) levels were measured at baseline and endline, respectively. IBC3 produced the highest acceptance level as compared to other formulas. The fortified IBC3 met 127.4% recommended dietary allowances for iron. Moreover, both fortified and unfortified IBC3 significantly increased the hemoglobin levels of adolescent girls with the higher improvement found in the group of fortified IBC3 (1.73±1.21 g/dL; P<0.05). However, the beneficial effects of the fortified IBC3 could not be observed on sTfR levels. Since the effect on Hb levels was significant with less effect, the intervention of IBC3 for only 2 months did not adequate to improve sTfR levels. Nevertheless, this study suggests that Fe-fortified IBC may be effective in preventing anemia among adolescent girls in Kupang, Indonesia.

A Three-Protein Panel to Support the Diagnosis of Sepsis in Children.

Sepsis is a syndrome without a standard validated diagnostic test. Early recognition is crucial. Serum proteome analysis in children with sepsis may identify new biomarkers. This study aimed to find suitable blood biomarkers for an early diagnosis of sepsis. An analytical observational case-control study was carried out in a single center. Children admitted to a Pediatric Intensive Care Unit with clinical diagnosed sepsis were eligible for study. A proteomic analysis conducted by mass spectrometry was performed. Forty patients with sepsis and 24 healthy donors were recruited. Proteomics results revealed 44 proteins differentially expressed between patients and healthy controls. Six proteins were selected to be validated: lactoferrin, serum amyloid-A1 (SAA-1), complement factor B, leucine-rich alpha-2 glycoprotein (LRG1), soluble interleukin-2 alpha chain receptor (sCD25) and soluble haptoglobin–hemoglobin receptor. Our results showed that sCD25, SAA-1, and LRG1 had high levels of specificity and sensitivity, as well as an excellent area under the ROC curve (>0.9). Our study provides a serum proteomic analysis that identifies new diagnostic biomarkers in sepsis. SAA-1, sCD25 and LRG1 were able to separate septic from healthy donor, so they could be used together with other clinical and analytical features to improve sepsis diagnosis in children.

Prenatal alcohol-related alterations in maternal, placental, neonatal, and infant iron homeostasis

Prenatal alcohol exposure (PAE) is associated with postnatal iron deficiency (ID), which has been shown to exacerbate deficits in growth, cognition, and behavior seen in fetal alcohol spectrum disorders. However, the mechanisms underlying PAE-related ID remain unknown. We aimed to examine biochemical measures of iron homeostasis in the mother, placenta, neonate, and 6.5-month-old infant. In a prenatally recruited, prospective longitudinal birth cohort in South Africa, 206 gravidas (126 heavy drinkers and 80 controls) were interviewed regarding alcohol, cigarette, and drug use and diet at 3 prenatal visits. Hemoglobin, ferritin, and soluble transferrin receptor (sTfR) were assayed twice during pregnancy and urinary hepcidin:creatinine was assayed once. Infant ferritin and hemoglobin were measured at 2 weeks and 6.5 months and sTfR was measured at 6.5 months. Histopathological examinations were conducted on 125 placentas and iron transport assays (iron regulatory protein-2, transferrin receptor-1, divalent metal transporter-1, ferroportin-1, and iron concentrations) were conducted on 63. In multivariable regression models, prenatal drinking frequency (days/week) was related to higher maternal hepcidin and to sequestration of iron into storage at the expense of erythropoiesis in mothers and neonates, as evidenced by a lower hemoglobin (g/dL)-to-log(ferritin) (ug/L) ratio [mothers: raw regression coefficient (β) = -0.21 (95% CI: -0.35 to -0.07); neonates: β = -0.15 (95% CI: -0.24 to -0.06)]. Drinking frequency was also related to decreased placental ferroportin-1:transferrin receptor-1 (β = -0.57 for logged values; 95% CI: -1.03 to -0.10), indicating iron-restricted placental iron transport. At 6.5 months, drinking frequency was associated with lower hemoglobin (β = -0.18; 95% CI: -0.33 to -0.02), and increased prevalences of ID (β = 0.09; 95% CI: 0.02-0.17) and ID anemia (IDA) (β = 0.13; 95% CI: 0.04-0.23). In causal inference analyses, the PAE-related increase in IDA was partially mediated by decreased neonatal hemoglobin:log(ferritin), and the decrease in neonatal hemoglobin:log(ferritin) was partially mediated by decreased maternal hemoglobin:log(ferritin). In this study, greater PAE was associated with an unfavorable profile of maternal-fetal iron homeostasis, which may play mechanistic roles in PAE-related ID later in infancy.

Physiologically based serum ferritin thresholds for iron deficiency in children and non-pregnant women: a US National Health and Nutrition Examination Surveys (NHANES) serial cross-sectional study

Serum ferritin concentrations are the most widely used indicator for iron deficiency. WHO determined that insufficient data are available to revise the serum ferritin thresholds of less than 12 μg/L for children and less than 15 μg/L for women, which were developed on the basis of expert opinion, to define iron deficiency. We aimed to derive new physiologically based serum ferritin concentration thresholds for iron deficiency in healthy young children and non-pregnant women using data from the US National Health and Nutrition Examination Survey (NHANES). In this serial cross-sectional study, we examined the relationship of serum ferritin with two independent indicators of iron-deficient erythropoiesis, haemoglobin and soluble transferrin receptor (sTfR), in children (12-59 months) and non-pregnant women (15-49 years) using cross-sectional NHANES data from 2003-06, 2007-10, and 2015-18. NHANES is a US national stratified multistage probability sample that includes a household interview followed by a standardised physical examination in a mobile examination centre. We excluded individuals with missing serum ferritin, sTfR, haemoglobin, or white blood cell counts measurements; non-pregnant women with missing C-reactive protein (CRP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) data were also excluded. In addition, individuals with infection (white blood cell counts >10·0×109/L) and non-pregnant women with possible liver disease (ALT >70 IU/L or AST >70 IU/L) and inflammation (CRP >5·0 mg/L) were excluded. We examined distributions of haemoglobin and sTfR with serum ferritin and used restricted cubic spline regression models to determine serum ferritin thresholds for iron-deficient erythropoiesis. 5964 children and 10 462 non-pregnant women had physical examinations and were screened for inclusion in the study, of whom 2569 (43·1%) children and 7498 (71·7%) non-pregnant women were included. At lower serum ferritin concentrations, median haemoglobin concentration decreased as sTfR concentration increased, with each varying in a curvilinear manner. Using restricted cubic spline plateau points to determine the onset of iron-deficient erythropoiesis, the serum ferritin thresholds identified by haemoglobin and sTfR concentrations were not different. For children, the haemoglobin identified serum ferritin threshold was 19·9 μg/L (95% CI 18·8-22·6) and the sTfR identified serum ferritin threshold was 20·0 μg/L (19·4-20·9; p=0·89). For women the haemoglobin identified serum ferritin threshold was 25·2 μg/L (24·2-26·2) and the sTfR identified serum ferritin threshold was 24·0 μg/L (23·3-24·6; p=0·05). The association between two independent indicators of iron-deficient erythropoiesis, haemoglobin and sTfR, identified serum ferritin concentration thresholds of about 20 μg/L for children and 25 μg/L for non-pregnant women, providing physiological evidence of potential new thresholds for consideration when determining the prevalence and distribution of iron deficiency in populations. In healthy children and non-pregnant women, physiologically based thresholds for iron deficiency might be more clinically and epidemiologically relevant than those based on expert opinion. Validation of this physiologically based approach in non-US populations might help the international harmonisation of serum ferritin thresholds for iron deficiency. None.

Effect of Fortification with Multiple Micronutrient Powder on the Prevention and Treatment of Iron Deficiency and Anaemia in Brazilian Children: A Randomized Clinical Trial.

Fortification with multiple micronutrient powder has been proposed as a public health intervention able to reduce micronutrient deficiencies in children. Our objective was to compare the effectiveness of fortification with multiple micronutrient powder with drug supplementation in the prevention and treatment of iron deficiency and anaemia. This was a cluster trial with anemic and non-anaemic children between six and 42 months old, in randomization data. Non anaemic children received fortification with multiple micronutrient powder or standard drug supplementation of ferrous sulfate associated with folic acid in a prevention dose. Anaemic children who were randomized to receive multiple micronutrient powder also received the recommended iron complementation for anaemia treatment. A total of 162 children were evaluated. The prevalence of anaemia decreased from 13.58 to 1.85%. Iron deficiency decreased from 21.74% to 7.89% (by serum ferritin) and iron deficiency decreased from 66.81 to 38.27% (by soluble transferrin receptor). No difference was identified between interventions for hemoglobin (p = 0.142), serum ferritin (p = 0.288), and soluble transferrin receptor (p = 0.156). Fortification with multiple micronutrient powder was effective in preventing iron deficiency and anaemia in children aged six to 48 months. In anaemic children; it was necessary to supplement the dose of multiple micronutrient powder with ferrous sulfate.

Nutritional Implications of Baby-Led Weaning and Baby Food Pouches as Novel Methods of Infant Feeding: Protocol for an Observational Study.

BackgroundThe complementary feeding period is a time of unparalleled dietary change for every human, during which the diet changes from one that is 100% milk to one that resembles the usual diet of the wider family in less than a year. Despite this major dietary shift, we know relatively little about food and nutrient intake in infants worldwide and virtually nothing about the impact of baby food “pouches” and “baby-led weaning” (BLW), which are infant feeding approaches that are becoming increasingly popular. Pouches are squeezable containers with a plastic spout that have great appeal for parents, as evidenced by their extraordinary market share worldwide. BLW is an alternative approach to introducing solids that promotes infant self-feeding of whole foods rather than being fed purées, and is popular and widely advocated on social media. The nutritional and health impacts of these novel methods of infant feeding have not yet been determined.ObjectiveThe aim of the First Foods New Zealand study is to determine the iron status, growth, food and nutrient intakes, breast milk intake, eating and feeding behaviors, dental health, oral motor skills, and choking risk of New Zealand infants in general and those who are using pouches or BLW compared with those who are not.MethodsDietary intake (two 24-hour recalls supplemented with food photographs), iron status (hemoglobin, plasma ferritin, and soluble transferrin receptor), weight status (BMI), food pouch use and extent of BLW (questionnaire), breast milk intake (deuterium oxide “dose-to-mother” technique), eating and feeding behaviors (questionnaires and video recording of an evening meal), dental health (photographs of upper and lower teeth for counting of caries and developmental defects of enamel), oral motor skills (questionnaires), and choking risk (questionnaire) will be assessed in 625 infants aged 7.0 to 9.9 months. Propensity score matching will be used to address bias caused by differences in demographics between groups so that the results more closely represent a potential causal effect.ResultsThis observational study has full ethical approval from the Health and Disability Ethics Committees New Zealand (19/STH/151) and was funded in May 2019 by the Health Research Council (HRC) of New Zealand (grant 19/172). Data collection commenced in July 2020, and the first results are expected to be submitted for publication in 2022.ConclusionsThis large study will provide much needed data on the implications for nutritional intake and health with the use of baby food pouches and BLW in infancy.Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12620000459921; http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379436.International Registered Report Identifier (IRRID)DERR1-10.2196/29048

Oxidative status in the β-thalassemia syndromes in Sri Lanka; a cross-sectional survey

In the β-thalassemias, oxidative stress, resulting from chronic hemolysis, globin chain imbalance, iron overload and depleted antioxidant defences, likely contributes to cell death, organ damage, anemia, hypoxia and inflammation. We assessed variations in these parameters in β-thalassemia syndromes in Sri Lanka.Between November 2017 and June 2018, we assessed children and adults attending two thalassemia centres in Sri Lanka: 59 patients with HbE β-thalassemia, 50 β-thalassemia major, 40 β-thalassemia intermedia and 13 HbS β-thalassemia. Median age was 26.0 years (IQR 15.3–38.8), 101 (62.3%) were female and 152 (93.8%) of Sinhalese ethnicity. Methemoglobin, plasma hemoglobin, heme and ferritin were measured as sources of oxidants; plasma total antioxidant capacity, haptoglobin, hemopexin and vitamins C and E assessed antioxidant status; plasma thiobarbituric acid reactive substances and 8-hydroxy–2′–deoxyguanosine assessed oxidative damage; hemoglobin, plasma erythropoietin and transferrin receptor assessed anemia and hypoxia and plasma interleukin-6 and C-reactive protein assessed inflammation. Fruit and vegetable intake was determined by dietary recall. Physical fitness was investigated using the 6-min walk test and measurement of handgrip strength.Oxidant sources were frequently increased and antioxidants depleted, with consequent oxidative damage, anemia, hypoxia and inflammation. Biomarkers were generally most abnormal in HbE β-thalassemia and least abnormal in β-thalassemia intermedia but also varied markedly between individuals with the same thalassemia syndrome. Oxidative stress and damage were also more severe in splenectomized patients and/or those receiving iron chelation therapy. Less than 15% of patients ate fresh fruits or raw vegetables frequently, and plasma vitamins C and E were deficient in 132/160 (82.5%) and 140/160 (87.5%) patients respectively. Overall, physical fitness was poor in all syndromes and was likely due to anemic hypoxia.Studies of antioxidant supplements to improve outcomes in patients with thalassemia should consider individual patient variation in oxidative status both between and within the thalassemia syndromes.

Identification and characterization of the hemoglobin-binding domain of hemoglobin receptor in Leishmania.

Leishmania internalize hemoglobin (Hb) via a specific receptor (HbR) for their survival. To identify the Hb-binding domain of HbR, we cloned and expressed several truncated proteins of HbR and determined their ability to bind Hb. Our findings reveal that 90% of Hb-binding activity is retained in HbR41-80 in comparison with HbR1-471 . We synthesized a 40 amino acid peptide (SSEKMKQLTMYMIHEMVEGLEGRPSTVRMLPSFVYTSDPA) corresponding to HbR41-80 and found that it specifically binds Hb. Subsequently, we found that the HbR41-80 peptide completely blocks Hb uptake in both promastigote and amastigote forms of Leishmania and, thereby, inhibits the growth of the parasite. These results demonstrate that HbR41-80 is the Hb-binding domain of HbR, which might be used as a potential therapeutic agent to inhibit the growth of Leishmania.