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Objective: Parental diabetes history is a well-known risk factor for type 2 diabetes and considered strong evidence for a genetic basis of type 2 diabetes. Whether this relationship is affected by other known risk factors, specifically obesity, remains unclear, possibly due to a relative paucity of lean diabetic patients.Research Design and Methods: This issue was investigated using data from a high-risk population from Mexico (National Health Survey 2000, n = 27,349), with observations replicated using U.S. citizens of Mexican descent from the National Health and Nutrition Examination Survey 2001-2002 and 2003-2004 (n = 1,568).Results: As expected, positive parental diabetes was a significant risk factor for type 2 diabetes, regardless of age, sex, or adiposity level. However, positive parental diabetes conferred greater risk in leaner individuals than in their overweight peers (P = 0.001). In other words, the effect of BMI on type 2 diabetes risk was smaller in the presence of parental diabetes history.Conclusions: These findings suggest that parental diabetes is a stronger risk factor for type 2 diabetes in the absence of obesity. Thus, studies in lean diabetic patients could help identify type 2 diabetes susceptibility genes. This study reinforces the concept that parental diabetes and BMI are independent type 2 diabetes risk factors and suggests that glycemic screening may be helpful in assessing type 2 diabetes risk in individuals with parental diabetes history, regardless of their overweight status. [ABSTRACT FROM AUTHOR]

Pegozafermin is a long-acting glycoPEGylated analog of fibroblast growth factor 21 (FGF21) in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. In a phase Ib/IIa placebo-controlled, double-blind, multiple ascending dose study in patients with NASH (NCT04048135), administration of pegozafermin resulted in clinically meaningful reductions in hepatic fat fraction (HFF), with a favorable safety and tolerability profile. We aimed to characterize the relationship between pegozafermin dosing, exposure and effects on HFF reduction. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling of data from the phase Ib/IIa study to identify model parameters and covariates affecting the exposure-response relationship. Clinical simulations were performed to help support dose selection for larger studies. Pegozafermin exposure was adequately described by a one compartment PK model, with one additional transit absorption compartment. PK/PD modeling demonstrated that HFF reduction was significantly related to pegozafermin exposure. HFF outcomes were correlated with average pegozafermin concentrations regardless of weekly dosing (q.w.) or dosing every 2 weeks (q2w). The significant PK/PD model covariates included baseline body weight, alanine aminotransferase level, and liver volume. Simulations showed that the 30 mg q.w. dose approximated the full PD effect; almost all patients would benefit from a greater than or equal to 30% HFF reduction, suggesting fibrosis regression. Furthermore, 44 mg q2w dosing (~22 mg q.w.) appeared to be an effective regimen for HFF reduction. Our modeling supports the feasibility of q.w. and q2w dosing for achieving favorable treatment outcomes in patients with NASH, and provides the rationale for dose selection for the phase IIb ENLIVEN study (NCT04929483)., (© 2023 89bio, Inc. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Pegozafermin (also known as BIO89-100) is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development to treat nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). In cell-based assays, pegozafermin had a similar receptor engagement profile as recombinant FGF21, with approximately eightfold higher potency at fibroblast growth factor receptor 1c (FGFR1c). In diabetic monkeys, once-weekly and once-every-2-weeks regimens of subcutaneous pegozafermin provided rapid and robust benefits for an array of metabolic biomarkers, including triglycerides, cholesterol, fasting glucose, glycated hemoglobin, adiponectin, alanine aminotransferase, food intake, and body weight. In a single ascending dose study in healthy volunteers, subcutaneously administered pegozafermin was associated with statistically significant improvements in triglycerides, low- and high-density lipoprotein-cholesterol, and adiponectin, an insulin-sensitizing and anti-inflammatory adipokine. Pharmacokinetic half-lives ranged from 55 to 100 hours over the clinically relevant dose range, consistent with the expected half-life extension by glycoPEGylation. These findings provide evidence that pegozafermin is a promising candidate molecule for the treatment of patients with NASH or SHTG. SIGNIFICANCE STATEMENT: Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis. Studies presented here demonstrate that a novel long-acting FGF21 analog, pegozafermin, has similar pharmacologic properties as FGF21 and that repeated, subcutaneous dosing of pegozafermin in diabetic monkeys and healthy humans improves lipid metabolism, glucose metabolism, weight, and liver transaminases. These results support future development of pegozafermin for the treatment of metabolic diseases, including nonalcoholic steatohepatitis and severe hypertriglyceridemia., (Copyright © 2023 by The Author(s).)

Background: Disruption in androgen profiles and testicular adrenal rest tumors in males with congenital adrenal hyperplasia (CAH) can negatively affect sexual activity and fertility. Adrenal hyperandrogenism suppresses gonadotropin secretion and testicular adrenal rest tumors (TARTS), despite being noncancerous lesions, cause obstructive azoospermia and impaired testosterone (T) production. Circulating T in men with uncontrolled CAH is often predominantly adrenal in origin, which is reflected in high androstenedione/testosterone ratios (A4/T). Therefore, decreased luteinizing hormone (LH) levels and an increased A4/T are markers of impaired fertility in these individuals., Methods: Oral tildacerfont 200 to 1000 mg once daily (QD) (n=10) or 100 to 200 mg twice daily (n=9 and 7) for 2 weeks (Study 201), and 400 mg QD (n=11) for 12 weeks (Study 202). Outcomes measured changes from baseline in A4, T, A4/T, and LH., Results: Mean T levels increased in Study 201 from 375.5 ng/dL to 390.5 ng/dL at week 2 (n=9), 485.4 ng/dL at week 4 (n=4) and 420.7 ng/dL at week 6 (n=4). In Study 202, T levels fluctuated in the normal range from 448.4 ng/dL at baseline to 412.0 ng/dL at week 12. Mean LH levels increased in Study 201 from 0.68 IU/L to 1.59 IU/L at week 2 (n=10), 1.62 IU/L at week 4 (n=5) and 0.85 IU/L at week 6 (n=4). In Study 202, mean LH levels increased from 0.44 IU/L at baseline to 0.87 IU/L at week 12. Mean A4/T decreased across both studies. In Study 201, the mean A4/T changed from a baseline of 1.28 to 0.59 at week 2 (n=9), 0.87 at week 4 (n=4), and 1.03 at week 6 (n=4). In Study 202, the A4/T decreased from baseline of 2.44 to 0.68 at week 12. Four men were hypogonadal at baseline; all experienced improved A4/T and 3/4 (75%) reached levels <1., Conclusion: Tildacerfont treatment demonstrated clinically meaningful reductions in A4 levels, and A4/T with concomitant increased LH levels indicating increased testicular T production. The data suggests improvement in hypothalamic-pituitary-gonadal axis function, but more data is required to confirm favorable male reproductive health outcomes., Competing Interests: Author AK is an employee of Rutgers University, a principal investigator for clinical trials in congenital adrenal hyperplasia with Spruce Biosciences Inc, and a consultant for Antares Pharma. Author RC is an employee of Spruce Biosciences Inc. The authors declare that this study received funding from Spruce Biosciences Inc. The funder had the following involvement with the study: participated with the study design, results and the decision to submit the findings for publication., (Copyright © 2023 Khattab and Charlton.)

Background: Management strategies for non-alcoholic steatohepatitis (NASH) are based predominantly on lifestyle modification, with no approved disease-modifying drugs yet available. We aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of pegozafermin (BIO89-100), a glycoPEGylated FGF21 analogue, in participants with NASH., Methods: This randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study enrolled adults (aged 21-75 years) who had NASH with stage F1-F3 fibrosis, or non-alcoholic fatty liver disease and a high risk of NASH (referred to in this study as phenotypic NASH) due to central obesity with type 2 diabetes, or central obesity with increased alanine aminotransferase (ALT) or a Fibroscan score of 7 kPa or greater, across 12 specialist centres and clinics in the USA. Patients were centrally randomised by use of an interactive web response system to receive subcutaneously administered pegozafermin (3, 9, 18, or 27 mg once weekly; 18 or 36 mg once every 2 weeks) or placebo for 12 weeks. The primary endpoints were the safety, tolerability, and pharmacokinetics of pegozafermin. This trial is registered with ClinicalTrials.gov (NCT04048135)., Findings: Between July 29, 2019, and Aug 3, 2020, 275 participants were screened and 81 (15 [19%] with biopsy-confirmed NASH) were randomly assigned: 62 to pegozafermin (six to 3 mg once weekly, 12 to 9 mg once weekly, 11 to 18 mg once weekly, ten to 27 mg once weekly, 14 to 18 mg once every 2 weeks, and nine to 36 mg once every 2 weeks) and 19 to placebo; 63 received pegozafermin and 18 received placebo, as one participant in the placebo group inadvertently received 3 mg pegozafermin once weekly. Adverse events were reported in eight (44%) of 18 participants in the pooled placebo group, six (86%) of seven in the 3 mg once weekly pegozafermin group, four (33%) of 12 in the 9 mg once weekly group, seven (64%) of 11 in the 18 mg once weekly group, seven (70%) of ten in the 27 mg once weekly group, eight (57%) of 14 in the 18 mg once every 2 weeks group, and eight (89%) of nine in the 36 mg once every 2 weeks group. The most common treatment-related adverse event was mild increased appetite (in ten [16%] of 63 participants in the pooled pegozafermin group vs none of 18 in the pooled placebo group), which was not associated with bodyweight gain. Two patients discontinued treatment due to an adverse event (one each in the 27 mg once weekly and 18 mg once every 2 weeks groups). No treatment-related serious adverse events or deaths occurred. Dose-proportional pharmacokinetics were observed. Anti-drug antibodies were detected in 41 (65%) of 63 participants treated with pegozafermin. By week 13, pegozafermin significantly reduced the least squares mean (LSM) absolute differences in hepatic fat fraction versus pooled placebo (-8·9% [95% CI -14·8 to -3·1; p=0·0032] for 3 mg once weekly, -11·5% [-16·1 to -6·9; p<0·0001] for 9 mg once weekly, -8·9% [-13·7 to -4·2; p=0·0004] for 18 mg once weekly, -14·9% [-20·1 to -9·7; p<0·0001] for 27 mg once weekly, -10·4% [-14·7 to -6·1; p<0·0001] for 18 mg once every 2 weeks, and -11·1% [-16·2 to -6·0; p<0·0001] for 36 mg once every 2 weeks). At week 13, significant LSM relative reductions versus pooled placebo in ALT were observed for pegozafermin 9 mg once weekly, 18 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. At week 13, significant LSM relative reductions versus pooled placebo in aspartate aminotransferase were observed for pegozafermin 3 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. Significant improvements were also observed with pegozafermin treatment for triglycerides (9 mg once weekly, 27 mg once weekly, and 18 mg once every 2 weeks), LDL-C (9 mg once weekly and 27 mg once weekly), HDL-C (3 mg once weekly and 18 mg once every 2 weeks), non-HDL-C (9 mg once weekly and 27 mg once weekly), adiponectin (all doses except for 36 mg once every 2 weeks), PRO-C3 (27 mg once weekly), and bodyweight (27 mg once weekly). Changes in insulin resistance and HbA 1c were not significant., Interpretation: Pegozafermin was generally well tolerated and associated with clinically meaningful reductions in liver fat, measures of liver function, and circulating lipids. Further evaluation of pegozafermin in individuals with NASH is warranted., Funding: 89bio., Competing Interests: Declaration of interests RL reports consultant fees from Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics; institutional research grant support from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals; and is a co-founder of LipoNexus Inc. EJL reports grants or contracts from 89bio, Akero Therapeutics, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Axcella Health, Boehringer Ingelheim, Bristol Myers Squibb, CytoDyn, Durect Corporation, Eli Lilly and Company, Enanta Pharmaceuticals, Galectin Therapeutics, Galmed Pharmaceuticals, Genentech, Gilead Sciences, Hanmi Pharmaceuticals, Intercept Pharmaceuticals, Janssen Pharmaceuticals, Laboratory for Advanced Medicine, Madrigal Pharmaceuticals, Merck & Co., Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Poxel, Roche, Sagimet Biosciences, Terns Pharmaceuticals, Valeant Pharmaceuticals, Viking Therapeutics, and Zydus Pharmaceuticals; and consultant fees from Boehringer Ingelheim, Bristol Myers Squibb, Metacrine, Sagimet Biosciences, and Terns Pharmaceuticals. JPF reports grants or contracts for their institution from 89bio, Akero, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Carmot Therapeutics, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; consulting fees from Akero, Altimmune, Axcella Health, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly, Gilead, Intercept, Metacrine, Merck, Novo Nordisk, and Pfizer; payment or honoraria (for lectures, presentations, speakers bureaus, manuscript writing, or educational events) from Eli Lilly, Merck, Sanofi, Echosens, and Novo Nordisk; support for attending meetings or travel, or both, from Eli Lilly and Novo Nordisk; and participation in data safety monitoring boards or advisory boards for, 89bio, Carmot Therapeutics, Eli Lilly, Sanofi, Merck, Pfizer, Gilead, Intercept, and Beckton Dickenson. LJ is an employee of, and has stock or stock options in, Antaros Medical, which received grants or contracts from the study sponsor for services performed in the study. BBF was an employee of ProSciento at the time of the study, which received grants or contracts from the study sponsor for services performed in the study; received support or travel (as a principal investigator), or both, for attending the investigator meeting at the start of the study; and participated in data safety monitoring for the study. LM reports consulting fees from, and has stock or stock options in, ProSciento, which received grants or contracts from the study sponsor for services performed in the study. MR (deceased) was an employee of 89bio at the time of the study. C-YC was an employee of 89bio at the time of the study. RWC is an employee of 89bio; has stock or stock options in 89bio, Gilead, and Ascendis Pharma; and is a volunteer (unpaid) faculty committee member for the Pediatric Endocrine Society Fellow's Retreat. LT is an employee of, and has stock or stock options in, 89bio; and holds a patent for the dosing regimen of the study drug. CH, HM, and MM are employees of, and have stock or stock options in, 89bio. GOL reports no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The study aimed to explore how having achondroplasia affects older children and adolescents' day-to-day functioning and well-being. Individual/focus group interviews were conducted with older children/adolescents between the ages of 9 to <18 years and diagnosed with achondroplasia to elicit key concepts. An adapted grounded theory approach informed the qualitative analysis of interview data. Thirty-two children and adolescents completed interviews. Study results revealed five impact domains, including physical health, functioning, school impacts, emotional well-being, and social well-being. Frequently reported impacts on physical health included low stamina/tiring easily (81%) and back pain (69%). Key impacts in the functioning domain were difficulty with reaching objects or high places (84%) and walking long distances (75%). Emotional impacts included feeling different (63%), worried/scared (47%), and embarrassed/self-conscious (47%). Impacts on social well-being included difficulty with sports or physical play (81%) and others treating child as younger than their actual age (75%). The most frequent school impact was trouble participating in physical education (81%). A preliminary theoretical model depicting the experiences of older children/adolescents with achondroplasia was constructed based on the analysis. The preliminary theoretical model of older children and adolescents' experiences of living with achondroplasia may be used to inform future research and clinical practice., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Currently, there is limited research on how having a child diagnosed with achondroplasia affects parents' lives. The purpose of the study was to investigate the experiences of parents of infants and young children less than two years of age with achondroplasia., Methods: Concept elicitation interviews were conducted with parents of children less than 2 years of age with achondroplasia in the United States and Spain. Using grounded theory methods modified for health outcomes research, a qualitative analysis of interview transcripts was conducted. Based on the qualitative analysis, a preliminary theoretical model of the experiences of parents of infants and young children with achondroplasia was developed., Results: Fifteen parents, including 14 mothers and 1 father from 15 unique families, participated in individual or focus group concept elicitation interviews in the US (n = 9) and Spain (n = 6). The qualitative analysis identified four key parent impact domains, which included caretaking responsibilities, impacts on emotional well-being, having worries and concerns about their child, and impacts on daily well-being. Frequently discussed caretaking responsibilities among parents were managing child's medical care/treatment (93%), obtaining adaptations/items for child (73%), and monitoring child to avoid complications of achondroplasia (67%). Emotional impacts included feeling stressed/overwhelmed (67%), depressed/sad (40%), and anxious/nervous (33%). Worries and concerns included worry/concern about the future (100%), concerns regarding child's physical health (87%), worry about child's social well-being (80%), concern for child's emotional well-being (73%), and worry about child being able to function independently (67%). Daily well-being impacts included family strain (60%), missed work time (47%), and missed/limited social activities (33%). Based on the qualitative findings, a preliminary theoretical model depicting the experiences of parents of infants and young children with achondroplasia was created., Conclusions: The study sheds light on the range of impacts that parents of infants and young children with achondroplasia may experience, including caretaking responsibilities, impacts on emotional well-being, worries/concerns regarding their child, and impacts on daily well-being. The theoretical model of parent experiences may provide a helpful framework for informing future research and clinical practice., (© 2021. The Author(s).)

This study's purpose was to provide qualitative evidence to support the development of two observer-reported outcome measures assessing the physical symptoms/complications of achondroplasia in children and impacts on children's quality of life. Individual/focus group concept elicitation interviews were conducted with parents of children aged 2 to <12 years with achondroplasia and experts. Qualitative analysis of transcripts, based on an adapted grounded theory approach, informed item generation and measure development. Cognitive debriefing (CD) interviews were conducted with parents to confirm relevance and understanding. Thirty-six parents participated in concept elicitation interviews. The analysis identified major physical symptoms/complications and impacts of achondroplasia, which informed the development of the Achondroplasia Child Experience Measures (ACEMs): ACEM-Symptom and ACEM-Impact. ACEM-Symptom was comprised of eight major symptoms/complications including pain (58%), ear infections/fluid in ear (56%), and low stamina/tiring easily (56%). ACEM-Impact consisted of 31 major impacts in the domains of daily functioning, emotional well-being, social well-being, and need for assistance/adaptive devices. Impacts on functioning included difficulty reaching objects/high places (89%) and toileting (67%). Emotional impacts included feeling different (53%) and feeling frustrated/annoyed (47%). Social impacts included difficulty participating in sports/physical play (86%) and being treated as younger than age (83%). Following CD interviews with 16 additional parents, validation-ready ACEM measures were generated. The study improves our understanding of the experiences of children with achondroplasia and provides evidence supporting the content validity of the ACEMs. Validated ACEMs may be used to assess potential benefits of future treatments for comorbidities of achondroplasia., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Purpose: This study's purpose was to develop a better understanding of the experiences of parents of children with achondroplasia and to provide qualitative evidence to support the development of a patient-reported outcome (PRO) measure of parent impacts., Methods: Concept elicitation (CE) individual/focus group interviews were conducted with parents of children aged 2 to < 12 years with achondroplasia in the United States and Spain. The qualitative analysis informed the PRO measure development. Cognitive debriefing (CD) interviews were conducted to ensure parent understanding and item relevance., Results: Thirty-six parents participated in individual/focus group CE interviews. The analysis identified parent impacts in four domains, including caretaking responsibilities, emotional well-being, family, and work, and results informed the development of the Achondroplasia Parent Experience Measure (APEM). Caretaking responsibilities included managing child's medical care (92%), helping child with self-care (67%), advocating for child (64%), assisting child (56%), and observing/monitoring child (e.g., to ensure safety; 47%). Impacts on parents' emotional well-being included worry about the future (75%), worry about child's physical health (67%), safety concerns (50%), feeling stressed/overwhelmed (44%), and worry about child's social relationships (42%). Impacts on family and work included family strain (56%), limiting/adapting family activities (42%), and missed work time (50%). CD interviews with an additional 16 parents of children with achondroplasia confirmed understanding and item relevance., Conclusion: The results improve our understanding of the experiences of parents of children with achondroplasia and provide qualitative evidence to support the content validity of the APEM. A psychometric study is needed to validate the measure.

Graves' disease is less common in prepubertal than pubertal children, and initial presentation with thyroid storm is rare. We report an 11-year-old prepubertal Hispanic girl who presented with a one-day history of respiratory distress, fever, and dysphagia. She had exophthalmos, a diffuse bilateral goiter and was agitated, tachycardic, and hypertensive. Nasal swab was positive for respiratory syncytial virus (RSV). She was diagnosed with thyroid storm and admitted to the pediatric intensive care unit. While infection is a known precipitant of thyroid storm and RSV is a common pediatric infection, to the best of our knowledge, this is the first reported case of RSV infection apparently precipitating thyroid storm in a prepubertal child.

A study was undertaken to find out the relative amounts of haem and non-haem iron absorbed from meals in which varying amounts of these substances were present. Four meals, each containing 6 mg of iron but with varying ratios of haem and non-haem iron, were fed to two groups of subjects, each group receiving two meals. The geometric mean percentage absorption of non-haem iron decreased from 18.0% (SD range 14.6-22.3%) to 6.4% (SD range 3.4-11.8%) as the non-haem iron content of the meal increased from 1.52 mg to 5.72 mg--there was therefore little variation in the actual amounts of non-haem iron absorbed from the different meals. In contrast, the geometric mean absorption of haem iron was approximately 20% from all four meals, although the haem iron content varied between 0.28 mg and 4.48 mg. The amount of haem iron absorbed was thus a linear function of the amount of haem iron in the meal. Two points emerged from the study. Firstly, the relative importance of haem iron in overall iron nutrition was confirmed. Secondly, the fact that the pattern of absorption in relation to dosage was so different for haem iron and non-haem iron suggested that a controlling mechanism for non-haem iron absorption may be located at the mucosal surface. This conclusion is based on the fact that haem iron, the percentage absorption of which was found to be independent of the size of the dose, is absorbed into the mucosal cell when still contained within the porphyrin ring and the iron thus bypasses some controlling mechanism at the mucosal border.

The effect of endotoxin on the processing of erythrocyte iron by reticuloendothelial cells of the liver and spleen was studied in rats using heat damaged erythrocytes labelled with 59Fe. Endotoxin did not alter the uptake of the damaged cells but markedly inhibited the subsequent early phase of iron release from the reticuloendothelial cells. The inhibition seemed to be due to both a decreased rate of labelled haem destruction and an increased incorporation of radioiron into ferritin. Although early iron release was decreased 0--2 h after endotoxin administration, the diversion of iron into ferritin was more marked when endotoxin was given 18 h before. The block in iron release was partially overcome in animals that had been kept on an iron free diet or had been phlebotomised. In these animals the decreased rate of haem catabolism remained unaltered but less iron was diverted into ferritin.

Serum ferritin, iron and haemoglobin (Hb) concentrations were determined in 103 pregnant women and in the cord of their normal full-term offspring. In 50 of the cases the placental non-haem iron was also measured. The correlations between serum ferritin concentration and other measurements of iron status were similar in both maternal and cord blood suggesting that cord serum ferritin concentration may, as in adults, reflect neonatal iron stores. The inverse relationship found between cord serum ferritin and hb concentrations (r = -0.35, P less than 0.001) suggests that the amount of iron in foetal stores is influenced by that required for Hb. When Hb levels are elevated, as was demonstrated in babies of older mothers, significantly lower serum ferritin were found. Thus a low cord serum ferritin concentration does not necessarily indicate that less iron was transferred to the foetus. Maternal iron reserve, as reflected by serum ferritin concentration, was shown to be related to the amount of non-haem iron in the placenta (r = 0.41, P less than 0.005), but this iron does not seem to form part of foetal iron stores as it does not correlate with measurements of foetal iron status. A week correlation between cord and maternal serum ferritin concentrations was demonstrated (r = 0.21, P less than 0.05) but its biological significance is questionable.

1. The modification of iron absorption from Fe(III)EDTA by agents known to promote or inhibit absorption was examined in 101 volunteer multiparous Indian women. Fe absorption from Fe(III)EDTA was compared with absorption of intrinsic food Fe in a further twenty-eight subjects. Finally the urinary excretion of radio-Fe after oral administration of 59Fe(III)EDTA was studied in twenty-four subjects and evidence of intraluminal exchange of Fe was examined. 2. Fe absorption from maize porridge fortified with Fe(III)EDTA was more than twice that from porridge fortified with FeSO4 . 7H2O. 3. Although bran decreased Fe absorption from FeSO4 . 7H2O approximately 11-fold, it had no significant effect on Fe absorption from Fe(III)EDTA. Nevertheless tea, which is a more potent inhibitor of Fe absorption, decreased absorption from Fe(III)EDTA 7-fold. 4. Fe absorption from Fe(III)EDTA given in water was only increased 40% by addition of 3 mol ascorbic acid/mol Fe but by 7-fold when the relative proportions were increased to 6:1. This enhancing effect was blunted when the Fe(III)EDTA was given with maize porridge. In these circumstances, an ascorbate:iron value of 3:1 (which doubles absorption from FeSO4 . 7H2O) produced no significant increase in Fe absorption, while a value of 6:1 produced only a 2 . 5-fold increase. 5. Fe absorption from Fe(III)EDTA was not altered by addition of maize porridge unless ascorbic acid was present. 6. Less than 1% of 59Fe administered as 59Fe(III)EDTA was excreted in the urine and there was no inverse relationship between Fe absorption and the amounts excreted (r 0 . 58, P less than 0 . 05). 7. Isotope exchange between 59Fe(III)EDTA and 59FeSO4 . 7H2O was demonstrated by finding a similar relative value for the two isotopes in urine and erythrocytes when the two labelled compounds were given together orally. This finding was confirmed by in vitro studies, which showed enhanced 59Fe solubilization from 59FeSO4 . 7H2O in maize porridge when unlabelled Fe(III)EDTA was added. 8. Although Fe absorption from Fe(III)EDTA was marginally higher it appeared to form a common pool with intrinsic food iron in most studies. It is postulated that the mechanism whereby Fe(III)EDTA forms a common pool with intrinsic food Fe differs from that occurring with simple Fe salts. When Fe is present in the chelated form it remains in solution and is relatively well absorbed because it is protected from inhibitory ligands. Simple Fe salts, however, are not similarly protected and are absorbed as poorly as the intrinsic food Fe. 9. It is concluded that Fe(III)EDTA may be a useful compound for food fortification of cereals because the Fe is well absorbed and utilized for haemoglobin synthesis. The substances in cereals which inhibit absorption of simple Fe salts do not appear to inhibit absorption of Fe from Fe(III)EDTA.

The absorption of fortification iron from an infant milk formula and from 3 infant cereals was studied in 121 multiparous women. The mean absorption was less than 3.2% when no added ascorbic acid was present. The nature of the iron compound added to infant cereals did not seem to influence the amount absorbed. Absorption was significantly improved when ascorbic acid was added, the mean increase being threefold with an iron:ascorbic ratio of 1:1.5 molar and more than sixfold with a ratio of 1:3 molar (about 10 mg ascorbic acid per mg iron).

1. Ventilation and cardiac frequency were measured during repeated treadmill exercise in three healthy subjects over 36 weeks, before, during and after iron-deficiency anaemia was produced and after iron treatment. The haemoglobin and 2,3-diphosphoglycerate concentrations and the oxygen-binding (P50) were measured. 2. There was an inverse relationship between the haemoglobin concentrations and the 2,3-diphosphoglycerate concentrations and the P50 values. 3. The mean cardiac frequencies during the fourth to tenth minutes of exercise showed a negative correlation with the haemoglobin concentrations in all three subjects, and the mean minute ventilations in two of them.

Non-haem-iron absorption from a variety of cereal and fibre meals was measured in parous Indian women, using the erythrocyte utilization of radioactive Fe method. The present study was undertaken to establish whether alteration of the phytate and polyphenol contents of sorghum (Sorghum vulgare) affected Fe absorption from sorghum meals, and to assess the influence of fibre on Fe absorption. Removing the outer layers of sorghum grain by pearling reduced the polyphenol and phytate contents by 96 and 92% respectively. This treatment significantly increased the geometric mean Fe absorption from 0.017 to 0.035 (t 3.9, P less than 0.005). The geometric mean Fe absorption from a sorghum cultivar that lacked polyphenols (albino sorghum) was 0.043, which was significantly greater than the 0.019 absorbed from bird-proof sorghum, a cultivar with a high polyphenol content (t 2.83, P less than 0.05). Fe was less well absorbed from the phytate-rich pearlings of the albino sorghum than from the pearled albino sorghum (0.015 v. 0.035 (t 8.4, P less than 0.0005]. Addition of sodium phytate to a highly Fe-bioavailable broccoli (Brassica oleracea) meal reduced Fe absorption from 0.185 to 0.037. The geometric mean Fe absorption from malted sorghum porridge was 0.024 when 9.5 mg ascorbic acid were added and 0.094 when the ascorbic acid was increased to 50 mg (t 3.33, P less than 0.005). This enhancing effect of 50 mg ascorbic acid was significantly depressed to 0.04 by tea (t 38.1, P less than 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum ferritin concentrations were found to be raised, often considerably, in 58 of 76 black patients with primary liver cancer (PLC). No correlation could be demonstrated between the serum ferritin concentration and several other measurements, including the following: hepatic iron stores measured chemically, the size of the tumour, serum transaminase values, and the presence or absence of cirrhosis in the non-tumorous liver. There was, however, a negative correlation between serum ferritin and alpha-foetoprotein concentrations. Ferritin was purified from PLC tissue obtained from three patients at necropsy and the distribution of isoferritins was determined by isoelectric focusing. Acidic isoferritins similar to those previously found in PLC tissue were obtained. Their acidic nature was confirmed chromatographically using DEAE cellulose. Because the serum ferritin in patients with PLC probably consists of a mixture of normal and acidic isoferritins, it is likely that the serum assay used in the present study underestimated the actual concentrations present. With the development of an assay which utlises a specific antibody against acidic PLC isoferritins, serum ferritin may prove to be a second marker for PLC.

1. The feasibility of improving iron nutrition by fortifying cane sugar with Fe and ascorbic acid was studied. 2. It was found to be possible to add a number of Fe salts together with ascorbic acid to sugar without affecting its appearance or storage properties. 3. The absorption of Fe from fortified sugar eaten with maize-meal porridge or made into jam or biscuits was measured in ninety-four volunteer multiparous Indian women using the 59-Fe erythrocyte utlization method. 4. The absorption of Fe from sugar fortified with ascorbic acid and ferrous sulphate and eaten with maize-meal porridge was increased about twofold in the ratio, ascorbic acid:Fe was 10:1 by weight. If the ratio was increased to 20:2, Fe absorption was increased a further threefold. 5. Sugar fortified with soluble Fe salts, including FeSO4.7H2O, discoloured both tea and coffee; sugar fortified with ferric orthophosphate did not have this effect. 6. Fe from FePO4.H2O was poorly absorbed when added with sugar to maize-meal porridge, and also when added with adequate quantities of ascorbic acid. This form of Fe was absorbed much less well than was the intrinsic Fe present in the maize. 7. When sugar fortified with FePO4.H2O and ascorbic acid was added to maize-meal porridge before cooling or was made into jam there was a several-fold increase in the amount of Fe absorbed.

The percentage absorption from a 3 mg dose of ferrous iron was measured in 50 subjects with iron stores that varied over a wide range. Iron status was assessed by a number of measurements, including the haemoglobin concentration, the plasma iron concentration, the total iron-binding capacity, the plasma ferritin concentration and the concentration of non-haem iron in the bone marrow. There were good inverse correlations between the log percentage iron absorption and both the log marrow non-haem iron concentration (r -0.94; P less than 0.001) and the log plasma ferritin concentration (r -0.78; P less than 0.001). In addition, there was a positive ferritin concentration (r +0.84; P less than 0.001). These results suggest that reticuloendothelial iron stores represent an important determinant of iron absorption and that their size can be guaged from the plasma ferritin concentration.

The effect of tea on iron absorption was studied in human volunteers. Absorption from solutions of FeCl3 and FeSO4, bread, a meal of rice with potato and onion soup, and uncooked haemoglobin was inhibited whether ascorbic acid was present or not. No inhibition was noted if the haemoglobin was cooked. The effect on the absorption of non-haem iron was ascribed to the formation of insoluble iron tannate complexes. Drinking tannin-containing beverages such as tea with meals may contribute to the pathogenesis of iron deficiency if the diet consists largely of vegetable foodstuffs.

1. The degree to which a tracer quantity of 55Fe bound to transferrin and introduced into the plasma 36 months previously had equilibrated with the body iron was studied in a subject who was phlebotomized repeatedly until iron-deficiency anaemia developed. 2. Analysis of the results with two mathematical models showed that equilibration with haemoglobin iron and storage iron was complete. 3. Estimates of the quantity of iron initially stored in the body by three different methods yielded values of 37.3, 33.1 and 34.8 mmol. 4. Since the previously determined mean initial plasma ferritin concentration was 185 micrograms/1 (462 pmol/1), there was 0.179-0.197 mmol of stored iron per 1 microgram of plasma ferritin/1. 5. The study suggests that the assumption on which currently accepted values for daily body iron loss were calculated is valid.

The rate of absorption of iron is adjusted according to body iron requirements, but the virtual absence of heme and the poor bioavailability of the nonheme iron in the diets of many people, especially in developing countries, means that the amount that can be absorbed is limited. Those whose requirements are increased by growth, menstruation, or pregnancy frequently cannot absorb enough. Sufficient is now known about the factors in food that increase or diminish the bioavailability of nonheme iron to permit the effective fortification of dietary staples, although the application of this information has proved difficult particularly in the Third World where nutritional iron deficiency is most prevalent. Effective fortification may lead to iron overload in those whose control of iron absorption is genetically defective, and recent evidence that the HLA-linked recessive gene for idiopathic hemochromatosis may occur much more commonly than hitherto suspected makes it imperative that an effective monitoring system should form a part of every fortification program.

Serum ferritin concentrations were measured in 651 Black male miners who originated from rural areas throughout southern Africa and who were aged between 17 and 57 years. The mean serum ferritin concentration of 229 microgram/l was above the normal range reported for White subjects, and in 52,8% of the subjects the values were greater than 200 microgram/l. The serum ferritin concentration rose with age, as did the proportion of subjects in each age group who exhibited high values (more than 200 microgram/l). The lowest mean ferritin concentration (112 microgram/l) as well as the lowest proportion of high values (22,9%) were found in subjects from the most northerly area studied. Similarly, the highest mean proportion of high values (66,3%) was seen in the most southerly group studied. Calculations from the present data suggest that the degree of iron overload is currently greater in rural than in urban Black male subjects.

Ferritin and ferric hydroxide represent two forms of iron which are less available for absorption than that present in the 'common pool' of non-haem dietary iron. In the present study the absorption of iron from these two compounds was compared in 35 multiparous women when fed in water, in maize porridge and in maize porridge containing 100 mg ascorbic acid. The geometric mean absorption for 3 mg ferritin iron was 0.7% and for ferric hydroxide, 2.4%. Comparable figures when fed with maize porridge were 0.4% and 0.4% respectively. When 100 mg ascorbic acid was present in the porridge, absorption was enhanced from both sources, being 12.1% for ferritin and 10.5% for ferric hydroxide. These results indicate that the fraction of iron in ferritin and ferric hydroxide that enters the 'common pool' of non-haem dietary iron is profoundly influenced by the nature of the diet. The greater the concentration of enhancing ligands, the closer does the absorption of iron from these compounds approximate that of the non-haem dietary iron pool.

1. Iron absorption from maize (Zea mays) and sorghum (Sorghum vulgare) beer was more than twelve-fold greater than from a gruel made from the constituents used to prepare the beer. 2. The effect of changes occurring during brewing were investigated. These changes include a decrease in the solid content, and the formation of 30 ml ethanol/1 and 5 ml lactic acid/1. 3. The presence of solid material was found to inhibit Fe absorption markedly, especially when the solid content was 100 g/l or more. 4. The presence of ethanol potentiated Fe absorption but the effect was only modest in gruels with a high solid content. 5. Fe absorption from a 2 ml lactic acid/l solution was four-fold greater than from a hydrochloric acid solution of the same pH. When lactic acid was added to a gruel containing 200 g solids/l the mean absorbtion rose from 0.4 to 1.2 %. 6. In a direct comparison, Fe absorption from beer was significantly better than from a gruel of similar pH containing lactic acid. 7. The results suggest that at least three factors are responsible for the enhanced Fe absorption from maize and sorghum beer. These include the removal of solids during fermentation and the presence of ethanol and of lactic acid in the final brew. 8. In order to reproduce the way in which beer is brewed domestically in Fe containers, a study was done in which beer was prepared in the presence of Fe wire. Under such circumstances Fe was rapidly dissolved and the final Fe concentration of the brew was 89 mg/l. However, the nature of the Fe-containing compound or compounds was not elucidated.

The iron status of 320 Indian women living in Chatsworth, Durban, who had volunteered for iron absorption studies, was assessed using a number of measurements. These included: radio-iron absorption, the transferrin saturation, the serum ferritin concentration and the haemoglobin concentration. In the sample as a whole, the prevalence of iron deficiency anaemia (haemoglobin concentration less than 12 g/dl, with two or more abnormal measurements of iron status) was 14,4%. A further 26% had depleted iron stores (serum ferritin less than 12 micrograms/l) and 8,4% also had evidence of iron-deficient erythropoiesis (serum ferritin less than 12 micrograms/l and transferrin saturation below 16%). A profile of iron status based on the cumulative frequency distribution of iron stores showed that the sample, with calculated median iron stores of 150 mg and lower and upper 10 percentiles of -355 mg and 655 mg respectively, was significantly more iron deficient than a sample of women studied in Washington State, USA. Of interest was the observation that all measurements of iron status were better in the older age groups, presumably as a result of the cessation of menstruation. In addition, there was evidence that the duration of menstruation, as volunteered in a brief history, had a significant effect on several measurements of iron status. This was particularly true of the serum ferritin concentration and radio-iron absorption, both of which reflect the size of the iron stores.

There is still controversy concerning the effects of increasing the dietary intake of iron on iron nutrition. This debate has not only centered on the question of efficacy but also on that of safety. At particular potential risk are those individuals with disorders such as idiopathic haemochromatosis, who absorb iron excessively from the diet. Data obtained in the present study and in several other investigations suggest that subjects homozygous for the mutant gene responsible for the disorder would develop clinical features of the disease at a younger age were the dietary iron intake to be increased. Iron stores in affected heterozygotes would increase but the size of the stores would probably equilibrate long before they had reached massive proportions. While these conclusions are drawn from a number of studies, there are enough unanswered questions to make it mandatory for any future fortification programmes, whether they be directed at the entire population or only at certain segments of it, to be carefully monitored. This can currently be achieved with serial plasma ferritin measurements, since the concentrations mirror the size of iron stores in the body.

The amount of radioiron released from rat peritoneal macrophages after phagocytosis of 59Fe labelled erythrocytes can be enhanced by addition of desferrioxamine. The effect is dose dependent and the iron chelated by desferrioxamine appears to be at the expense of ferritin. However, desferrioxamine does not appear to chelate iron already incorporated into ferritin. It seems likely that the iron comes from a labile chelatable pool through which the iron from haemoglobin catabolism passes before being incorporated into ferritin. The desferrioxamine appears to enter the macrophage and chelate iron to form ferrioxamine which subsequently leaves the macrophage. In vivo it was not possible to show substantial iron chelaton by desferrioxamine in rats when 59Fe labelled non-viable red cells were injected intravenously. This suggests that in vivo mobilization of reticuloendothelial iron by desferrioxamine may be of limited significance.