Reared-apart/reared-together Chinese twins and virtual twins: Evolving research program and general intelligence findings.

China's One-Child Policy (1979-2015) limited rural families to two children and urban families to one child. This practice, which led to the abandonment of hundreds of thousands of female infants, is indirectly responsible for the separate placement of infant twins. The availability of this sample launched the first prospective study of these pairs. Participants include families and twins comprising 15 monozygotic (MZA) pairs and 7 dizygotic (DZA) pairs from countries throughout the world. The research program is described, and the initial wave of IQ scores for MZA and DZA twin pairs is examined in the first comprehensive report from this study. The twins' mean age at participation was 9.41 years (SD = 6.36), and their ages ranged from 3.19 to 24.98 years. Informative contrasts with adopted-together Chinese twins and virtual twins (same-age unrelated individuals reared together) highlight shared genetic and environmental effects on intellectual development. Applied directions based on findings from these novel samples are described.

[Assessment of two frailty scales for the preoperative period]. / Fragilidad: en busca de herramientas de evaluación preoperatoria.

BACKGROUND: In the perioperative context, a frailty evaluation scale must consider certain characteristics such as validation, execution speed, simplicity, the capacity to measure multiple dimensions and not being dependent on a cognitive or physical test that could not be performed prior to surgery. The test should select patients that could benefit from interventions aimed to improve their postoperative outcomes. AIM: To validate two frailty evaluation scales for the perioperative period. MATERIAL AND METHODS: The Risk Analysis Index with local modifications (RAI-M) were applied to 201 patients aged 73 ± 7 years (49% women) and the Edmonton frailty scale were applied in 151 patients aged 73 ± 7 years (49% women) in the preoperative period. Their results were compared with the Rockwood frailty index. RESULTS: The Edmonton frail scale showed adequate psychometric properties and assessed multiple dimensions through 8 of the 11 original questions, achieving a discrimination power over 80% compared to the Rockwood Index. The RAI- M, demonstrated solid psychometric properties with a tool that examines 4 dimensions of frailty through 15 questions and reviewing the presence of 11 medical comorbidities. This scale had a discrimination power greater than 85% and it was significantly associated with prolongation of the planned hospital stay and mortality. CONCLUSIONS: RAI-M is a short and easily administered scale, useful to detect frailty in the preoperative period.

Fragilidad: en busca de herramientas de evaluación preoperatoria / Assessment of two frailty scales for the preoperative period

Background: In the perioperative context, a frailty evaluation scale must consider certain characteristics such as validation, execution speed, simplicity, the capacity to measure multiple dimensions and not being dependent on a cognitive or physical test that could not be performed prior to surgery. The test should select patients that could benefit from interventions aimed to improve their postoperative outcomes. Aim: To validate two frailty evaluation scales for the perioperative period. Material and Methods: The Risk Analysis Index with local modifications (RAI-M) were applied to 201 patients aged 73 ± 7 years (49% women) and the Edmonton frailty scale were applied in 151 patients aged 73 ± 7 years (49% women) in the preoperative period. Their results were compared with the Rockwood frailty index. Results: The Edmonton frail scale showed adequate psychometric properties and assessed multiple dimensions through 8 of the 11 original questions, achieving a discrimination power over 80% compared to the Rockwood Index. The RAI- M, demonstrated solid psychometric properties with a tool that examines 4 dimensions of frailty through 15 questions and reviewing the presence of 11 medical comorbidities. This scale had a discrimination power greater than 85% and it was significantly associated with prolongation of the planned hospital stay and mortality. Conclusions: RAI-M is a short and easily administered scale, useful to detect frailty in the preoperative period.

Twins Reared Apart and Twins in Families: The Findings Behind the Fascination.

Dr. Irving I. Gottesman was very creative in applying twin research designs to test hypotheses and predictions about human behavior. Two designs stand out among others: twins reared apart from birth and the twin-family study. I (NS) was inspired to incorporate both of these approaches into my own research programs at California State University, Fullerton. Gottesman's involvement and contributions to reared-apart twin research are described, followed by selected findings from the Minnesota Study of Twins Reared Apart (MISTRA), the Fullerton Study of Chinese Twins Reared Apart (CTA), a case report on separated monozygotic (MZ) female twins from South Korea, and doubly exchanged MZ male twin pairs from Colombia, South America. Recent findings from an ongoing twin-family study of social closeness, and future directions, are also presented.

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.

The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich's ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell iron-processing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial iron-processing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.

The ins and outs of mitochondrial iron-loading: the metabolic defect in Friedreich's ataxia.

Friedreich's ataxia is a cardio- and neurodegenerative disease due to decreased expression of the mitochondrial protein, frataxin. This defect results in mitochondrial iron-overload, and in this review, we discuss the mechanisms that lead to this iron accumulation. Using a conditional knockout mouse model where frataxin is deleted in the heart, it has been shown that this mutation leads to transferrin receptor-1 upregulation, resulting in increased iron uptake from transferrin. There is also marked downregulation of ferritin that is required for iron storage and decreased expression of the iron exporter, ferroportin 1, leading to decreased cellular iron efflux. The increased mitochondrial iron uptake is facilitated by upregulation of the mitochondrial iron transporter, mitoferrin 2. This stimulation of iron uptake probably attempts to rescue the deficit in mitochondrial iron metabolism that is due to downregulation of mitochondrial iron utilization, namely, heme and iron-sulfur cluster (ISC) synthesis and also iron storage (mitochondrial ferritin). The resultant decrease in heme and ISC synthesis means heme and ISCs are not exiting the mitochondrion for cytosolic use. Hence, increased mitochondrial iron uptake coupled with decreased utilization and release leads to mitochondrial iron-loading. More generally, disturbance of mitochondrial iron utilization in other diseases probably also results in similar compensatory alterations.

Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant.

We used the muscle creatine kinase (MCK) conditional frataxin knockout mouse to elucidate how frataxin deficiency alters iron metabolism. This is of significance because frataxin deficiency leads to Friedreich's ataxia, a disease marked by neurologic and cardiologic degeneration. Using cardiac tissues, we demonstrate that frataxin deficiency leads to down-regulation of key molecules involved in 3 mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase Nfs1), mitochondrial iron storage (mitochondrial ferritin), and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, and ferrochelatase). This marked decrease in mitochondrial iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excessive mitochondrial iron observed. This effect is compounded by increased iron availability for mitochondrial uptake through (i) transferrin receptor1 up-regulation, increasing iron uptake from transferrin; (ii) decreased ferroportin1 expression, limiting iron export; (iii) increased expression of the heme catabolism enzyme heme oxygenase1 and down-regulation of ferritin-H and -L, both likely leading to increased "free iron" for mitochondrial uptake; and (iv) increased expression of the mammalian exocyst protein Sec15l1 and the mitochondrial iron importer mitoferrin-2 (Mfrn2), which facilitate cellular iron uptake and mitochondrial iron influx, respectively. Our results enable the construction of a model explaining the cytosolic iron deficiency and mitochondrial iron loading in the absence of frataxin, which is important for understanding the pathogenesis of Friedreich's ataxia.

Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood.

Hepcidin is a major regulator of iron metabolism. Hepcidin-based therapeutics/diagnostics could play roles in hematology in the future, and thus, hepcidin transport is crucial to understand. In this study, we identify alpha2-macroglobulin (alpha2-M) as the specific hepcidin-binding molecule in blood. Interaction of 125I-hepcidin with alpha2-M was identified using fractionation of plasma proteins followed by native gradient polyacrylamide gel electrophoresis and mass spectrometry. Hepcidin binding to nonactivated alpha2-M displays high affinity (Kd 177 +/- 27 nM), whereas hepcidin binding to albumin was nonspecific and displayed nonsaturable kinetics. Surprisingly, the interaction of hepcidin with activated alpha2-M exhibited a classical sigmoidal binding curve demonstrating cooperative binding of 4 high-affinity (Kd 0.3 microM) hepcidin-binding sites. This property probably enables efficient sequestration of hepcidin and its subsequent release or inactivation that may be important for its effector functions. Because alpha2-M rapidly targets ligands to cells via receptor-mediated endocytosis, the binding of hepcidin to alpha2-M may influence its functions. In fact, the alpha2-M-hepcidin complex decreased ferroportin expression in J774 cells more effectively than hepcidin alone. The demonstration that alpha2-M is the hepcidin transporter could lead to better understanding of hepcidin physiology, methods for its sensitive measurement and the development of novel drugs for the treatment of iron-related diseases.

The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation.

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant.

Identification of the di-pyridyl ketone isonicotinoyl hydrazone (PKIH) analogues as potent iron chelators and anti-tumour agents.

(1) In an attempt to develop chelators as potent anti-tumour agents, we synthesized two series of novel ligands based on the very active 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) group. Since lipophilicity and membrane permeability play a critical role in Fe chelation efficacy, the aldehyde moiety of the PCIH series, namely 2-pyridylcarboxaldehyde, was replaced with the more lipophilic 2-quinolinecarboxaldehyde or di-2-pyridylketone moieties. These compounds were then systematically condensed with the same group of acid hydrazides to yield ligands based on 2-quinolinecarboxaldehyde isonicotinoyl hydrazone (QCIH) and di-2-pyridylketone isonicotinoyl hydrazone (PKIH). To examine chelator efficacy, we assessed their effects on proliferation, Fe uptake, Fe efflux, the expression of cell cycle control molecules, iron-regulatory protein-RNA-binding activity, and (3)H-thymidine, (3)H-uridine and (3)H-leucine incorporation. (2) Despite the high lipophilicity of the QCIH ligands and the fact that they have the same Fe-binding site as the PCIH series, surprisingly none of these compounds were effective. In contrast, the PKIH analogues showed marked anti-proliferative activity and Fe chelation efficacy. Indeed, the ability of these ligands to inhibit proliferation and DNA synthesis was similar or exceeded that found for the highly cytotoxic chelator, 311. In contrast to the PCIH and QCIH analogues, most of the PKIH group markedly increased the mRNA levels of molecules vital for cell cycle arrest. (3) In conclusion, our studies identify structural features useful in the design of chelators with high anti-proliferative activity. We have identified a novel class of ligands that are potent Fe chelators and inhibitors of DNA synthesis, and which deserve further investigation.

Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats.

BACKGROUND & AIMS: Hepcidin is an antimicrobial peptide thought to be involved in the regulation of intestinal iron absorption. To further investigate its role in this process, we examined hepatic and duodenal gene expression in rats after the switch from a control diet to an iron-deficient diet. METHODS: Adult rats on an iron-replete diet were switched to an iron-deficient diet and the expression of iron homeostasis molecules in duodenal and liver tissue was studied over 14 days. Intestinal iron absorption was determined at these same time-points by measuring the retention of an oral dose of (59)Fe. RESULTS: Iron absorption increased 2.7-fold within 6 days of switching to an iron-deficient diet and was accompanied by an increase in the duodenal expression of Dcytb, divalent metal transporter 1, and Ireg1. These changes precisely correlated with decreases in hepatic hepcidin expression and transferrin saturation. No change in iron stores or hematologic parameters was detected. CONCLUSIONS: This study showed a close relationship between the expression of hepcidin, duodenal iron transporters, and iron absorption. Both hepcidin expression and iron absorption can be regulated before iron stores and erythropoiesis are affected, and transferrin saturation may signal such changes.

Erythroid differentiation and protoporphyrin IX down-regulate frataxin expression in Friend cells: characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobinization.

Friedreich ataxia (FA) is caused by decreased frataxin expression that results in mitochondrial iron (Fe) overload. However, the role of frataxin in mammalian Fe metabolism remains unclear. In this investigation we examined the function of frataxin in Fe metabolism by implementing a well-characterized model of erythroid differentiation, namely, Friend cells induced using dimethyl sulfoxide (DMSO). We have characterized the changes in frataxin expression compared to molecules that play key roles in Fe metabolism (the transferrin receptor [TfR] and the Fe transporter Nramp2) and hemoglobinization (beta-globin). DMSO induction of hemoglobinization results in a marked decrease in frataxin gene (Frda) expression and protein levels. To a lesser extent, Nramp2 messenger RNA (mRNA) levels were also decreased on erythroid differentiation, whereas TfR and beta-globin mRNA levels increased. Intracellular Fe depletion using desferrioxamine or pyridoxal isonicotinoyl hydrazone, which chelate cytoplasmic or cytoplasmic and mitochondrial Fe pools, respectively, have no effect on frataxin expression. Furthermore, cytoplasmic or mitochondrial Fe loading of induced Friend cells with ferric ammonium citrate, or the heme synthesis inhibitor, succinylacetone, respectively, also had no effect on frataxin expression. Although frataxin has been suggested by others to be a mitochondrial ferritin, the lack of effect of intracellular Fe levels on frataxin expression is not consistent with an Fe storage role. Significantly, protoporphyrin IX down-regulates frataxin protein levels, suggesting a regulatory role of frataxin in Fe or heme metabolism. Because decreased frataxin expression leads to mitochondrial Fe loading in FA, our data suggest that reduced frataxin expression during erythroid differentiation results in mitochondrial Fe sequestration for heme biosynthesis.

Ototoxicidade: diagnóstico, prevençäo e tratamento / Ototoxicity: diagnosis, prevention and treatment

O uso de medicamentos ototóxicos produziu inúmeros deficientes auditivos. Os efeitos colaterais atingem o ouvido interno além de outros órgäos, principalmente o rim säo antibióticos, diuréticos e substâncias usadas como armas no combate a várias doenças. Os otorrinolaringologistas devema alertar seus colegas médicos sobre os riscos da ototoxicidade. Deveriam ainda estar aptos a avaliar e acompanhar os pacientes que tiveram comcprometimento do ouvido interno durante ou após a terapia. O presente trabalho apresenta uma sumária revisäo sobre o tema, seus aspectos clínicos, patologia e tratamento. Tem como objetivo salientar importantes aspectos de interesse do especialista e do médico generalista. Destaca, à luz dos recentes avanços da farmacologia e à partir da melhor compreensäo da histofisiologia do ouvido interno, com o advento da microscopia eletrônica, as alteraçöes histopatológicas presentes no fenômeno da ototoxicidade