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Purpose of Review: The aim of this report is to summarize the conclusions of the II Regional Meeting on Histoplasmosis in the Americas held in Manaus, Brazil, on March 22–24, 2019. Recent Findings: Persons living with advanced HIV are at high risk for developing histoplasmosis. Clinical signs and symptoms of this disease are often non-specific, making it difficult to establish a diagnosis. Although with the recent technological advances, in vitro diagnostics and medicines for histoplasmosis are often not available in many regions around the world. In addition, histoplasmosis is often not included in HIV care and treatment programs, resulting in inadequate health system planning and missed opportunities to save lives. Summary: The II Regional Meeting on Histoplasmosis in the Americas gathered a multidisciplinary audience. Developed recommendations to be included in the WHO guidelines for diagnosis and treatment of histoplasmosis in advanced HIV were the product of this meeting, and guidelines are aimed to be published in early 2020. © 2019, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Background and Aim: p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes. Methods: Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0–2), moderate (stage: 3–4), and severe fibrosis/cirrhosis (stage: 5–6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5′-nuclease assays. Results: The rs236918 allele C frequency increased from stages 0–2 to 5–6 (7.1% vs 13.6%, vs 21.9%, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2%) compared with only 17% in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28%. Conclusions: These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.

La vita scorre sul filo teso del desiderio che condiziona l'agire dell'uomo facendogli compiere grandi voli o trascinandolo in vertiginose cadute. Dalla legge mosaica al messaggio cristiano, dalla classicita' al pensiero moderno, la cultura occidentale ha sperimentato questa duplice natura del desiderio: impetuoso vortice di energia vitale e abisso insaziabile che risucchia ogni cosa. Il comandamento biblico impone ordine e misura a questa naturale tendenza dell'uomo. Cosa puo' significare non desiderare nell'era della fantasmagoria delle merci e della societa' dei consumi? Il comandamento piu' inattuale che costituisce l'ultima e la piu' inascoltata Parola. Thou Shall Not Covet Thy Neighbour's Wife Nor Thy Neighbour's Goods. Life flows along a course defined by desires, which influence humans' behaviour and lead them to accomplish remarkable feats but also toward great defeats. From the Law of Moses to the Christian message, from the classic age to the modern era, Western culture has constantly experienced desire's two-faced nature: a reckless vortex of vital energy and an insatiable abyss that consumes all. The Biblical Commandment imposes order and restraint on this natural tendency of humanity. But what does it mean not to desire in a context of material wealth and rampant consumerism? The least timely Commandment is perhaps the last and most ignored Word.

In this work, we have compared the DC and RF performances of two different PHEMT devices both based on a double D doped AlGaAs/InGaAs/AlGaAs Strained Single Quantum Well , with the gate evaporated either on an AlGaAs surface or on a GaAs one. In the last case an AlAs stop etch layer was introduced in the vertical structure. The effects on the stability of the RF performances during the device RF operation when the gate evaporation was performed either on GaAs or on AlGaAs were investigated too.

In this paper, which considers the world case-material and that of the National Cancer Institute of Milan, the indications, contraindications, limits and diagnostic potential of transcutaneous lung biopsy in the diagnosis of unspecified peripheral pulmonary condensation are evaluated both in clinical and in radiological terms.

From the analysis of 167 patients with lung cancer operated by radical resection at the National Cancer Institute of Milan and from the review of the literature, the authors reach the following conclusions: a) Prognosis of lung cancer is related to symptoms. Prognosis is better in asymptomatic patients and in those with long-term primary symptoms than in patients with short-term symptoms, or with clinical signs of mediastinal involvement or metastases. Symptomatologic classification is therefore useful also in a pretherapeutic phase. b) Although in asymptomatic patients there are better chances of cure, mass screening in asymptomatic people may be unsuccessful because of the limited number of asymptomatic cancers and the limits in radiographic diagnosis. This latter, in fact, even if rouled out in a preclinical phase, is not early. c) We need new epidemiological trends to improve both the effectiveness of mass screening and therapy in asymptomatic people.

Objectives: The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary metastasectomy. Methods: The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe ( n = 13), the United States ( n = 4) and Canada ( n = 1). Of these patients, 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 cases, sarcoma in 2173, germ cell in 363, and melanoma in 328. The disease-free interval was 0 to 11 months in 2199 cases, 12 to 35 months in 1857, and more than 36 months in 1620. Single metastases accounted for 2383 cases and multiple lesions for 2726. Mean follow-up was 46 months. Analysis was performed by Kaplan-Meier estimates of survival, relative risks of death, and multivariate Cox model. Results: The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 13% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease-free interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27% for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free intervals of 36 months or more, and single metastases. Conclusions: These results confirm that lung metastasectomy is a safe and potentially curative procedure. Resectability, disease-free interval, and number of metastases enabled us to design a simple system of classification valid for different tumor types. (J Thorac Cardiovasc Surg 1997;113:37-49)

In non small cell lung cancer (NSCLC) patients undergoing surgery after induction chemotherapy, all mediastinal lymphnodes potentially involved by tumor should be resected whenever possible. Paratracheal bilateral lymphadenectomy for left sided tumors can be disabling, i.e. median sternotomy plus a thoracotomy to reach the subcarinal region. From the right side, an extensive ipsilateral dissection is feasible through a standard thoracotomy, but contralateral lymphnodes, especially in the left hilum and aortopulmonary window are considered inaccessible. A technical tip is shown to reach and dissect the left paratracheal and aortopulmonary window nodes through a simple right thoracotomy in right-lung cancer. The procedure has been carried out in 3 cases and proved to be technically feasible. The value of such a procedure as to staging accuracy, local disease control and survival should be evaluated in a clinical trial setting.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Stereotactic body irradiation offers a non-invasive treatment modality for patients with early stage NSCLC who are not amenable to surgery or other invasive approaches because of their poor medical condition.Forty-three inoperable patients with NSCLC were treated with SBRT at our institution. A mean total dose of 30.5 Gy in 1-4 fractions was applied. The median follow-up duration was 14 months (range 6-36 months).The actuarial survival at two years was 53%: two patients died from cancer progression whereas a further 8 patients died from comorbidities. Acute toxicity was practically absent, with 7 (16.3%) patients suffering from grade 1 symptoms and two from (4.6%) grade II effects. At the time of this report, only 1 patient had grade II and 6 patients (13.9%) grade I chronic symptoms.Our results compare favourably with recently published studies and confirm that stereotactic radiotherapy has the potential to produce high local control rates with a low risk of lung toxicity in patients not amenable to curative resection. The low grade of side-effects is encouraging for shortening the treatment using a greater dose per fraction.

Background. Several inherited diseases cause hyperferritinemia with or without iron overload. Differential diagnosis is complex and requires an extensive work-up. Currently, a clinical-guided approach to genetic tests is performed based on gene-by-gene sequencing. Although reasonable, this approach is expensive and time-consuming and Next Generation Sequencing (NGS) technology may provide cheaper and quicker large-scale DNA sequencing. Methods. We analysed 36 patients with non-HFE-related hyperferritinemia. Liver iron concentration was measured in 33 by magnetic resonance. A panel of 25 iron related genes was designed using SureDesign software. Custom libraries were generated and then sequenced using Ion Torrent PGM. Results. We identified six novel mutations in SLC40A1, three novel and one known mutation in TFR2, one known mutation and a de-novo deletion in HJV, and a novel mutation in HAMP in ten patients. In silico analyses supported the pathogenic role of the mutations. Conclusions. Our results support the use of an NGS-based panel in selected patients with hyperferritinemia in a tertiary center for iron metabolism disorders. However, 26 out of 36 patients did not show genetic variants that can individually explain hyperferritinemia and/or iron overload suggesting the existence of other genetic defects or gene-gene and gene-environment interactions needing further studies.

Since February 2020 the SARS-CoV-2 virus pandemic caused the reduction of spaces and medical and nurse staff dedicated to outpatients because of the urgent needs in the intensive, sub-intensive, and ward units in Lombardia region in Italy. In our Centre we regularly follow patients with hereditary anemias (ThSA), and hemochromatosis (HH). We aimed to evaluate these patients’ emotional responses during the pandemic through online survey. 44 ThSA (55%) and 54 HH (54%) answered the questionnaire. Both ThSA and HH reported high level of anxiety, worries and concern regarding SARS-Cov-2 pandemic that was the sum of several components: i. general fear for a new and potentially lethal disorder; ii. additional disease-related risk; iii. decreased standard care. About 40% of ThSA and more than half HH asked for more attention, information and protection regarding SARS-Cov-2 infection. These findings indicate: i. the need to guarantee adequate management of patients with rare diseases even in the case of an emergency as SARS-Cov-2 was and could be in the next future; ii. the need for exhaustive information to develop “healthy concern” in patients in order to contain both their anxiety and defensive attitude, thus preventing them from denial with ensuing greater exposure to risk.

Aceruloplasminemia is an ultra-rare and fatal autosomal recessive disease with a long lasting neurological disabling period of life caused by mutations in ceruloplasmin gene. Disease phenotype is heterogeneous and variably characterized by iron-restricted erythropoiesis and microcytic anemia, hyperferritinemia with tissue iron accumulation in liver, pancreas and brain, diabetes, retinopathy and neurodegeneration. Although most heterozygotes are asymptomatic, they might present with significant neurological symptoms at some point in their lives. We report here a patient with hyperferritinemia and severe depressive disorder, harbouring two mutations in ceruloplasmin in the compound heterozygous state (p.Pro477Leu and p.Gly895Ala). Both mutations are classified as deleterious in silico, but in vitro functional study partially confirmed it. Our findings suggest that the two mutations cooperate in inducing low ceruloplasmin production in the range observed in aceruloplasminemia heterozygotes and raise the question whether this might increase patient's susceptibility to neurologic manifestations.

Background and Aim: HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. Material and Methods: Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrho-sis. Results: GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. Conclusions: Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.

HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression.

Objective: During hypoxia, hepcidin expression is inhibited to allow iron mobilization to sustain erythropoietic expansion. We analyzed molecular mechanisms underlying hypoxia-induced hepcidin inhibition in an in vivo model of acute hypoxia. Methods: Mice were kept under normal or hypoxic conditions for 6hours and 15hours and treated with α-PDGF-BB antibody or PDGF-BB receptor inhibitor. Blood, liver, spleen, and bone marrow were collected to extract RNA and protein or to quantify EPO and PDGF-BB. mRNA and protein levels were assessed by RT-PCR and Western blot. Results: Hepcidin was strongly inhibited at 15hours, and this downregulation followed erythropoiesis activation and upregulation of several growth factors. PDGF-BB, erythroferrone, GDF15, and TWSG1 were upregulated by hypoxia in the bone marrow, but not in spleen or liver. Inactivation of PDGF-BB or its receptor suppressed the hypoxia-induced hepcidin inhibition. Conclusion: Spleen and liver are not involved in the early stages of hypoxia-induced hepcidin downregulation. Our data support the role of PDGF-BB and probably also of erythroferrone in the recruitment of iron for erythropoiesis in the hypoxia setting. The rapid normalization of all the erythroid factors against persistent hepcidin suppression suggests that other signals are involved that should be clarified in future studies.

Hepcidin transcription is strongly down-regulated under hypoxic conditions, however whether hypoxia inhibits hepcidin directly or indirectly is still unknown. We investigated the time course of hypoxia-mediated hepcidin down-regulation in vivo in healthy volunteers exposed to hypobaric hypoxia at high altitude and, based on the hypothesis that circulating factors are implicated in hepcidin inhibition, we analyzed the effect of sera of these volunteers exposed to normoxia and hypoxia on hepcidin expression in Huh-7 cell lines. Hypoxia led to a significant hepcidin down-regulation in vivo that was almost complete within 72 h of exposure and followed erythropoietin induction. This delay in hepcidin down-regulation suggests the existence of soluble factor/s regulating hepcidin production. We then stimulated HuH-7 cells with normoxic and hypoxic sera to analyze the effects of sera on hepcidin regulation. Hypoxic sera had a significant inhibitory effect on hepcidin promoter activity assessed by a luciferase assay, although the amount of such decrease was not as relevant as that observed in vivo. Cellular mRNA analysis showed that a number of volunteers' sera inhibited hepcidin expression, concurrently with ID1 inhibition, suggesting that inhibitory factor(s) may act through the SMAD-pathway.

Although hyperferritinemia may be reflective of elevated total body iron stores, there are conditions in which ferritin levels are disproportionately elevated relative to iron status. Autosomal dominant forms of hyperferritinemia due to mutations in the L−ferritin IRE or in A helix of L−ferritin gene have been described, however cases of isolated hyperferritinemia still remain unsolved. We describe 12 Italian subjects with unexplained isolated hyperferritinemia (UIH). Four probands have affected siblings, but no affected parents or offspring. Sequencing analyses did not identify casual mutations in ferritin gene or IRE regions. These patients had normal levels of intracellular ferritin protein and mRNA in peripheral blood cells excluding pathological ferritin production at transcriptional and post-transcriptional level. In contrast with individuals with benign hyperferritinemia caused by mutations affecting the ferritin A helix, low rather than high glycosylation of serum ferritin was observed in our UIH subjects compared with controls. These findings suggest that subjects with UIH have a previously undescribed form of hyperferritinemia possibly attributable to increased cellular ferritin secretion and/or decreased serum ferritin clearance. The cause remains to be defined and we can only speculate the existence of mutations in gene/s not directly implicated in iron metabolism that could affect ferritin turnover including ferritin secretion.

Hepcidin is the main regulator of systemic iron homeostasis, acting by inhibiting macrophages iron release and intestinal iron absorption. During hypoxia hepcidin expression is inhibited to allow iron requirement to bone marrow to sustain erythropoietic expansion, but mechanisms of hypoxia-induced hepcidin down-regulation are partially unknown. Our aim was to improve our knowledge on hypoxia modulation of hepatic hepcidin, investigating the role of erythroid and iron-related pathways using in vitro and in vivo studies. We firstly studied the effect of hypoxia on healthy volunteers living at high altitude for 24h and 72h, confirming that hypoxia is a strong inhibitor of hepcidin production and that this inhibition followed EPO induction. Indeed s-hepcidin was strictly down-regulated at 72h of hypoxia while EPO levels were already markedly increased at 24h slightly decreasing thereafter. We then analyzed the effect of sera of these subjects on hepcidin expression in HuH-7 cells using both luciferase assay and RT-PCR. HAMP wild-type promoter activity decreased after exposure to hypoxic sera, suggesting that circulating factors present in sera may modulate hepcidin expression. However, analysis of the transcripts gave less homogenous results. In fact only a subgroup of hypoxic sera significantly inhibited hepcidin. These sera also induced a significant ID1 down-regulation indicating that inhibitory factor(s) seems to act through the SMADs pathway. Our results also suggest that a cellular model cannot reproduce what really happens in vivo that might depend to complex events involving both circulating and tissue factors. Therefore, we took advantages from a mouse model. For hypoxia challenge, C57BL/6 mice were housed in a hypoxic chamber at 10% O2 for 6 and 15h. mRNA levels of erythroid genes were assessed in liver, spleen and bone marrow by RT-PCR. Hamp1 levels were slightly increased after 6h of hypoxia and strongly down-regulated after 15h. After 6h we already observed a marked activation of transcription of all the erythroid genes analyzed (Pdgf-b, Fam132b, Gdf-15 and Twsg-1) in bone marrow (but not in spleen) that return to baseline levels after 15h. To better analyze the role of PDGF-BB, normoxic and hypoxic mice were treated with PDGF-BB neutralizing antibody or PDGF-BB receptor inhibitor immediately prior to hypoxic challenge. Inactivation of PDGF-BB or its receptor suppressed the hypoxia-induced hepcidin inhibition confirming the importance of PDGF-BB in hepcidin regulation. However, no changes in CREB/H protein were observed suggesting that this molecule is not involved in hepcidin regulation in this setting. In conclusion, our studies demonstrated that hypoxia-induced hepcidin regulation is a quick event secondary to erythropoietic activation. Indeed hepcidin decreased after up-regulation of transcription of several erythroid genes that return to baseline when hepcidin reached the maximum inhibition. Our studies indicate that PDGF-BB is a good candidate as hepcidin erythroid regulators but also suggest that hypoxia induced-hepcidin suppression is the result of cooperation of multiple signals that need to be dissected.

BACKGROUND The effects of multimodality treatment on the survival of patients with esophageal carcinoma are unclear. The authors performed a prospective, Phase II study to assess the long-term results of chemotherapy plus radiotherapy (RT) on patients with esophageal squamous cell carcinoma. METHODS Of 106 consecutive patients who were recruited between 1985 and 1992, 101 patients were evaluable. Cisplatin (100 mg/m2 per day) on Day 1 and fluorouracil (1000 mg/m2 per day) on Days 1–4 were given for two cycles, with concomitant RT (30 grays [Gy] in 15 fractions) over 19 days. Patients with potentially resectable tumors were then assessed for curative surgery; the other patients received two more courses of chemotherapy and further RT (20 Gy in 10 fractions). RESULTS Of 40 patients who were candidates for surgery, 32 patients underwent surgery, and 24 patients had complete resection; 8 patients (25%) had no residual tumor in the specimen, and 12 patients (37%) had microscopic foci only. Surgical mortality was high (22%). Of 61 nonsurgical patients, 37 patients (61%) achieved complete clinical remission, and 14 patients (23%) achieved partial remission. The median survival for the entire series was 15 months (range, 1–136 months). The overall survival rate was 22% at 5 years and 12% at 10 years. At 10 years, freedom from disease progression was similar in the two groups (24%), whereas the median survival (22 months vs. 12 months) and the overall survival rates (17% vs. 9%) were better in nonsurgical patients compared with surgical patients, respectively, probably in relation to high surgical mortality. The larynx was preserved in 28% of 32 patients with cervical disease sites, with a 10-year disease free survival rate of 31%. Three deaths were attributed to nonsurgical treatments. CONCLUSIONS Careful multidisciplinary pretreatment evaluation can identify patients who are ineligible for surgery without compromising long-term results. For patients with inoperable disease, chemoradiotherapy can produce relatively good long-term results. The combined approach without surgery can permit laryngeal preservation in a useful fraction of patients. Cancer 2002;94:352–61. © 2002 American Cancer Society.

Si mette a tema il dialogo tra religioni come richiamo all’intimo legame tra religione, accoglienza, rifiuto della violenza, comunità universale degli uomini, punto di convergenza positivo tra universalismo e pluralismo religioso

Hepcidin is a regulatory hormone that plays a major role in controlling body iron homeostasis. Circulating factors (holotransferrin, cytokines, erythroid regulators) might variably contribute to hepcidin modulation in different pathological conditions. There are few studies analysing the relationship between hepcidin transcript and related protein expression profiles in humans. Our aims were: a. to measure hepcidin expression at either hepatic, serum and urinary level in three paradigmatic iron overload conditions (hemochromatosis, thalassemia and dysmetabolic iron overload syndrome) and in controls; b. to measure mRNA hepcidin expression in two different hepatic cell lines (HepG2 and Huh-7) exposed to patients and controls sera to assess whether circulating factors could influence hepcidin transcription in different pathological conditions. Our findings suggest that hepcidin assays reflect hepatic hepcidin production, but also indicate that correlation is not ideal, likely due to methodological limits and to several post-trascriptional events. In vitro study showed that THAL sera down-regulated, HFE-HH and C-NAFLD sera up-regulated hepcidin synthesis. HAMP mRNA expression in Huh-7 cells exposed to sera form C-Donors, HFE-HH and THAL reproduced, at lower level, the results observed in HepG2, suggesting the important but not critical role of HFE in hepcidin regulation.

Iron is tightly connected to oxygen homeostasis and erythropoiesis. Our aim was to better understand how hypoxia regulates iron acquisition for erythropoiesis in humans, a topic relevant to common hypoxia-related disorders. Forty-seven healthy volunteers participated in the HIGHCARE project. Blood samples were collected at sea level and after acute and chronic exposure to high altitude (3400-5400 m above sea level). We investigated the modifications in hematocrit, serum iron indices, erythropoietin, markers of erythropoietic activity, interleukin-6, and serum hepcidin. Hepcidin decreased within 40 hours after acute hypoxia exposure (P < .05) at 3400 m, reaching the lowest level at 5400 m (80% reduction). Erythropoietin significantly increased (P < .001) within 16 hours after hypoxia exposure followed by a marked erythropoietic response supported by the increased iron supply. Growth differentiation factor-15 progressively increased during the study period. Serum ferritin showed a very rapid decrease, suggesting the existence of hypoxia-dependent mechanism(s) regulating storage iron mobilization. The strong correlation between serum ferritin and hepcidin at each point during the study indicates that iron itself or the kinetics of iron use in response to hypoxia may signal hepcidin down-regulation. The combined and significant changes in other variables probably contribute to the suppression of hepcidin in this setting.