The equilibrium between the ventricular and lumbar cerebrospinal fluid (CSF) compartments may be disturbed (in terms of flow and biochemistry) in patients with chronic hydrocephalus (CH). Using flow magnetic resonance imaging (MRI) and CSF assays, we sought to determine whether changes in CSF were associated with biochemical alterations. Nine elderly patients with CH underwent phase-contrast MRI. An index of CSF dynamics (Idyn) was defined as the product of the lumbar and ventricular CSF flows. During surgery, samples of CSF were collected from the lumbar and ventricular compartments and assayed for chloride, glucose and total protein. The lumbar/ventricular (L/V) ratio was calculated for each analyte. The ratio between measured and expected levels (Ibioch) was calculated for each analyte and compared with Idyn. Idyn varied from 0 to 100.103μl2.s2. In contrast to the L/V ratios for chloride and glucose, the L/V ratio for total protein varied markedly from one patient to another (mean ± standard deviation (SD): 2.63 ± 1.24). The Ibioch for total protein was strongly correlated with the corresponding Idyn (Spearman’s R: 0.98; p < 5 × 10−5).We observed correlated alterations in CSF flow and biochemical parameters in patients with CH. Our findings also highlight the value of dynamic flow analysis in the interpretation of data on CSF biochemistry.

Neuroinflammation and iron accumulation are hallmarks of a variety of adult neurodegenerative diseases. In Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII, a pediatric neurodegenerative disease that shares some features with adult neurodegenerative diseases), the progressive accumulation of heparan sulfate oligosaccharides (HSOs) induces microglia and astrocytes to produce pro-inflammatory cytokines leading to severe neuroinflammation. The objectives of the present study were (1) to measure the local iron concentration and to assess iron metabolism in the brain of a MPSIIIB murine model and (2) to identify the brain cells involved in this accumulation. We found that iron accumulation in MPSIIIB mice primarily affected the cerebral cortex where hepcidin levels were higher than in wild-type mice, and increased with aging. This increase was correlated with low expression of ferroportin 1 (FPN1), and thus brain iron retention. Moreover, we showed in vitro that HSOs are directly responsible for the production of hepcidin and the relative decrease in FPN1 expression when added to cultures of microglia and, to a lesser extent, to cultures of astrocytes. In contrast, no significant differences were observed in neurons. Hepcidin induction results from activation of the TLR4 pathway and STAT3 signaling, and leads to iron retention within microglia. Our results show that microglia have a key role in cerebral hepcidin overexpression and thus in the brain iron accumulation observed in the MPSIIIB model.

No abstract

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the dystrophin gene leading to the absence of the normal dystrophin protein. The efforts of many laboratories brought new treatments of DMD to the reality, but ongoing and forthcoming clinical trials suffer from absence of valuable biomarkers permitting to follow the outcome of the treatment day by day and to adjust the treatment if needed. In the present study the levels of 128 urinary proteins including growth factors, cytokines and chemokines were compared in urine of DMD patients and age related control subjects by antibody array approach. Surprisingly, statistically significant difference was observed only for urinary ferritin whose level was 50 times higher in young DMD patients. To explain the observed high urinary ferritin content we analysed the levels of iron, iron containing proteins and proteins involved in regulation of iron metabolism in serum and urine of DMD patients and their age-matched healthy controls. Obtained data strongly suggest that elevated level of urinary ferritin is functionally linked to the renal management of myoglobin iron derived from leaky muscles of DMD patients. This first observation of the high level of ferritin in urine of DMD patients permits to consider this protein as a new urinary biomarker in muscular dystrophies and sheds light on the mechanisms of iron metabolism and kidney functioning in DMD.

BACKGROUND Haem oxygenases (HO) catabolise haem, which is the prosthetic group of numerous haemoproteins. Thus, multiple primary cellular pathways and functions rely on haem availability. HO exists in two isoforms, both expressed in the placenta, namely HO-1 and HO-2, the first being inducible. Haem oxygenases, particularly HO-1, have garnered specific interest in the field of physiological and pathological placental function. These enzymes mediate haem degradation by cleaving the alpha methene bridge to produce biliverdin, which is subsequently converted to bilirubin, carbon monoxide and iron. HO-1 has anti-inflammatory and antioxidant activities. SEARCH METHODS An initial literature analysis was performed using PubMed on 3 October 2018 using key terms such as ‘haem oxygenase and pregnancy’, ‘haem oxygenase and placenta’, ‘HO-1 and pregnancy’, ‘HO-1 and placenta’, ‘HO and placenta’, ‘HO and pregnancy’, ‘genetic variant and HO’, ‘CO and pregnancy’, ‘CO and placenta’, ‘Bilirubin and pregnancy’, ‘Iron and pregnancy’ and ‘PPAR and Haem’, selecting consensus conferences, recommendations, meta-analyses, practical recommendations and reviews. A second literature analysis was performed, including notable miscarriages, foetal loss and diabetes mellitus, on 20 December 2019. The three authors studied the publications independently to decipher whether they should be included in the manuscript. OBJECTIVE AND RATIONALE This review aimed to summarise current pieces of knowledge of haem oxygenase location, function and regulation in the placenta, either in healthy pregnancies or those associated with miscarriages and foetal loss, pre-eclampsia, foetal growth restriction and diabetes mellitus. OUTCOMES HO-1 exerts some protective effects on the placentation, probably by a combination of factors, including its interrelation with the PGC-1α/PPAR pathway and the sFlt1/PlGF balance, and through its primary metabolites, notably carbon monoxide and bilirubin. Its protective role has been highlighted in numerous pregnancy conditions, including pre-eclampsia, foetal growth restriction, gestational diabetes mellitus and miscarriages. WIDER IMPLICATIONS HO-1 is a crucial enzyme in physiological and pathological placentation. This protective enzyme is currently considered a potential therapeutic target in various pregnancy diseases.

No abstract

Iron is required for energy production, DNA synthesis, and cell proliferation, mainly as a component of the prosthetic group in hemoproteins and as part of iron-sulfur clusters. Iron is also a critical component of hemoglobin and plays an important role in oxygen delivery. Imbalances in iron metabolism negatively affect these vital functions. As the crucial barrier between the fetus and the mother, the placenta plays a pivotal role in iron metabolism during pregnancy. Iron deficiency affects 1.2 billion individuals worldwide. Pregnant women are at high risk of developing or worsening iron deficiency. On the contrary, in frequent hemoglobin diseases, such as sickle-cell disease and thalassemia, iron overload is observed. Both iron deficiency and iron overload can affect neonatal development. This review aims to provide an update on our current knowledge on iron and heme metabolism in normal and pathological pregnancies. The main molecular actors in human placental iron metabolism are described, focusing on the impact of iron deficiency and hemoglobin diseases on the placenta, together with normal metabolism. Then, we discuss data concerning iron metabolism in frequent pathological pregnancies to complete the picture, focusing on the most frequent diseases.

Context Myotonic dystrophy (DM) is an autosomal dominant disorder characterized mainly by myotonia but also by primary hypogonadism. No study has reported on fertility management of patients affected by DM type 1 (DM1). Objective This study investigates the impact of CTG repeats in the DMPK gene on semen quality and preimplantation genetic diagnosis (PGD) outcome. Design This is a monocentric retrospective observational study conducted from January 2003 to January 2019. Setting Antoine Béclère University Hospital, Clamart, France. Patients Three groups were compared in this study: male DM1 patients (Group A, n = 18), unaffected partners of DM1 female patients (Group B, n = 30), and proven fertile men (Group C, n = 33). Reproductive outcomes after PGD were compared between groups A and B. Results Sperm volume was reduced in group A (2.0 mL) when compared with groups B (3.0 mL; P &lt; 0.01) and C (3.5 mL; P &lt; 0.01). Progressive motility in raw sperm was also decreased in group A (30%) as compared to group C (40%; P &lt; 0.01). The median number of progressive spermatozoa retrieved after sperm preparation was 2.7 million (M) in group A, which was significantly less than those of groups B (10.0 M; P &lt; 0.01) and C (62.2 M; P &lt; 0.01). Sperm motility was inversely correlated to the number of CTG repeats (Spearman r2 = 0.48, Pearson r2 = 0.35). Cumulative live birth rate per transfer was similar between groups, with 32.2% in group A versus 26.8% in group B. Conclusions As a precautionary measure, we advise physicians to perform regular monitoring of semen quality in affected males, which would allow sperm cryopreservation should semen parameters fall. PGD allows good reproductive outcomes without disease transmission.