[Ukrainians Refugees: how to address their health needs in times of migration crisis?] / Réfugiés d'Ukraine : comment répondre à leurs besoins de santé en période de crise migratoire ?

February 2022: Russia attacks Ukraine. Anticipating the wave of refugees generated by this war, the Geneva University Hospitals create a Ukraine Task Force. In this context, the Programme Santé Migrants (PSM), a reference consultation for refugees, realises that it will not be able to cope with the number of those coming from Ukraine in addition to the others, and creates a parallel structure: the PSM bis. The article describes how it was set up and the challenges that were faced, in particular: express training of staff in ambulatory medicine in a context of migratory crisis, focus on early identification of mental health problems and their management. This experience highlights the importance of a coordinated, interdisciplinary, and culturally adapted approach to responding to a crisis situation.

Février 2022 : la Russie attaque l'Ukraine. Anticipant la vague de réfugiés générée par cette guerre, les Hôpitaux universitaires de Genève créent une Task Force Ukraine. Dans ce contexte, le Programme santé migrants (PSM), consultation de référence pour les réfugiés, réalise qu'il ne pourra pas faire face au nombre de ceux venant d'Ukraine en plus des autres et créé une structure parallèle : le PSM bis. L'article relate comment elle s'est mise en place et les défis qui ont été affrontés, notamment : formation express du personnel à la médecine ambulatoire dans un contexte de crise migratoire et focus sur l'identification précoce des problèmes de santé mentale et leur prise en charge. Cette expérience souligne l'importance d'une approche coordonnée, interprofessionnelle et culturellement adaptée, pour répondre à une situation de crise.

[Cruralgia heralding the rupture of an abdominal aneurysm - reminder through a clinical case]. / Cruralgie annonciatrice de la rupture d'un anévrisme abdominal - Rappel au travers d'un cas clinique.

Abdominal aneurysm is a common pathology that affects mainly men and for which there are many risk factors. This pathology predominantly stays asymptomatic until rupture and symptoms depend on location. We report the case of a 71-year-old patient. She is presenting herself to the emergency room for a nagging pain, typical of a left cruralgia as she is both febrile and shivering. The abdominal scanner is showing a ruptured infra renal aortic aneurysm. The patient is transferred to universities for an uncomplicated stent. Despite a cruralgia that seemed quite banal, both clinical and anamnestic arguments suggested an abdominal aortic rupture.

L'anévrisme abdominal est une pathologie fréquente, prédominante chez les hommes et pour laquelle il existe de nombreux facteurs de risque. Majoritairement, cette pathologie reste asymptomatique jusqu'à la rupture, et les symptômes dépendent de la localisation. Nous présentons le cas d'une patiente de 71 ans qui se présente aux urgences pour la persistance d'une cruralgie gauche, avec un état fébrile et des frissons. Le scanner abdominal décrit un anévrisme rompu de l'aorte infrarénale. La patiente est transférée en milieu universitaire pour la mise en place d'une endoprothèse sans complication. Malgré cette cruralgie d'allure banale, c'est la convergence de faisceaux d'arguments cliniques et anamnestiques qui doit faire évoquer une rupture de l'aorte abdominale.

Mental retardation in Down syndrome: Two ways to treat.

Mental retardation is a progressive condition in Down syndrome: intelligence starts to decline linearly within the first year. This phenomenon could be related to the overproduction of a toxic compound, hydrogen sulfide. Indeed, a gene located on chromosome 21 controls the production of cystathionine-ß-synthase, an enzyme involved in hydrogen sulfide production in the central nervous system. It has recently been demonstrated that excess cystathionine-ß-synthase levels are needed and sufficient to induce cognitive phenotypes in mouse models of Down syndrome. Thus, two therapeutic options might be used in Down syndrome patients: the use of a specific cystathionine ß-synthase inhibitor and the use of an effective antidote to reduce hydrogen sulfide toxicity. Prenatal treatment of Down syndrome fetuses is also suggested.

Gene therapy: a novel way to treat respiratory failure?

Respiratory failure leads to tissue hypoxia and subsequent organ damage. The crocodile hemoglobin affinity for oxygen is significantly reduced in the presence of CO2, allowing crocodiles to stay under water for more than 1h. The crocodile bicarbonate effect can possibly be transplanted into the human hemoglobin by replacing only five and seven amino acid residues in the ß-globin and α-globin chains, respectively. The resulting hybrid formed by these modified chains has been named Scuba hemoglobin. The in vitro production of Scuba hemoglobin by human hematopoietic stem cells and their reintroduction into the blood could be an interesting tool to improve tissue oxygenation in patients suffering from respiratory failure.

Delta1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline.

UNLABELLED: Delta1-pyrroline-5-carboxylate synthase (P5CS) catalyses the reduction of glutamate to Delta1-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine. Recently, we reported a newly recognised inborn error due to deficiency of P5CS in two sibs, one presenting at birth with hypotonia, dysmorphic signs, pes planus and clonic seizures. Both developed progressive neurodegeneration and peripheral neuropathy, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes mild hyperammonaemia, hypo-ornithinaemia, hypocitrullinaemia, hypo-argininaemia and hypoprolinaemia. Incorporation of 3H-proline into protein was deficient in fibroblasts incubated with 3H-glutamate. Both patients are homozygous for the missense mutation R84Q in P5CS. Here, we describe the clinical phenotype of the sibs in detail and show that a relative deficiency of urea cycle intermediates (ornithine, citrulline and arginine) during fasting periods results in a paradoxical hyperammonaemia. Furthermore, we show the results of ornithine loading tests and indirect enzyme studies corroborating the biological significance of the defect in P5CS in vivo. CONCLUSION: The metabolic phenotype of Delta1-pyrroline-5-carboxylate synthase deficiency is easily missed. The combination of low levels of ornithine, citrulline, arginine and proline plus a tendency to hyperammonaemia or one of the above together with a clinical phenotype of neurodegeneration with peripheral neuropathy and/or cataracts and connective tissue manifestations should suggest this disorder. Early recognition would allow a therapeutic trial with citrulline and proline.

[H2S, a new neuromodulator]. / H2S, un nouveau neuromodulateur.

The formation of H2S from cyst(e)ine is catalyzed by three enzymes, cystathionine beta synthase, cystathionase, and 3-mercaptopyruvate sulfurtransferase. In the liver, kidney, enterocytes and vascular smooth muscle cells, H2S is principally synthesized by cystathionase. In contrast, it is synthesized by cystathionine beta synthase in the brain and partially by 3-mercaptopyruvate sulfurtransferase in cardiac tissue. H2S is catabolized, essentially in mitochondria by thiosulfate reductase. The sulfite generated is then oxidized to sulfate by sulfite oxidase. The amount of thiosulfate excreted in the urine is the best indicator of H2S biosynthesis, together with sulfhemoglobin determination in erythrocytes. H2S acts as a neuromodulator in the brain, increasing responses mediated by NMDA receptors, facilitating the induction of long-term potentialization in the hippocampus. H2S also acts as a vasodilator, acting directly on ATP-dependent potassium channels in vascular smooth muscle cells. The concentration of H2S is abnormally low in the brains of subjects with Alzheimer's disease, due to changes in the concentration of the physiological activator of cystathionine beta synthase. The overproduction of H2S described in subjects with Down's syndrome probably results from the overproduction of cystathionine beta synthase, as the gene encoding this protein is located on chromosome 21.

The neuronal SAPK/JNK pathway is altered in a murine model of hyperhomocysteinemia.

Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine concentrations and causes hyperhomocysteinemia, a common risk factor for vascular disease, stroke and possibly neurodegenerative diseases. Various neuronal diseases have been associated with hyperhomocysteinemia, but the molecular mechanisms of homocysteine toxicity are unknown. We investigated the pathways involved in the pathological process, by analyzing differential gene expression in neuronal tissues. We used a combination of differential display and cDNA arrays to identify genes differentially expressed during hyperhomocysteinemia in brain of CBS-deficient mice. In this murine model of hyperhomocysteinemia, both plasma and brain homocysteine concentrations were high. Several genes were found to be differentially expressed in the brains of CBS-deficient mice, and the identities of some of these genes suggested that the SAPK/JNK pathway was altered in the brains of CBS-deficient mice. We therefore investigated the activation of proteins involved in the SAPK/JNK cascade. JNK and c-Jun were activated in the hippocampal neurones of CBS-deficient mice, suggesting that the SAPK/JNK pathway may play an important role in the development of neuronal defects associated with hyperhomocysteinemia.

Altered gene expression in liver from a murine model of hyperhomocysteinemia.

Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up- or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.

Methylenetetrahydrofolate reductase polymorphism in the etiology of Down syndrome.

A methylenetetrahydrofolate reductase polymorphism (677 C/T mutation) was recently implicated in the etiology of Down syndrome. We studied a cohort of 85 women carrying fetuses with Down syndrome and found no difference in the frequencies of the three groups of subjects (C/C, C/T, T/T) between Down syndrome mothers and controls.