[For an institutional outreach approach in emergency medical services]. / Développer une culture institutionnelle de l'« aller vers ¼ dans les Samu.

FOR AN INSTITUTIONAL OUTREACH APPROACH IN EMERGENCY MEDICAL SERVICES. The "outreach" approach has become the new paradigm of social action. With the creation of regional health agencies, the decompartmentalization between curative medicine, preventive medicine and medico-social care is accelerating. The political will to transpose social tools to the medical field requires removing the confusion between the logic of "outreach" (of Samusocial) and "outside the walls" (of Samu). Especially since Samu, as interface organizations, are privileged hospital actors for this decompartmentalization. The approach initiated by the pediatric Samu of Paris shows that this transposition is possible, both at the individual and institutional levels.

DÉVELOPPER UNE CULTURE INSTITUTIONNELLE DE L'« ALLER VERS ¼ DANS LES SAMU. La démarche de l'« aller vers ¼ est devenue le nouveau paradigme de l'action sociale. Avec la création des agences régionales de santé, le décloisonnement entre médecine curative, médecine préventive et prise en charge médico-sociale s'accélère. La volonté politique de transposer les outils du social au champ médical nécessite de lever la confusion entre les logiques de l'« aller vers ¼ (du Samu social) et du « hors les murs ¼ (du Samu). D'autant que les Samu, en tant qu'organisations d'interface, sont des acteurs hospitaliers privilégiés pour ce décloisonnement. La démarche initiée par le Samu pédiatrique de Paris montre que cette transposition est possible, aussi bien au niveau individuel qu'au niveau institutionnel.

Copper acetate aerosols: A possible tool complementary to vaccination in fight against SARS-CoV-2 and variants replication.

In SARS-CoV-2, at the S1/S2 furin cleavage site, a four amino acid insert (P-R-R-A) not found in closely related corona viruses, has been shown to facilitate entry into respiratory epithelial cells and promote virus transmission, infectivity and virulence. By cupric aerosol treatment, complexation of these four amino acids (-P-R-R-A-), at the spike (S) protein site will lead to a conformational change possibly impeding SARS-CoV-2 replication process in the respiratory track. Since these four amino acids yield strong and stable copper complexes, subsequent to a steric hindrance, this complexation will disturb the furin-like protease cleavage at the spike protein site as it has been recently shown in vitro with copper gluconate. The compilation of stability constants for copper amino-acid complex formation, showing values of the same order of magnitude for all the twenty proteinogenic amino-acids demonstrate thermodynamically that copper amino-acid chelation for SARS-CoV-2 virus will not be affected by mutations leading to amino acid exchanges in the spike protein region. Given its low toxicity, and its very low stability formation constant, copper acetate is proposed rather than copper gluconate for possible cupric aerosol or nasal spray treatments aimed at impeding SARS-CoV-2 multiplication. It will open different medical perspectives, complementary to vaccination, in the fight against COVID 19 native virus, variants and future mutants.

Ultrastructural study of liver and lead tissue concentrations in young mallard ducks (Anas platyrhynchos) after ingestion of single lead shot.

Lead (Pb) represents a serious threat to wildlife and ecosystems. The aim of this study was to examine the subcellular effects of dietary Pb pellet ingestion on mallard (Anas platyrhynchos) livers. After ingestion of a single Pb shot (LS4 size class: 0.177 ± 0.03 g) in 41 mallard ducks (22 males and 19 females) versus 10 controls (5 males and 5 females), all 7-week old, a morphologic study was conducted by TEM (transmission electron microscopy) of liver at the subcellular level. The results in treated mallards showed at a magnification of 2500 X that hepatic parenchyma was altered as evidenced by intralysosomal electron-dense deposits, which are compatible with Pb deposits. Further, at a higher magnification (15,000 X) in both genders, deterioration of mitochondria was observed in which the crests and, to a lesser extent, outer membrane were lysed. While the rough endoplasmic reticulum was fragmented, intracytoplasmic electron-dense material compatible with Pb deposits was maximally visible, thereby underscoring the deeply destructive effect of this metal on the subcellular architecture of the liver. In addition, applying an optimized and validated method in a clean room using electrothermal atomic absorption spectrophotometer (ETAAS) with Zeeman background correction, the objective was to improve and refine certain indispensable measurements pertaining to Pb impregnation in tissues other than liver such as kidneys, bones, and feathers of mallards. Data demonstrated show that compared with controls, Pb accumulation increases significantly, not only in the liver (3-fold), but also in the bones and the feathers (14-fold). No significant difference was noted between males and females. Bearing in mind the marked subcellular toxicity attributed to Pb, this study reinforces present-day arguments advocating limitation of game consumption.

Copper brain protein protection against free radical-induced neuronal death: Survival ratio in SH-SY5Y neuroblastoma cell cultures.

In Creutzfeldt Jakob, Alzheimer and Parkinson diseases, copper metalloproteins such as prion, amyloid protein precursor and α-synuclein are able to protect against free radicals by reduction from cupric Cu+2 to cupreous Cu+. In these pathologies, a regional copper (Cu) brain decrease correlated with an iron, zinc or manganese (Mn) increase has previously been observed, leading to local neuronal death and abnormal deposition of these metalloproteins in ß-sheet structures. In this study we demonstrate the protective effect of Cu metalloproteins against deleterious free-radical effects. With neuroblastoma SH-SY5Y cell cultures, we show that bovine brain prion protein in Cu but not Mn form prevents free radical-induced neuronal death. The survival ratio of SH-SY5Y cells has been measured after UV irradiation (free radical production), when the incubating medium is supplemented with bovine brain homogenate in native, Cu or Mn forms. This ratio, about 28% without any addition or with bovine brain protein added in Mn form, increases by as much as 54.73% with addition to the culture medium of native bovine brain protein and by as much as 95.95% if the addition is carried out in cupric form. This protective effect of brain copper protein against free radical-induced neuronal death has been confirmed with Inductively Coupled Plasma Mass Spectrometry Mn and Cu measurement in bovine brain homogenates: respectively lower than detection limit and 9.01µg/g dry weight for native form; lower than detection limit and 825.85µg/g dry weight for Cu-supplemented form and 1.75 and 68.1µg/g dry weight in Mn-supplemented brain homogenate.

Optimisation of Direct Copper Determination in Human Breast Milk Without Digestion by Zeeman Graphite Furnace Atomic Absorption Spectrophotometry with Two Chemical Modifiers.

Milk is an important food in the human diet, and copper (Cu) in human milk is indispensable to children's normal growth and development. It is consequently important that Cu deficiency, occurring in malnourished women or in malabsorption following bariatric surgery, be prevented. The objective of this work is to provide hospital-based paediatricians with a tool enabling rapid measurement of Cu in human breast milk through a technique that biology laboratories can easily apply. Using electrothermal atomic absorption spectrophotometry with Zeeman correction, we have optimized this method with two chemical modifiers and without digestion for analytical procedure. Detection limits and quantification limits for Cu in human milk were found to be 0.077 and 0.26 µmol/L, respectively. Within-run (n = 30) and between-run (n = 15) variations in a pool of human milk samples were 1.50 and 3.62%, respectively. Average recoveries ranged from 98.67 to 100.61%. The reliability of this method was also confirmed by analysing certified reference material (10%). In breast milk samples collected from 100 lactating mothers, Cu mean (±1 SD) was 7.09 ± 1.60 µmol/L. In conclusion, with minimal preparation and quick determination, the method proposed is suitable for measurement of Cu in human breast milk.

Is brain copper deficiency in Alzheimer's, Lewy body, and Creutzfeldt Jakob diseases the common key for a free radical mechanism and oxidative stress-induced damage?

In Alzheimer's (AD), Lewy body (LBD), and Creutzfeldt Jakob (CJD) diseases, similar pathological hallmarks have been described, one of which is brain deposition of abnormal protease-resistant proteins. For these pathologies, copper bound to proteins is able to protect against free radicals by reduction from cupric Cu++ to cupreous Cu+. We have previously demonstrated in bovine brain homogenate that free radicals produce proteinase K-resistant prion after manganese is substituted for copper. Since low brain copper levels have been described in transmissible spongiform encephalopathies, in substantia nigra in Parkinson's disease, and in various brain regions in AD, LBD, and CJD, a mechanism has been proposed that may underlie the neurodegenerative processes that occur when copper protection against free radicals is impaired. In peptide sequences, the alpha acid proton near the peptide bond is highly mobile and can be pulled out by free radicals. It will produce a trivalent α-carbon radical and induce a free radical chain process that will generate a D-amino acid configuration in the peptide sequence. Since only L-amino acids are physiologically present in mammalian (human) proteins, it may be supposed that only physiological L-peptides can be recycled by physiological enzymes such as proteases. If a D-amino acid is found in the peptide sequence subsequent to deficient copper protection against free radicals, it will not be recognized and might alter the proteasome L-amino acid recycling from brain peptides. In the brain, there will result an accumulation of abnormal protease-resistant proteins such as those observed in AD, LBD, and CJD.

Interlaboratory comparison study on lead in blood, in external quality assessment schemes since 1996: a progress report.

In 1992, at the request of the French labor ministry, an External Quality Control for lead in whole blood (F-EQCPbB) came into being. After 15 years (1996-2011), the ministry wished to exploit the database collected with a sufficient number of laboratories. Indeed, the number of participating laboratories had decreased from 73 to 41. However, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread of the results over the entire range of tested PbB (9 and 700 µg/l). So, it was that in laboratories having participated for >10 years, the good scores rose between 1996 and 2011 from 49% to 93%. To sum up, analysis has shown progressive and highly pronounced diminution of CVs (%) for all the ranges having undergone testing. We have observed increasing use of inductively coupled plasma with mass spectrometry (from 9% in 2005 to 29% in 2011) and decreasing use of electrothermal atomic absorption spectrometry. That said, and provided that they are based on the same degree of expertise in metrology, on all tested concentrations the two analytical techniques yield results that are not statistically different. Thanks to the F-EQCPbB, laboratories have enhanced their proficiency and registered demonstrably improved performance.

[The external quality assessment schemes for lead in blood organized by the French national agency for medicine and health product safety: a synthesis of 15 years of activity]. / L'évaluation externe de la qualité des analyses de plombémie organisée par l'Agence nationale de sécurité du médicament et des produits de santé : bilan de 15 années de contrôle.

In 1992, at the request of the French labor ministry following questions on the ability of medical biology laboratories to satisfactorily measure blood lead level (PbB), a national PbB quality control came into being. Only in 1996 did this external quality control include a number of laboratories sufficient to allow for a significant retrospective evaluation. After fifteen years (1996-2011), The French National Agency for Medicines and Health Products Safety wished to exploit the database collected. The number of participating laboratories went down from 73 to 41. On the other hand, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread decrease of the results over the entire range of tested PbBs (9 to 700 µg/L). Since 2006, we have observed increasing use of the inductively coupled plasma with mass spectrometry and decreasing use of electrothermal atomic absorption spectrometry. Provided that they rely on identical metrology expertise, the two analytical techniques lead to results on all the tested concentrations that are not statistically different.

If exposure to aluminium in antiperspirants presents health risks, its content should be reduced.

Since aluminium (Al) pervades our environment, the scientific community has for many years raised concerns regarding its safety in humans. Al is present in numerous cosmetics such as antiperspirants, lipsticks and sunscreens. Al chlorohydrate is the active antiperspirant agent in underarm cosmetics and may constitute for Al a key exposure route to the human body and a potential source of damage. An in vitro study has demonstrated that Al from antiperspirant can be absorbed through viable human stripped skin. The potential toxicity of Al has been clearly shown and recent works convincingly argue that Al could be involved in cancerogenic processes. Nowadays, for example, Al is suspected of being involved in breast cancer. Recent work in cells in culture has lent credence to the hypothesis that this metal could accumulate in the mammary gland and selectively interfere with the biological properties of breast epithelial cells, thereby promoting a cascade of alterations reminiscent of the early phases of malignant transformation. In addition, several studies suggest that the presence of Al in human breast could influence metastatic process. As a consequence, given that the toxicity of Al has been widely recognized and that it is not a physiological component in human tissues, reducing the concentration of this metal in antiperspirants is a matter of urgency.

Aluminium overload after 5 years in skin biopsy following post-vaccination with subcutaneous pseudolymphoma.

Aluminium hydroxide is used as an effective adjuvant in a wide range of vaccines for enhancing immune response to the antigen. The pathogenic role of aluminium hydroxide is now recognized by the presence of chronic fatigue syndrome, macrophagic myofasciitis and subcutaneous pseudolymphoma, linked to intramuscular injection of aluminium hydroxide-containing vaccines. The aim of this study is to verify if the subcutaneous pseudolymphoma observed in this patient in the site of vaccine injection is linked to an aluminium overload. Many years after vaccination, a subcutaneous nodule was discovered in a 45-year-old woman with subcutaneous pseudolymphoma. In skin biopsy at the injection site for vaccines, aluminium (Al) deposits are assessed by Morin stain and quantification of Al is performed by Zeeman Electrothermal Atomic Absorption Spectrophotometry. Morin stain shows Al deposits in the macrophages, and Al assays (in µg/g, dry weight) were 768.10±18 for the patient compared with the two control patients, 5.61±0.59 and 9.13±0.057. Given the pathology of this patient and the high Al concentration in skin biopsy, the authors wish to draw attention when using the Al salts known to be particularly effective as adjuvants in single or repeated vaccinations. The possible release of Al may induce other pathologies ascribed to the well-known toxicity of this metal.

In vitro study of percutaneous absorption of aluminum from antiperspirants through human skin in the Franz™ diffusion cell.

Aluminum salts such as aluminum chlorohydrate (ACH) are known for use as an active antiperspirant agent that blocks the secretion of sweat. A local case report of hyperaluminemia in a woman using an aluminum-containing antiperspirant for 4 years raises the problem of transdermal absorption of aluminum (Al). Only a very limited number of studies have shown that the skin is an effective barrier to transdermal uptake of Al. In accordance with our analytical procedure, the aim of this study with an in vitro Franz™ diffusion cell was to measure aluminum uptake from three cosmetic formulations of antiperspirant: the base for an "aerosol" (38.5% of ACH), a "roll-on" emulsion (14.5% ACH), and a "stick" (21.2%), by samples of intact and stripped human skin (5 donors). The Al assays were performed by Zeeman Electrothermal Atomic Absorption Spectrophotometry (ZEAAS). Following contacts lasting 6, 12 and 24h, the Al assays showed only insignificant transdermal absorption of Al (≤0.07% of the quantity of Al deposited) and particularly low cutaneous quantities that varied according to the formulations (1.8 µg/cm² for "aerosol base" and "stick" - 0.5 µg/cm² for the "roll-on"). On stripped skin, for which only the "stick" formulation was tested, the measured uptake was significantly higher (11.50 µg/cm² versus 1.81 µg/cm² for normal skin). These results offer reassurance as regards to the use of antiperspirants for topical application of ACH-containing cosmetic formulations on healthy skin over a limited time span (24h). On the other hand, high transdermal Al uptake on stripped skin should compel antiperspirant manufacturers to proceed with the utmost caution.

Pharmacological inhibition of PKR in APPswePS1dE9 mice transiently prevents inflammation at 12 months of age but increases Aß42 levels in the late stages of the Alzheimer's disease.

The double-stranded RNA-dependent protein kinase (PKR) is switched on by a wide range of stimuli, including the amyloid peptide. Then, PKR transmits signals to the translational machinery, apoptosis and inflammatory signaling pathways by interacting with some adapters. In virus-infected cells, PKR engages the nucleus factor κB (NF-κB) pathway. In many models of Alzheimer's disease (AD) and patients with AD, PKR was activated. Furthermore, there is strong evidence implicating the inflammatory process in the AD brain. However, the PKR involvement in inflammatory responses in AD is not elucidated. Based on our previous in vitro results, the aim of this study was to evaluate the effects of a pharmacological inhibition of PKR in inflammation in APPswePS1dE9 transgenic mice. Our results showed that PKR inhibition prevented the NF-κB activation and production of tumor necrosis factor alpha (TNFα) and interleukin (IL)-1ß at 12 months of age without decrease of Aß42 levels and memory deficits. Surprisingly, PKR inhibition failed to prevent IL-1ß- mediated inflammation and induced a great increase in ß-amyloid peptide (Aß42) levels at 18 months of age. In this model, our findings highlight the lack of relationship between inflammation and Aß42 levels. Moreover, the age-dependent inflammatory response must be carefully taken into account in the establishment of an anti-inflammatory therapy in AD.

An analytical procedure for the determination of aluminum used in antiperspirants on human skin in Franz™ diffusion cell.

A local case report of hyperaluminemia (aluminum concentration: 3.88 µmol/L) in a woman using an aluminum-containing antiperspirant for 4 years raises the question of possible transdermal uptake of aluminum salt as a future public health problem. Prior to studying the transdermal uptake of three commercialized cosmetic formulas, an analytical assay of aluminum (Al) in chlorohydrate form (ACH) by Zeeman Electrothermal Atomic Absorption Spectrophotometer (ZEAAS) in a clean room was optimized and validated. This analysis was performed with different media on human skin using a Franz(™) diffusion cell. The detection and quantification limits were set at ≤ 3 µg/L. Precision analysis as within-run (n = 12) and between-run (n = 15-68 days) yield CV ≤ 6%. The high analytic sensitivity (2-3 µg/L) and low variability should allow an in vitro study of the transdermal uptake of ACH.

Will leaded young mallards take wing? Effects of a single lead shot ingestion on growth of juvenile game-farm Mallard ducks Anas platyrhynchos.

This study aims to monitor retention of a single ingested lead shot in young mallards, and to evaluate effect on growth in relation to lead shot size class during late wing growth and the first wing molt period (8 to 12 weeks old). Toxicological tests, radiography and biometric measurements were conducted on 51 juvenile Mallard ducks. Forty one of them were given per os a single lead shot in three different commercially available sizes: No. 2 (LS2), No. 4 (LS4) and No. 6 (LS6). Less than 20% of total lead shots were found on X-rays at Day 21 (D) and none remained at D28, with mean retention time in gizzard calculated 12.85±1.34 days for all treated groups. Young ducks developed high blood lead levels for each LS treatment at D15 in males and females, the maximal values being for LS2 (297.00±78.64 µg/100 mL and 483.14±83.70 µg/100 mL, respectively (p<0.001)). Zinc protoporphyrin (ZPP) levels increased at D15 with LS2 and LS4 in males and only with LS6 in females. Treated ducks developed no symptoms of plumbism except light diarrhea, and at D40, all mallards had survived. We found that LS2 pellets released more lead in gizzards and produced the highest levels of blood lead, suggesting that LS2 pellets are more likely to intoxicate mallards than smaller sizes. The biometric measurements performed showed no statistical difference in weight or bill and wing length between control and treated groups, a finding suggesting that absorption of a single lead shot by young Mallard ducks does not affect their development during the first wing molt period, and appears not to compromise the flight capacity of young (post-juvenile) mallards. However, younger mallards and/or effects on growth of exposure to more than a single-shot dose still need to be investigated.

[Late-onset vaccination-induced subcutaneous pseudolymphoma]. / Pseudolymphome sous-cutané postvaccinal de survenue tardive.

Persistent subcutaneous nodules arise on rare occasions at sites of injection of aluminium hydroxide-adsorbed vaccine. We report a case following a diphtheria, tetanus and pertussis vaccination. The late onset of the lesion, four years after the injection, led to an uncertain preoperative diagnosis. Histopathologic examination showed features of a subcutaneous pseudolymphoma. The demonstration of aluminium by Morin staining and atomic absorption spectrometry on a paraffin-embedded tissue probe supported the diagnosis of a vaccination-induced pseudolymphoma.

Regulation of initiation factors controlling protein synthesis on cultured astrocytes in lactic acid-induced stress.

The goals of this work were first to assess whether the lactic acidosis observed in vivo in ischemia may by itself explain the inhibition of protein synthesis described in the literature and second to study the factors controlling the initiation of protein synthesis under lactic acid stress. Primary rat astrocyte cultures exposed to pH 5.25 underwent cell death and a strong inhibition of protein synthesis assessed by [3H]methionine incorporation, which was solely due to acidity of the extracellular medium and was not related to lactate concentrations. This result was associated with a weak phosphorylation of eukaryotic initiation factor (eIF)4E and a rapid phosphorylation of eIF2alpha via the kinases PKR and PKR-like endoplasmic reticulum kinase. The inhibition of PKR by PRI led first to a significant but not complete dephosphorylation of eIF2alpha that probably contributed to maintain the inhibition of the protein synthesis and second to surprising phosphorylations of extracellular signal-regulated protein kinase, p70S6K and eIF4E, suggesting a possible cross-link between the two pathways. Conversely, cell death was weak at pH 5.5. Protein synthesis was decreased to a lesser extent, the phosphorylation of eIF2alpha was limited, extracellular signal-regulated protein kinase 1/2 was activated and its downstream targets, p70S6K and eIF4E, were phosphorylated. However, the strong phosphorylation of eIF4E was not associated with an activation of the eIF4F complex. This last result may explain why protein synthesis was not stimulated at pH 5.5. However, when astrocytes were exposed at pH 6.2, corresponding to the lower pH observed in hyperglycemic ischemia, no modification in protein synthesis was observed. Consequently, lactic acidosis cannot, by itself, provide an explanation for the decrease in protein synthesis previously reported in vivo in ischemia.

Lack of correlation between nutritional status and seroprotection against influenza in a long term care facility.

UNLABELLED: We conducted a prospective study in a long-term care facility. Virologic diagnosis was assessed using viral isolation, polymerase chain reaction and serology for all patients with a flu-like syndrome. Albumin, vitamins and trace elements were also measured. RESULTS: The risk of influenza increased 6.5-fold in patients with an antibody titer of 40 during the influenza outbreak (P=0.04). Micronutrients and vitamins deficiencies were important. Patients with antibody titer >1:40 could still be infected by the virus without correlation with the nutritional status. CONCLUSION: Humoral protection with a titer >1:40 might not be protective in the elderly. Nutritional deficiencies were too prevalent to detect any effect on the results.

Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes.

Group I metabotropic glutamate receptors (mGluRs) have been demonstrated to play a role in synaptic plasticity via a rapamycin-sensitive mRNA translation signaling pathway. Various growth factors can stimulate this pathway, leading to the phosphorylation and activation of mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that modulates the activity of several translation regulatory factors, such as p70S6 kinase. However, little is known about the cellular and molecular mechanisms that bring the plastic changes of synaptic transmission after stimulation of group I mGluRs. Here, we investigated the role of the mTOR-p70S6K and the ERK1/2-p70S6K pathways in rat striatal and hippocampal synaptoneurosomes after group I mGluR stimulation. Our findings show that (S)-3,5-dihydroxyphenylglycine (DHPG) increases significantly the activation of mTOR and p70S6K (Thr389, controlled by mTOR) in both brain areas. The mTOR activation is dose-dependent and requires the stimulation of mGluR1 subtype receptors as for the p70S6K activation observed in striatum and hippocampus. In addition, the p70S6K (Thr421/Ser424) activation via the ERK1/2 activation is increased and involved also mGluR1 receptors. These results demonstrate that group I mGluRs are coupled to mTOR-p70S6K and ERK1/2-p70S6K pathways in striatal and hippocampal synaptoneurosomes. The translational factor p70S6K could be involved in the group I mGluRs-modulated synaptic efficacy.