Low exposition to lithium prevents nephrogenic diabetes insipidus but not microcystic dilations of the collecting ducts in long-term rat model.

Lithium induces nephrogenic diabetes insipidus (NDI) and microcystic chronic kidney disease (CKD). As previous clinical studies suggest that NDI is dose-dependent and CKD is time-dependent, we investigated the effect of low exposition to lithium in a long-term experimental rat model. Rats were fed with a normal diet (control group), with the addition of lithium (Li+ group), or with lithium and amiloride (Li+/Ami group) for 6 months, allowing obtaining low plasma lithium concentrations (0.25 ± 0.06 and 0.43 ± 0.16 mmol/L, respectively). Exposition to low concentrations of plasma lithium levels prevented NDI but not microcystic dilations of kidney tubules, which were identified as collecting ducts (CDs) on immunofluorescent staining. Both hypertrophy, characterized by an increase in the ratio of nuclei per tubular area, and microcystic dilations were observed. The ratio between principal cells and intercalated cells was higher in microcystic than in hypertrophied tubules. There was no correlation between AQP2 messenger RNA levels and cellular remodeling of the CD. Additional amiloride treatment in the Li+/Ami group did not allow consistent morphometric and cellular composition changes compared to the Li+ group. Low exposition to lithium prevented overt NDI but not microcystic dilations of the CD, with differential cellular composition in hypertrophied and microcystic CDs, suggesting different underlying cellular mechanisms.

A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome.

BACKGROUND: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. METHODS: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays. RESULTS: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. CONCLUSION: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.

Efficacy of oral manganese and D-galactose therapy in a patient bearing a novel TMEM165 variant.

TMEM165-CDG has first been reported in 2012 and manganese supplementation was shown highly efficient in rescuing glycosylation in isogenic KO cells. The unreported homozygous missense c.928G>C; p.Ala310Pro variant leading to a functional but unstable protein was identified. This patient was diagnosed at 2 months and displays a predominant bone phenotype and combined defects in N-, O- and GAG glycosylation. We administered for the first time a combined D-Gal and Mn2+ therapy to the patient. This fully suppressed the N-; O- and GAG hypoglycosylation. There was also striking improvement in biochemical parameters and in gastrointestinal symptoms. This study offers exciting therapeutic perspectives for TMEM165-CDG.

Scurvy complicated with Capnocytophaga sputigena sepsis as a possible cause of death of king Saint-Louis of France (1270 AD).

The cause of death of Saint-Louis is not known, but recent findings indicated that he presented scurvy and inflammatory jaw disease, which has been associated with infection by oral commensals. Here, we have the exceptional opportunity to analyze the relics of the viscera of King Saint-Louis. A 4.3 g sample from the viscera relics of King Saint-Louis conserved in Versailles' cathedral was subjected to radiocarbon dating, electronic and optic microscopy, and elementary, palynological, molecular, proteomics and microbiological analyses including specific PCR and v3v4 16 S rRNA gene amplification prior to large-scale sequencing using an Illumina MiSeq instrument. The measured radiocarbon age was Cal 1290 CE-1400, which was compatible with that of the viscera of St Louis viscera, considering the addition of lime, incense and vegetables within the human organs. Elemental and palynological analyses confirmed a medieval embalming process. Proteomics analysis identified mainly human muscle and blood proteins. Specific PCR for plague, amoebiasis, shigellosis and typhoid fever was negative. C. sputigena was identified as the main pathogenic species representing 10.8 % of all microbial sequences. In contrast, C. sputigena was found in only 0.001 % of samples sequenced in our center, and the 23 positive human samples showed a dramatically lower abundance (0.02-2.6 %). In the literature, human infections with C. sputigena included odontitis, dental abscess, sinusitis, thoracic infections and bacteremia, particularly in immunocompromised patients with oral and dental diseases consistent with recent analysis of King Saint-Louis' jaw. C. sputigena, a commensal of the mouth that is potentially pathogenic and responsible for fatal bacteremia, may have been the cause of the king's death.

Anti-Cancer and Radio-Sensitizing Properties of New Bimetallic (N-Heterocyclic Carbene)-Amine-Pt(II) Complexes.

Bioactive NHC-transition metal complexes have shown promise as anti-cancer agents, but their potential use as radiosensitizers has been neglected so far. We disclose here a new series of bimetallic platinum(II) complexes displaying NHC-type bridging ligands, (bis-NHC)[trans-Pt(RNH2)I2]2, that have been synthesized via a simple, two-step procedure. They display cytotoxicity in the micromolar range on cancerous cell lines, accumulate in cells, and bind to genomic DNA, by inducing DNA damages. Notably, these bimetallic complexes demonstrate significant radiosensitizing effects on both ovarian cells A2780 and nonsmall lung carcinoma cells H1299. Further investigations revealed that bimetallic species make irradiation-induced DNA damages more persistent by inhibiting repair mechanisms. Indeed, a higher and persistent accumulation of both γ-H2AX and 53BP1 foci post-irradiation was detected, in the presence of the NHC-Pt complexes. Overall, we provide the first in vitro evidence for the radiosensitizing properties of NHC-platinum complexes, which suggests their potential use in combined chemo-radio therapy protocols.

High Response Rate and Corticosteroid Sparing with Arsenic Trioxide-Based First-Line Therapy in Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) occurs in 20% to 50% of recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Corticosteroids (CS) remain the first-line therapy but have suboptimal efficacy and carry a risk of long-term side effects. New agents with a better safety profile and higher efficacy are urgently needed. This study aimed to evaluate the efficacy and safety of a first-line combination of arsenic trioxide (ATO) and CS in adult patients with cGVHD requiring systemic therapy after first allo-HSCT for a hematologic disease. In this prospective national multicenter single-arm open-label Phase II study conducted in 5 university hospital centers in France, ATO was started within 10 days of CS at 1 mg/kg/day. Patients received 11 infusions per cycle of 28 days at a dose of .15 mg/kg per infusion. According to the clinical response and depending on the clinician's opinion, patients received 1 or 2 cycles of treatment. Cycles were separated by an 8- to 11-week interval from the first infusion of ATO. Patients were evaluated at 6 weeks, 14 weeks, 6 months, 9 months, and 12 months after the first ATO infusion, using the Chronic GVHD Activity Assessment Form A. The primary endpoint was preliminary efficacy based on the overall response rate (ORR; complete response [CR] or partial response [PR]) at 6 months. Response rates were estimated with 2-sided 95% exact confidence intervals (CIs). Twenty-one patients entered the study and received at least 1 ATO infusion (1 incomplete cycle for 1 patient, 1 complete cycle for 11 patients, and 2 complete cycles for 9). Six patients continued ongoing cyclosporine A (CsA) treatment after inclusion, and 4 other patients resumed CsA treatment during the study. The ORR at 6 months was 75.0% (95% CI, 50.9% to 91.3%), with CR in 35% and PR in 40%. Failure-free survival was 90.0% (95% CI, 65.6% to 97.4%) at 6 months and 65.0% (95% CI, 40.3% to 81.5%) at 12 months. The progression-free survival rate was 95.0% (95% CI, 69.5% to 99.3%) at 6 months and 83.8% (95% CI, 57.7% to 94.5%) at 12 months. The mean CS dose was decreased by 74.6 ± 32.7% from baseline to the 6-month visit and by 91.0 ± 14.6% from baseline to the 12-month visit. CS was definitively stopped in 30.0% of patients at the 6-month visit and in 47.4% at the 12-month visit. Two patients died, at 7 months and 12 months after the first ATO infusion from causes unrelated to ATO. One patient withdrew because of transient hepatotoxicity. The first-line combination of ATO and CS was associated with a high clinical response rate and rapid CS sparing in cGVHD after previous allo-HSCT.

Importance des réseaux sociaux dans l'origine des intoxications : à propos d'un cas d'empoisonnement par la paraphénylènediamine.

Une femme de 63 ans rapporte avoir acheté une « pierre noire ¼ pour se protéger de la Covid-19 à la suite de conseils trouvés sur des réseaux sociaux. Dans les 24 heures qui suivent l'absorption d'une cuillère à soupe d'un mélange de « pierre ¼ avec du miel, apparaissent des myalgies puis une altération de l'état général qui la conduit à consulter aux urgences après 5 jours. L'examen clinique est sans autre particularité alors que le bilan biologique rapporte une insuffisance rénale aiguë et une rhabdomyolyse. L'évolution est marquée par une aggravation de l'insuffisance rénale nécessitant plusieurs séances d'hémodialyse. Les circonstances d'apparition des symptômes associées à la consommation de la « pierre ¼ font suspecter une origine toxique. Un tube de sang et la « pierre ¼ sont adressés au Laboratoire de toxicologie biologique pour analyses. La « pierre ¼ friable, noire en surface, blanche en interne, est soluble dans les alcools et peu soluble dans l'eau. L'analyse par plasma à couplage inductif - spectrométrie de masse - ne retrouve ni éléments métalliques, ni métalloïdes. L'analyse par chromatographie gazeuse couplée à la spectrométrie de masse met en évidence un pic identifié comme de la paraphénylènediamine (PPD). Une analyse par spectroscopie UV permet d'estimer la pureté de la « pierre ¼ à plus de 99 %. La PPD utilisée comme teinture capillaire noire ou adjuvant du henné est responsable d'intoxications graves, majoritairement volontaires, caractérisées par une détresse respiratoire, une rhabdomyolyse associée à des douleurs musculaires et à une insuffisance rénale. À l'exception de la détresse respiratoire, notre patiente a présenté tous les signes cliniques de l'intoxication. L'absence de détection de la PPD dans le plasma s'explique tant par la mise en œuvre de méthodes non adaptées à la détection de ce type de composés chimiques, que par le délai écoulé depuis la consommation de la « pierre ¼.

Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage.

Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. γ-H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.

Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic).

BACKGROUND: Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. METHODS: This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). RESULTS: Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4). CONCLUSIONS: A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01738360  registered 30 November 2012.

Chlorine Solutions for a Safe Method of Decontamination of Breast Pump Milk Collection Kits Before and After the Coronavirus Disease 2019 Pandemic.

To promote breast feeding and breast pumping is essential for the most vulnerable infants even if the current coronavirus disease 2019 (COVID-19) pandemic sanitary crisis imposes more stringent hygienic measures. As recommended by the Centers for Disease Control and Prevention, World Health Organization, and Milk Bank Association, "after each pumping session, all pump part that come into contact with breast milk should be appropriately disinfected." The present study proposed different methods than can be used and focus on the safety analysis of chlorine solution (CS) in terms of residual hypochlorous acid (HCA) and total trihalomethanes (THM). We also performed an efficacy testing of the CS approach to decontaminate the devices used to collect the milk (breast pumps and bottles). The bacteriologic results of 1,982 breast pump milk samples collected in three different settings showed a major decrease of the microbial contamination using either sterile device or decontamination with CS compared to a simple soap washing. The main messages from our study are to propose a guideline for the safe use of CS and to define situations when breast pump decontamination might be necessary: vulnerable babies for which sterile device is recommended; special circumstances, for example the current COVID-19 pandemic; special situations, for example women living in precarious conditions; or women pumping their milk at work but that would have low or no access to boiled water. Overall, cold decontamination reduced losses of milk for bacteriological reasons in human milk banks and may also be interesting to prevent horizontal contamination by virus like COVID-19.

Neutrophils from hereditary hemochromatosis patients are protected from iron excess and are primed.

Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, neutrophil function may be severely altered in conditions of iron overload, as observed in chronically transfused patients. Therefore, a tight regulation of neutrophil iron homeostasis seems to be critical for avoiding iron toxicity. Hepcidin is the key iron regulator in organisms; however, no studies have investigated its role in maintaining neutrophil iron homeostasis or characterized neutrophil function in patients with hereditary hemochromatosis (HH), a common iron overload genetic disorder that results from a defect in hepcidin production. To explore these issues, we studied 2 mouse models of iron overload: an experimentally induced iron overload model (EIO), in which hepcidin is increased, and a genetic HH model of iron overload with a deletion of hepatic hepcidin. We found that iron-dependent increase of hepatic hepcidin results in neutrophil intracellular iron trapping and consecutive defects in oxidative burst activity. In contrast, in both HH mouse models and HH patients, the lack of hepcidin expression protects neutrophils from toxic iron accumulation. Moreover, systemic iron overload correlated with a surprising neutrophil priming and resulted in a more powerful oxidative burst. Indeed, important factors in neutrophil priming and activation, such as tumor necrosis factor α (TNF-α), VCAM-1, and ICAM-1 are increased in the plasma of HH patients and are associated with an increase in HH neutrophil phagocytosis capacity and a decrease in L-selectin surface expression. This is the first study to characterize neutrophil iron homeostasis and associated functions in patients with HH.

Accumulation of Lithium in the Hippocampus of Patients With Bipolar Disorder: A Lithium-7 Magnetic Resonance Imaging Study at 7 Tesla.

BACKGROUND: Lithium (Li) is a first-line treatment for bipolar disorder (BD). To study its cerebral distribution and association with plasma concentrations, we used 7Li magnetic resonance imaging at 7T in euthymic patients with BD treated with Li carbonate for at least 2 years. METHODS: Three-dimensional 7Li magnetic resonance imaging scans (N = 21) were acquired with an ultra-short echo-time sequence using a non-Cartesian k-space sampling scheme. Lithium concentrations ([Li]) were estimated using a phantom replacement approach accounting for differential T1 and T2 relaxation effects. In addition to the determination of mean regional [Li] from 7 broad anatomical areas, voxel- and parcellation-based group analyses were conducted for the first time for 7Li magnetic resonance imaging. RESULTS: Using unprecedented spatial sensitivity and specificity, we were able to confirm the heterogeneity of the brain Li distribution and its interindividual variability, as well as the strong correlation between plasma and average brain [Li] ([Li]B ≈ 0.40 × [Li]P, R = .74). Remarkably, our statistical analysis led to the identification of a well-defined and significant cluster corresponding closely to the left hippocampus for which high Li content was displayed consistently across our cohort. CONCLUSIONS: This observation could be of interest considering 1) the major role of the hippocampus in emotion processing and regulation, 2) the consistent atrophy of the hippocampus in untreated patients with BD, and 3) the normalization effect of Li on gray matter volumes. This study paves the way for the elucidation of the relationship between Li cerebral distribution and its therapeutic response, notably in newly diagnosed patients with BD.

Parenteral Zinc Intake in Newborns With Jejunostomy or Ileostomy: Results of a Monocentric Cohort Study.

OBJECTIVES: The aim of the study was to assess zinc status of newborns with parenteral nutrition with or without a small bowel stoma, to determine the incidence of zinc deficit, and to determine the clinical factors associated with plasma zinc levels. METHODS: Monocentric cohort study including all liveborn infants receiving zinc parenteral intake at 500 µg ·â€Škg ·â€Šday and who benefited from at least 1 plasma zinc assessment during hospitalization. RESULTS: Sixty-eight dosages of zinc were performed in 50 newborns, divided into 3 groups (no stoma = 26, jejunostomy = 11, ileostomy = 13). Thirty-seven of the 50 infants were born preterm. The mean ± standard deviation plasma zinc was 14.9 ±â€Š4.3 µmol/L and was similar among the 3 groups. Sixty-four percent, 3%, and 34% of zinc values were within, below, and above the normal range, respectively. In infants with jejunostomy, only 1 plasma zinc value (5%) was below the reference range. Plasma zinc levels were negatively correlated with stoma output (r = -0.449; P = 0.013). In contrast to patients with limited intestinal losses (ie, no stoma and ileostomy groups) no association between zinc levels and postmenstrual age was observed in infants with a jejunostomy suggesting that 500 µg ·â€Škg ·â€Šday was adequate not only in preterm infants but also in term infants with a jejunostomy. CONCLUSION: Plasma zinc levels decrease significantly with the increase of stoma output volume of newborns with small bowel stoma. Zinc deficit was prevented in newborns with a small bowel stoma receiving of 500 µg ·â€Škg ·â€Šday of parenteral zinc.

Micronutrients Deficiencies in 374 Severely Malnourished Anorexia Nervosa Inpatients.

INTRODUCTION: Anorexia nervosa (AN) is a complex psychiatric disorder, which can lead to specific somatic complications. Undernutrition is a major diagnostic criteria of AN and it can be associated with several micronutrients deficiencies. OBJECTIVES: This study aimed to determinate the prevalence of micronutrients deficiencies and to compare the differences between the two subtypes of AN (restricting type (AN-R) and binge-eating/purging type (AN-BP)). METHODS: We report a large retrospective, monocentric study of patients that were hospitalized in a highly specialized AN inpatient unit between January 2011 and August 2017 for severe malnutrition treatment in the context of anorexia nervosa. RESULTS: Three hundred and seventy-four patients were included, at inclusion, with a mean Body Mass Index (BMI) of 12.5 ± 1.7 kg/m². Zinc had the highest deficiency prevalence 64.3%, followed by vitamin D (54.2%), copper (37.1%), selenium (20.5%), vitamin B1 (15%), vitamin B12 (4.7%), and vitamin B9 (8.9%). Patients with AN-BP type had longer disease duration history, were older, and had a lower left ventricular ejection fraction (LVEF) (p < 0.001, p = 0.029, p = 0.009) when compared with AN-R type patients who, instead, had significantly higher Alanine Aminotransferase (ALT) and Brain Natriuretic Peptide (BNP) levels (p < 0.001, p < 0.021). In the AN-BP subgroup, as compared to AN-R, lower selenium (p < 0.001) and vitamin B12 plasma concentration (p < 0.036) was observed, whereas lower copper plasma concentration was observed in patients with AN-R type (p < 0.022). No significant differences were observed for zinc, vitamin B9, vitamin D, and vitamin B1 concentrations between the two types of AN patients. CONCLUSION: Severely malnourished AN patients have many micronutrient deficiencies. Micronutrients status must be monitored and supplemented to prevent deficiency related complications and to improve nutritional status. Prospective studies are needed to explore the symptoms and consequences of each deficiency, which can aggravate the prognosis during recovery.

Spirulina platensis and silicon-enriched spirulina equally improve glucose tolerance and decrease the enzymatic activity of hepatic NADPH oxidase in obesogenic diet-fed rats.

The prevalence of metabolic syndrome components, such as obesity, glucose intolerance and hepatic steatosis, is rapidly increasing and becoming a major issue of public health. The present work was designed to determine the effects of Spirulina platensis (Sp) algae and silicon-enriched Sp on major metabolic syndrome components in obesogenic diet-fed rats. Forty male Wistar rats were divided into 4 groups. Ten rats were fed a control diet and 30 rats were fed a high fat (HF) diet. The HF groups were divided into three groups and supplemented with placebo or Sp or Si-enriched Sp for 12 weeks. Dietary intake and body weight were recorded. Oral glucose tolerance test and surrogate metabolic syndrome (insulin, leptin, adiponectin and lipids), mitochondrial function (enzymatic activity of respiratory chain complexes and ß-hydroxyacyl-CoA dehydrogenase), NADPH oxidase activity and several long-established oxidative stress markers were measured in the blood and liver. The HF diet induced obesity, glucose intolerance, hepatic steatosis and huge metabolic alterations, associated with higher NADPH oxidase activity and lower hepatic sulfhydryl group and glutathione contents. Otherwise, the Sp and Sp + Si supplements showed some interesting effects on rat characteristics and particularly on blood and hepatic metabolic parameters. Indeed, the intake of Sp or Sp + Si mainly improved glucose tolerance and decreased the enzymatic activity of hepatic NADPH oxidase. Overall, Si supplementation of spirulina does not appear to have more beneficial effects than spirulina alone. Other experiments with different species of rats/mice, different diets or different durations of diet intake should be undertaken to confirm or invalidate these results.

Platinum Complexes Can Bind to Telomeres by Coordination.

It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.

A comparative study of edetate calcium disodium and dimercaptosuccinic acid in the treatment of lead poisoning in adults.

BACKGROUND: We evaluated the efficacy of two antidotes, edetate calcium disodium (CaNa2EDTA) and dimercaptosuccinic acid (DMSA), for the treatment of lead poisoning in adults. METHODS: Thirty-seven patients with blood lead concentrations >40 µg/dL and positive CaNa2EDTA lead mobilization were randomized to receive 1050 mg/m2/day of oral DMSA (n = 21) or 500 mg/m2/day of intravenous CaNa2EDTA (n = 16) over two five-day courses separated by a 10-day rest period. Efficacy of treatment was evaluated by blood lead assays on the first day of the two courses and 14 days after the end of treatment and baseline CaNa2EDTA lead mobilization test and 14 days after the end of treatment. RESULTS AND CONCLUSION: Both treatments significantly reduced the prevalence of clinical symptoms, blood lead levels and CaNa2EDTA lead mobilization and were well tolerated. DMSA had a greater impact on reducing blood lead concentrations (p = .005) and CaNa2EDTA on lead mobilization (p = .04). Comparison of equimolar doses showed that CaNa2EDTA was more effective than DMSA (p < .001).