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.

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.

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).

Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.

A multivalent phosphorus dendrimer 1G3 and its corresponding Cu-complex, 1G3-Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway.

Antioxidant trace elements serum levels in long-term parenteral nutrition (PN): Prevalence and infectious risk associated with deficiencies, a retrospective study from a tertiary home-PN center.

INTRODUCTION: Antioxidants essential trace elements (TEs), selenium (Se), zinc (Zn) and copper (Cu) are key dietary components and their supplementation in parenteral nutrition (PN) is recommended. However, the frequency of marginal deficiencies and related clinical outcomes remain poorly known in patients receiving long-term PN. METHODS AND OBJECTIVES: We conducted a retrospective observational study whose aim was to determine in a cohort of patients (n = 73) with chronic intestinal failure (CIF) enrolled in a tertiary home PN center and receiving long-term PN with systematic multi-TE supplementation, the prevalence of low serum TEs levels. The goal was also to assess mid-term incidence of serious infection and its associated factors. RESULTS: Among the 73 studied patients, 21.9%, 13.9% and 21.1% had low serum Se (<0.9 µmol/l), Cu (<12.7 µmol/l) and Zn (<12.5 µmol/l) levels, respectively. There was no difference between short bowel syndrome (SBS) and non-SBS patients. 30 patients had at least one of the three serum TEs levels under the cut-off values of deficiency. No specific disease and/or underlying intestinal anatomy were associated with low serum TEs concentration. Cumulative incidence rates of serious infection were 11.1% 95CI[5.7-21.0] and 19.5% 95CI[12.0-30.7] at 6 months and 1 year, respectively. Central venous catheter-related bloodstream infection was the most common infection. Low serum Se was independently associated with a higher risk to develop serious infection (HR 2.65 95CI[1.01-6.97]). CONCLUSION: Low serum TEs concentration is a frequent condition in patients with CIF even with systematic multi-TE supplementations. Se deficiency exposes to a greater risk of serious infection. This suggests that frequent TEs dosage in this population as well as individually tailored supplementation may be beneficial.

Evaluation of oxaliplatin exposure of healthcare workers during heated intraperitoneal perioperative chemotherapy (HIPEC).

The aim of this study was to evaluate air and surface contaminations, and internal contamination of healthcare workers during open-abdomen HIPEC using oxaliplatin. Platinum (Pt) was measured in urine of exposed workers and in multiple air and surface samples. Three successive HIPEC procedures were investigated in each of the two hospitals participating in the study. Analysis of air samples did not detect any oxaliplatin contamination. Heavy contamination of the operating table, the floor at the surgeon's feet, and the surgeon's overshoes were observed. Hand contamination was observed in surgeons using double gloves for intra-abdominal chemotherapy administration, but not in those using three sets of gloves. Pt was not detected in urine samples obtained after HIPEC (<5 ng/L). The main risk of HIPEC is related to direct or indirect skin exposure and can be prevented by correct use of adapted protective equipment.

The heart of Blessed Anne-Madeleine Remuzat: a biomedical approach of "miraculous" heart conservation.

We present here the results of our inter-disciplinary examination of the mummified heart of Blessed Anne-Madeleine Remuzat (1696-1730). This organ has been examined in the context of a canonization process. This analysis is related to important aspects of the early history of anatomy in Europe, that of "Holy autopsies", and to the relationship between anatomical investigations, Catholic theology, and religious/medical customs. According to anatomical, genetic, toxicological, and palynological analyses, it has been shown that this organ has not been naturally ("miraculously") conserved but embalmed using myrtle, honey, and lime. Moreover, a right ventricle dilatation has been diagnosed, that may represent a post-tuberculosis condition and may have played a role in the cause of death of this religious figure.

Evaluation of environmental contamination by platinum and exposure risks for healthcare workers during a heated intraperitoneal perioperative chemotherapy (HIPEC) procedure.

UNLABELLED: The study was plan to assess platinum (Pt) contamination in the operating room and its exposure to health workers during heated intraperitoneal perioperative chemotherapy (HIPEC) using oxaliplatin. MATERIALS AND METHODS: Pt was measured in urinary and environmental (air and surfaces) samples via inductively coupled plasma mass spectrometry (ICP-MS). Urinary samples were obtained from 11 members of the staff before and after the procedure and from 6 controls. Samples from 15 surfaces and from 3 filters from the air extractors were also analyzed for Pt contamination. RESULTS: Before HIPEC, Pt levels in urinary samples were similar in both the exposed and control groups; concentrations were below the limit of detection (i.e., 1.5 ng/L). No elevation was observed in the exposed group at the end of the procedure. Surgeon gloves were heavily contaminated. On other analyzed surfaces, lesser amounts of Pt were measured, ranging from 2 ng on the surgeon's hands to 183 ng on the forceps. All three air filters tested negative. CONCLUSION: No contamination of healthcare workers or of the air in the operating room was detected. However, the heavy contamination of the surgeon's gloves demonstrates why doubling of specialized gloves for the surgeon should be mandatory.

[Lead poisoning from traditional Indian medicines]. / Intoxication par le plomb résultant de l'utilisation d'un remède traditionnel indien.

BACKGROUND: The use of traditional remedies is spreading rapidly in developed countries. Although it is commonly thought that such medications are not harmful because they are of natural origin, they often contain dangerous ingredients, especially heavy metals. Several cases of poisoning, mainly lead poisoning, have been published, but none to our knowledge in France. We recently observed a case of lead poisoning in a man who had been taking ayurvedic remedies. CASE: A 32-year-old man was repeatedly hospitalized for paroxysmal abdominal pain with constipation, weight loss, anemia, and mild elevation of liver enzyme levels. Four months after the initial admission, blood lead measurement showed heavy metal poisoning. The patient was treated with a chelating agent and recovered uneventfully. Investigation revealed that the lead source was self-medication with an ayurvedic remedy, a powder used for four weeks before the first hospitalization. DISCUSSION: To our knowledge this is the first reported French case of lead poisoning due to a traditional remedy. The problem is undoubtedly more widespread, however, for use of traditional remedies is growing more here, and many of them contain dangerous ingredients. Patients from communities known to use traditional medicines or recently returned from countries where such treatments are widespread should be directly questioned about their use of these remedies, because this information will not usually be volunteered. Information directed at populations at risk is also advisable, for most users are unaware that so-called 'natural' medicines can be dangerous.

Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma.

Human T-cell lymphotropic virus type 1 associated adult T-cell leukemia/lymphoma carries a very poor prognosis due to its intrinsic resistance to chemotherapy. Although zidovudine (AZT) and alpha-interferon (IFN) yield some responses and improve ATL prognosis, alternative therapies are needed. Arsenic trioxide (As) dramatically synergizes with IFN to induce growth arrest and apoptosis of ATL leukemia cells in vitro. These results prompted us to initiate a phase II trial of As/IFN combination in seven patients with relapsed/refractory ATL (four acute and three lymphoma). Four patients exhibited a clear initial response (one complete remission and three partial remissions). Yet, the treatment was discontinued after a median of 22 days because of toxicity (three patients) or subsequent progression (four patients). Six patients eventually died from progressive disease (five patients) or infection (one patient), but the remaining patient is still alive and disease free at 32 months. Pharmacokinetic studies showed that maximum arsenic blood levels (median 0.46 microM) were slowly achieved (8-15 days). In conclusion, arsenic/IFN treatment is feasible and exhibits an anti-leukemia effect in very poor prognosis ATL patients despite a significant toxicity. Future studies should assess the best timing for arsenic therapy: frontline with IFN/AZT or as maintenance after induction.

Lead reduces messenger RNA and protein levels of cytochrome p450 aromatase and estrogen receptor beta in human ovarian granulosa cells.

Exposure to lead causes decreased fertility in women. In the present study, we examined the in vitro effects of lead on cytochrome p450 aromatase (p450 arom) and on estrogen receptor beta (ERbeta), two key proteins for the human ovary. Aromatase is required for the bioconversion of androgen to estradiol; ERbeta mediates estrogen effects in granulosa cells. Granulosa cells were collected from women undergoing in vitro fertilization and then cultured with 10 microM lead acetate. Using atomic absorption spectrometry, we showed that lead accumulated in cells. Aromatase activity as measured by a tritiated water production assay was significantly reduced. Using semiquantitative reverse transcription-polymerase chain reaction and Western blotting procedures, we showed that p450 arom and ERbeta mRNA and protein content were both significantly reduced. Adding 10 microg/ml of cycloheximide, a protein inhibitor, did not eliminate the effects of lead. The present results support the hypothesis that the action of lead on fertility in women may result, in part, from the down-regulation of p450 arom and ERbeta gene transcription in ovarian granulosa.