Methylmalonic acidemia and hyperglycemia: an unusual association

Introduction: Hyperglycemia is an exceptional manifestation of methylmalonic acidemia (MMA). We describe a patient with MMA in whom we observed a hyperglycemia which improved under treatment of the metabolic crisis. Case report: A 14 month-old boy presented with an acute generalized dystonia and lethargy preceded by fever, vomiting and lethargy at the age of 13 months. Biological investigations showed a hyperglycemia, a lactic acidosis and a hyperammonemia. Urinary organic acid analysis showed accumulation of methylmalonic acid, tiglylglycine and methylcitrate leading to the diagnosis of MMA. The patient underwent symptomatic treatment with rapid improvement of general condition, consciousness and gradual normalization of biological parameters especially glycemia after 6 days without using insulinotherapy. Discussion: MMA is an autosomal recessive disorder caused by a deficiency of methylmalonyl-CoA mutase resulting in methylmalonic acid accumulation. Biochemically, the disorder is typically characterized by: metabolic acidosis, ketonemia or ketonuria, hyperammonemia, leukopenia, thrombocytopenia and anemia. Hypoglycemia is a frequent manifestation of MMA. Our patient presented a hyperglycemia, which is unusual in MMA, since we found only three patients reported with this association. Pathophysiology remains unknown. In reported cases, hyperglycemia was treated by insulin therapy and reducing glucose intravenous infusion, with fatal outcome. In our patient glycemia spontaneously normalized after treatment of the metabolic crisis. Conclusion: Hyperglycemia is an exceptional manifestation of MMA and could be a seriousness marker.     

Antibacterial activity of Thymoquinone,an active principle of <Emphasis Type="Italic">Nigella sativa</Emphasis> and its potency to prevent bacterial biofilm formation

Background  

Thymoquinone is an active principle of Nigella sativa seed known as "Habbah Al-Sauda" in Arabic countries and "Sinouj" in Tunisia. Bacterial biofilms tend to exhibit significant tolerance to antimicrobials drugs during infections.     

Population pharmacokinetics and Bayesian estimation of cyclosporine in a Tunisian population of hematopoietic stem cell transplant recipient

Purpose

Therapeutic drug monitoring of cyclosporine minimizes the risk of toxicity and acute rejection after transplantation. Areas under the curve (AUCs) rather than trough concentration-based monitoring are recommended. Population pharmacokinetics (PopPK) modeling and Bayesian estimation seem to be the best way to predict cyclosporine disposition and dose requirements to achieve the therapeutic target in an individual patient because of the possibility of predicting cyclosporine AUC using only a few blood samples. Our objectives were to build a PopPk model for cyclosporine in a Tunisian population of HSCT patients and to develop a Bayesian method for the estimation of individual cyclosporine AUC.

Patients and methods

The PopPk of cyclosporine was studied using nonlinear mixed effects modeling (NONMEM) in 30 patients (index group) receiving cyclosporine on a twice-daily basis. Ten blood samples were collected after steady-state morning cyclosporine dose. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements in an independent group of 30 patients (test group).

Results

A two-compartment model with first-order absorption and a lag time provided the best fitting. The population mean estimate and interindividual variability from the final model for CL, Ka, Tlag, V1, V2, and Q were 25.4?L/h (CV?=?38.72?%), 0.214?h^?1(CV?=?28.5?%), 0.382?h, 10.9?L (85.73?%), 496?L, and 5?L/h, respectively. Covariates had no discernible effects on cyclosporine pharmacokinetics in our population. Bayesian estimation provided an accurate estimation of AUC, although a bias was observed leading to slight underprediction of AUC (bias ?1.03?%). A very satisfactory precision was observed (RMSE 12.07?%).

Conclusion

We report a PopPK model for cyclosporine in Tunisian HSCT patients. Bayesian estimation using only three concentrations provides good prediction of cyclosporine exposure. These tools allow us to routinely estimate cyclosporine AUC in a clinical setting.     

Unusual cause of syncope in a 17 year-old young woman: left ventricular hydatid cyst

Cardiac involvement in echinococcosis remains a singular finding, possibly associated with confusing symptomatology. We report the original case of a 17 year-old young woman, referred to our cardiology department for repeated exertion syncopes, and ultimately, proven through echocardiography, serologies and magnetic resonance imaging to have a massive hydatid cyst developing inside the left ventricular cavity towards the outflow tract. The cyst has been surgically completely removed with excellent results.     

Enhanced expression of STIM1/Orai1 and TRPC3 in platelets from patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (DM2) is a metabolic syndrome that contributes to both macrovascular and microvascular disorders, where platelet hyperaggregability, associated to abnormal intracellular Ca²⁺ homeostasis, plays an important role. We have now investigated the expression of different proteins associated to Ca²⁺ entry, a major Ca²⁺ signalling event. DM2 donors were randomly selected from normotensive patients with glycosylated Hb levels (HbA1c) over 6%. Control subjects were normal age- and gender-matched healthy people with HbA1c levels in the normal range (3.5–5%). Expression of TRPC1, 3 and 6, STIM1 and Orai1 was analyzed by Western blotting in DM2 patients and controls. Expression of TRPC1 in platelets from DM2 donors and controls was similar; however, expression of TRPC6 is reduced in platelets from DM2 patients as compared to healthy controls. We have found that expression of TRPC3, Orai1 and STIM1 is enhanced in DM2 subjects as compared to controls. Our findings provide an explanation to the enhanced Ca²⁺ entry induced by physiological agonists in platelets from DM2 patients.     

Olive tree wood phenolic compounds with human platelet antiaggregant properties

Oleuropein and (+)-cycloolivil are natural polyphenolic compounds with a significant radical scavenging activity present in olive tree. We have investigated the antiaggregant effects of oleuropein and (+)-cycloolivil isolated from an ethyl acetate extract of olive tree wood. Oleuropein and (+)-cycloolivil reduced the ability of thrombin to stimulate platelet aggregation. Both compounds reduced thrombin-evoked Ca²⁺ release and entry to a similar extent to hydroxytyrosol. This effect was greater in platelets from patients with type 2 diabetes mellitus than in controls. Thrombin-, thapsigargin- and 2,5-di-(tert-butyl)-1,4-hydroquinone (TBHQ)-evoked protein tyrosine phosphorylation, which is involved in Ca²⁺ signalling and platelet aggregation, is inhibited by oleuropein and (+)-cycloolivil. oleuropein and (+)-cycloolivil are natural oxygen radical scavengers that reduce thrombin-induced protein tyrosine phosphorylation, Ca²⁺ signalling and platelet aggregation. These observations suggest that oleuropein and (+)-cycloolivil may prevent thrombotic complications associated to platelet hyperaggregability and be the base for the development of antiaggregant therapeutic strategies.     

Chromosomal microarray analysis in a girl with mental retardation and spina bifida

Chromosomal imbalances comprise a major cause of mental retardation, particularly in association with congenital malformations and dysmorphic features. Chromosomal analysis using banded karyotyping is limited by the low resolution of this technique, and cryptic chromosomal rearrangements cannot be detected. We describe a 6-year-old girl with mental retardation, mild growth, congenital malformation, and facial anomalies. Chromosomal analysis with karyotyping produced normal results. Because the phenotype suggested chromosomal abnormality, microarray comparative genomic hybridization was used to search for a possible cryptic anomaly. A subtelomeric chromosomal imbalance, consisting of partial trisomy 2q35 and partial monosomy 3p26, was detected and confirmed using fluorescence in situ hybridization. This rearrangement was inherited from an equilibrated maternal t(2;3) reciprocal translocation. Comparative genomic hybridization array in similar situations is useful in detecting cryptic chromosomal rearrangements, identifying genes contained in deleted or duplicated regions, establishing a precise phenotype-genotype correlation, and offering unambiguous genetic counseling.     

SHARE road map for HealthGrids: Methodology

The SHARE¹ project (http://www.eu-share.org) was asked to identify the key developments needed to achieve wide adoption and deployment of HealthGrids throughout Europe. The project was asked to organise these as milestones on a road map, so that all technical advances, social actions, economic investments and ethical or legal initiatives necessary for HealthGrids would be seen together in a single coherent document. The full road map includes an extensive analysis of several case studies exploring their technical requirements, full discussion of the ethical, legal, social and economic issues which may impede early deployment, and concludes with an attempt to reconcile the tensions between technological developments and regulatory frameworks. This paper has been restricted to the technical aspects of the project.SHARE built on the work of the ‘HealthGrid’ initiative so we begin by, reviewing work carried out in various European HealthGrid projects and report on joint work with numerous European collaborators. Following many successful HealthGrid projects, HealthGrid published a ‘White Paper’ which establishes the foundations, potential scope and prospects of an approach to health informatics based on a grid infrastructure. The White Paper demonstrates the ways in which the HealthGrid approach supports many modern trends in medicine and healthcare, such as evidence-based practice, integration across levels, from molecules and cells, through tissues and organs to the whole person and community, and the promise of individualised healthcare. SHARE was funded by the European Commission to define a research roadmap for a ‘HealthGrid for Europe’, to be seen as the preferred infrastructure for biomedical and healthcare projects in the European Research Area.     

Intra‐articular hip neurofibromas in von Recklinghausen's disease

Neurofibromatosis is a genetic disorder with osteo‐articular manifestations. The intra‐articular location of neurofibroma is scarce.