Light-chain only multiple myeloma is due to the absence of functional (productive) rearrangement of the IgH gene at the DNA level

Although most multiple myeloma (MM) cases are characterized by the detection of a monoclonal immunoglobulin in the serum, about 15% of the patients present only immunoglobulin light chains, detected either in the urine or serum or both. These patients are designated as having light-chain (LC) MM. Using fiber-fluorescent in situ hybridization, and in contrast to patients and myeloma cell lines secreting heavy chains (who presented a legitimate functional IgH rearrangement in every case), LC MM never displayed a functional IgH recombination. Interestingly, most LC MM cases presented one IgH allele with a germline configuration (including the DJ region), the second allele being usually involved in an illegitimate recombination. Of note, most of these translocations occurred close to (or at) switch regions, even though in some cases, breakpoints involving nonswitch regions were observed. Thus, this study clearly showed that LC MM is due to the absence of legitimate IgH rearrangement at the DNA level, reflecting possible abnormalities in the IgH gene recombinations during B-cell maturation. Furthermore, it showed that this defect did not prevent the activation of the switch process because most of 14q32 translocations observed in LC MM occurred at switch regions.     

BRCA1, BRCA2, AR and IGF-I expression in prostate cancer: correlation between RT-qPCR and immunohistochemical detection

Identification and characterization of biomarkers in prostate cancer are important for improving the diagnosis. The aim of this study was to determine differences in the expression of 4 genes according to the stage of malignancy in prostate cancer. We analyzed BRCA1, BRCA2, androgen receptor (AR) and IGF-I gene expression in a cohort of 98 prostate biopsies. We used TaqMan RT-qPCR for mRNA detection, and correlation with proteins was performed using immunohistochemistry. Among the 98 studied prostate biopsies, high heterogeneity in the expression of the 4 genes was detected among the different histological types. However, down-regulation of BRCA1 and BRCA2 mRNA was detected, particularly in the normal tissues. The expression of AR was dependent on the stage of the tumor. The IGF-I gene was specifically expressed in the tumor tissues. Upon comparison between protein and mRNA expression for BRCA1, BRCA2 and AR, we obtained a trend; however, this did not achieve statistical significance. Regarding IGF-I, a correlation between mRNA expression and staining intensity of the protein was found to be significant (p<0.012). The AR biomarker was found to be slightly correlated with the prostate cancer diagnosis (p=0.013). AR was found to be decreased in the tumors with a 43% sensitivity and 90% specificity. The relative risk of 2.05 (1.13-3.69) indicated a 2?fold higher chance of cancer occurrence when AR was ≤0.206.     

Quantification of eight new antidepressants and five of their active metabolites in whole blood by high-performance liquid chromatography-tandem mass spectrometry

A liquid chromatography-tandem mass spectrometry method is described for the blood determination of selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram), serotonin noradrenaline reuptake inhibitors (milnacipram and venlafaxine), a noradrenergic and specific serotoninergic antidepressant (mirtazapine) and five of their active metabolites (norfluoxetine, desmethylcitalopram, didesmethylcitalopram, desmethylvenlafaxine, and desmethylmirtazapine). After a liquid-liquid extraction from blood, the compounds and the internal standard (methylrisperidone) were eluted on a XTerra RP18 column with a gradient of acetonitrile/ammonium formate buffer 4 mmol/L pH 3.2. They were then detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode. The calibration curves were linear over the range 5-500 ng/mL (20-2000 ng/mL for venlafaxine and desmethylvenlafaxine). The limit of quantification was set at 5 ng/mL for each compound (except for venlafaxine and desmethylvenlafaxine: 20 ng/mL). The bias were lower than 12%. Intraday and interday precisions, expressed as variation coefficient, were lower than 11%. The extraction recoveries were between 70 and 90% except for desmethylmirtazapine, desmethylvenlafaxine, milnacipram, and didesmethylcitalopram. This specific and sensitive method allows management of intoxication and is suitable for the routine determination of antidepressants in forensic investigations.     

A phase I and pharmacokinetic study of plitidepsin in children with advanced solid tumours: an Innovative Therapies for Children with Cancer (ITCC) study

AimsTo determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2 weeks (one cycle) to children with refractory or relapsed solid tumours.MethodsConsecutive cohorts of patients were treated according to a standard ‘3 + 3’ design with escalating doses of plitidepsin at 4, 5 and 6 mg/m². Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity.ResultsThirty-eight of 41 patients registered received plitidepsin. Dose-limiting toxicities during the first three treatment cycles related to myalgia, elevated creatine phosphokinase, transaminase increase and nausea/vomiting. The RD for plitidepsin is 5 mg/m². PK analyses revealed high inter-patient variability in plasma, but a similar clearance of plitidepsin in children and adolescents. One partial response confirmed at 4 weeks in a patient with neuroblastoma and one unconfirmed partial response in a pancreatoblastoma were observed; four other patients with neuroblastoma, medulloblastoma, glioblastoma and rhabdoid tumour had disease stabilisations lasting ⩾3 months.ConclusionPlitidepsin administered to children as a 3-h infusion every 2 weeks is received with manageable toxicity for children with cancer, and the RD is 5 mg/m². Pharmacokinetic parameters in children and adolescents are comparable to adults. Future phase II studies of plitidepsin are warranted, and our results suggest that plitidepsin could be appropriately developed in combination with other antitumour where myelosuppression is dose-limiting.     

NIRS‐measured oxy‐ and deoxyhemoglobin changes associated with EEG spike‐and‐wave discharges in a genetic model of absence epilepsy: The GAERS

Purpose: Absence epilepsy may be severe and is frequently accompanied by cognitive delay, yet its metabolic/hemodynamic aspects have not been established. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an isomorphic, predictive, and homologous model of human absence epilepsy. We studied hemodynamic changes related to generalized spike‐and‐wave discharges (GSWDs) in GAERS by using a technique with high temporal resolution: near‐infrared spectroscopy (NIRS). We hypothesized that conflicting results from other techniques might be due to the averaging of a biphasic response such as the one we described in children. Methods: NIRS is particularly suitable for monitoring changes in the concentrations of oxy‐, deoxy‐, and total hemoglobin (HbO₂, HHb, and HbT), using the specific absorption properties of living tissues in the near infrared range. We obtained concomitant high quality electroencephalography (EEG)–NIRS recordings in six GAERS (total of 444 seizures), and tested whether the discharges were related to changes in cardiac or respiration rates. Results: The onset of GSWDs was preceded by a deactivation, followed by an activation that was possibly due to seizure‐suppression mechanisms. The end was marked by a deactivation. The onset of GSWDs was associated with a decrease and the end with a brief increase in respiratory rate. Discussion: Our results differ partially from those of previous studies on hemodynamic aspects of GSWDs (many of which describe a simple deactivation), probably due to differences in temporal resolution and data processing; however, they are consistent with metabolic studies, functional magnetic resonance imaging (fMRI) studies on WAG/Rij rats, and some results in children with absence epilepsy.     

High-resolution electroencephalography and source localization in neonates

Although Electroencephalography (EEG) source localization is being widely used in adults, this promising technique has not yet been applied to newborns because of technical difficulties, such as lack of data concerning the newborn skull conductivity, thickness, and homogeneity. Using a new type of EEG headcap molded on each baby's head, we aimed to determine whether this technique could be adapted to neonates, and to evaluate the importance of these technical difficulties. We carried out EEG source reconstruction of the recordings of five neonates using dipole fit algorithm. We used four different head models for each neonate, obtained from individual MRI scans: normal skull thickness and conductivity of 0.0042 S/m; normal thickness and conductivity of 0.33 S/m; increased thickness and conductivity of 0.0042 S/m; and normal thickness and conductivity with a modeled bregma fontanel. Dipole locations were consistent with MRI and clinical data. The mean difference between the dipole locations in the 0.0042 and the 0.33 S/m skull layer models was 11.6 +/- 2.5 mm, with an average 29.7% decrease in magnitude for the 0.33 S/m model but no significant changes for the dipoles orientation. Skull layer thickness had a large influence on magnitude, but no significant effect on position and orientation. The mean difference between the dipole locations induced by the modeled fontanel was 2.0 +/- 2.1 mm, with an average 2.1% increase in magnitude. Our results show that EEG source localization is feasible in neonates. With further development, the technique may prove useful for neurological evaluation of neonates.     

Effects of anti-depressants on olfactory sensitivity in mice

RATIONALE AND OBJECTIVES: Some studies have underlined a decrease in olfactory sensitivity in patients suffering from depression. The present study aims to evaluate the effects of current anti-depressant drugs on the olfactory sensitivity in mice. METHODS MICE: (N degrees =22) were tested in a Y-maze with a choice between an odorant (butanol) or distilled water before and during 3 weeks of daily intra-peritoneal injection of either citalopram or clomipramine. Their performance was compared with those of a control group (N degrees =11) injected with a saline solution. RESULTS: The results showed a significant decrease in olfactory sensitivity with both anti-depressants during the three weeks of treatment. CONCLUSION: The antidepressant induced alteration in serotonin and/or noradrenaline transmission in the olfactory bulb may account for the altered olfactory sensitivity observed in this study.     

A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system

Listeria monocytogenes is a human intracellular pathogen that is able to survive in the gastrointestinal environment and replicate in macrophages, thus bypassing the early innate immune defenses. Peptidoglycan (PG) is an essential component of the bacterial cell wall readily exposed to the host and, thus, an important target for the innate immune system. Characterization of the PG from L. monocytogenes demonstrated deacetylation of N-acetylglucosamine residues. We identified a PG N-deacetylase gene, pgdA, in L. monocytogenes genome sequence. Inactivation of pgdA revealed the key role of this PG modification in bacterial virulence because the mutant was extremely sensitive to the bacteriolytic activity of lysozyme, and growth was severely impaired after oral and i.v. inoculations. Within macrophage vacuoles, the mutant was rapidly destroyed and induced a massive IFN-beta response in a TLR2 and Nod1-dependent manner. Together, these results reveal that PG N-deacetylation is a highly efficient mechanism used by Listeria to evade innate host defenses. The presence of deacetylase genes in other pathogenic bacteria indicates that PG N-deacetylation could be a general mechanism used by bacteria to evade the host innate immune system.     

Diffuse large B-cell lymphoma in hyperimmunoglobulinemia E syndrome

We report a case of diffuse large B-cell lymphoma occurring in a patient with the hyperimmunoglobulinemia E syndrome, a rare immune disorder defined by elevated immunoglobulin E levels and recurrent bacterial and fungal infections often manifesting as cold abscesses. This case further supports the notion that patients with hyperimmunoglobulinemia E have an increased risk of lymphoid malignancies and should be closely monitored. Despite a theoretic risk of severe infectious complications, chemotherapy was well tolerated and resulted in a sustained complete remission.