Cefazolin tissue concentrations with a prophylactic dose administered before sleeve gastrectomy in obese patients: a single centre study in 116 patients.

BACKGROUND: In obese patients undergoing sleeve gastrectomy, the blood and fatty-tissue concentrations of cefazolin required for adequate antibiotic prophylaxis are uncertain. METHODS: This was a single centre prospective study in obese (Group A: 40≤ BMI ≤50 kg m-2) and severely obese (Group B: 50< BMI ≤65 kg m-2) patients undergoing bariatric surgery. Blood and fatty-tissue samples were collected after a cefazolin 4 g i.v. injection. The primary aim was to compare cefazolin concentrations in subcutaneous fatty tissue with a targeted tissue concentration of 4 µg g-1 according to Staphylococcus aureus resistance breakpoint. RESULTS: One hundred and sixteen patients were included: 79 in Group A and 37 in Group B. At the beginning of the surgery, cefazolin concentration in subcutaneous fatty tissue was 12.2 (5.4) µg g-1 in Group A and 12 (6.1) µg g-1 in Group B (P=0.7). At the end, cefazolin concentrations in subcutaneous fatty tissue were 9.0 (4.9) and 7.8 (4.2) µg g-1 in Groups A and B, respectively (P=0.2). The plasma concentration of free cefazolin during surgery was higher in Group A than in Group B (P<0.0001). Fatty-tissue concentrations of 95% and 83% patients in Groups A and B, respectively, were above S. aureus resistance breakpoint. CONCLUSIONS: After a 4 g dose, the concentrations of cefazolin in fatty tissue were above the 4 µg g-1 tissue concentration target, providing adequate antibiotic tissue concentrations during bariatric surgery. As cefazolin concentration in fatty tissue is a surrogate endpoint, the results should be considered in conjunction with the results on free cefazolin concentrations in subcutaneous tissue. CLINICAL TRIAL REGISTRATION: NCT01537380.

Binary zero-order diffractive and anti-reflective optical elements in silicon for the mid-infrared.

We propose a novel method for the design of binary two-level diffractive optical elements that provide an efficient diffractive function while reducing the reflectivity of a high-index interface. The structure can be fabricated with a single patterning step and is particularly useful for the mid-infrared spectral range. The concept is based on zero-order transmission gratings using subwavelength microstructures. To demonstrate the concept a Dammann grating has been realized in silicon and characterized in the mid-infrared by scanning the far-field intensity distribution.

[Cathinones use in Paris]. / Usage de cathinones à Paris.

BACKGROUND: The pattern of recreational drug use has changed over the last decade and now includes a multitude of substances sold as "research chemicals" or new psychoactive substances, "NPS". In France, synthetic cathinones emerged in 2008 (while first mentioned by the French police force in 2007 first alerts among users appeared in 2008) and have grown to be popular drugs of abuse. Under the Official Journal dated 11th June 2010, only mephedrone has been listed as narcotics but "designer drugs" have synthesized new substitute cathinones in order to avoid anti-drug laws. However, since July 2012, in France, all synthetic drugs from the cathinones family have been banned and listed as narcotics following the example of United Kingdom. Despite their recent classification and inclusion on narcotic list, they are readily available on Internet and used widely. Paris Addictovigilance Centre observed a signal of derivate cathinones abuse (21 cases over a two-year period). OBJECTIVE: Paris Addictovigilance Centre and Marmottan Hospital wanted to describe the use of cathinones in the Paris area and alert the health care community about the abuse identification and risk assessment problems of these compounds. After a review of derivated cathinone's chemical structure, pharmacology and toxicology, this article seeks to provide patricians with a clinical description and treatment's modality. RESULTS: Most users of synthetic cathinones will experience euphoria, increased energy, talkativeness, openness and increased sexual arousal. Signs and symptoms of toxicity are consistent with a sympathomimetic toxidrome. The main reasons for care access are psychiatric (hallucinations, psychotic symptoms, agitation) and addiction disorders. Somatic complications were described with various patterns of symptoms such as headache, tachycardia, confusional states, rhabdomyolysis with renal failure or serotonin syndrome. The most important fact is the apparition of the "slam" phenomenon among men who have sex with men (MSM). The "slam" is a compound of three characteristic elements: injection, sexual party and psychostimulant drug. According to users, "slam" is convenient for group sex and is used it to put them into a good mood and a disinhibition state. These compounds cause fast dependence syndrome with strong craving and prolonged psychiatric symptoms and increase infectious risk (HIV, VHC, VHB…). The cathinones family is not detected in conventional urine drug screenings. We point out the lack of confirmatory analytic testing data which remains the only way to determine the actual etiology of the clinical effects observed since drug users do not always know exactly what they took. These substances can be identified by special analyses using gas chromatography or liquid chromatography and mass spectroscopy technology. CONCLUSION: This injection drug is used in order to increase sexual desire, delay orgasm and decrease sexual inhibition and is prevalent in many studies on MSM samples. Cathinones would popularize the "slam". Harm reduction policy requires specific MSM interventions on both sexual and drug addiction networks.

Leaf wounding or simulated herbivory in young N. attenuata plants reduces carbon delivery to roots and root tips.

MAIN CONCLUSION: In Nicotiana attenuata seedlings, simulated herbivo ry by the specialist Manduca sexta decreases root growth and partitioning of recent photoassimilates to roots in contrast to increased partitioning reported for older plants. Root elongation rate in Nicotiana attenuata has been shown to decrease after leaf herbivory, despite reports of an increased proportion of recently mobilized photoassimilate being delivered towards the root system in many species after similar treatments. To study this apparent contradiction, we measured the distribution of recent photoassimilate within root tissues after wounding or simulated herbivory of N. attenuata leaves. We found no contradiction: herbivory reduced carbon delivery to root tips. However, the speed of phloem transport in both shoot and root, and the delivery of recently assimilated carbon to the entire root system, declined after wounding or simulated herbivory, in contrast with the often-reported increase in root partitioning. We conclude that the herbivory response in N. attenuata seedlings is to favor the shoot and not bunker carbon in the root system.

Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [(18)F]PBR102 and [ (18)F]PBR111 in a model of excitotoxin-induced neuroinflammation.

PURPOSE: The in vivo binding parameters of the novel imidazopyridine TSPO ligand [(18)F]PBR102 were assessed and compared with those of [(18)F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). METHODS: Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [(18)F]PBR102 or [(18)F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration-time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [(125)I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. RESULTS: The BPs of [(18)F]PBR102 [(18)F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [(11)C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP. CONCLUSION: [(18)F]PBR102 and [(18)F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [(11)C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation.

Handheld device quantifies breath acetone for real-life metabolic health monitoring.

Non-invasive breath analysis with mobile health devices bears tremendous potential to guide therapeutic treatment and personalize lifestyle changes. Of particular interest is the breath volatile acetone, a biomarker for fat burning, that could help in understanding and treating metabolic diseases. Here, we report a hand-held (6 × 10 × 19.5 cm3), light-weight (490 g), and simple device for rapid acetone detection in breath. It comprises a tailor-made end-tidal breath sampling unit, connected to a sensor and a pump for on-demand breath sampling, all operated using a Raspberry Pi microcontroller connected with a HDMI touchscreen. Accurate acetone detection is enabled by introducing a catalytic filter and a separation column, which remove and separate undesired interferents from acetone upstream of the sensor. This way, acetone is detected selectively even in complex gas mixtures containing highly concentrated interferents. This device accurately tracks breath acetone concentrations in the exhaled breath of five volunteers during a ketogenic diet, being as high as 26.3 ppm. Most importantly, it can differentiate small acetone changes during a baseline visit as well as before and after an exercise stimulus, being as low as 0.5 ppm. It is stable for at least four months (122 days), and features excellent bias and precision of 0.03 and 0.6 ppm at concentrations below 5 ppm, as validated by proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS). Hence, this detector is highly promising for simple-in-use, non-invasive, and routine monitoring of acetone to guide therapeutic treatment and track lifestyle changes.

Pitfalls and potential of high-throughput plant phenotyping platforms.

Automated high-throughput plant phenotyping (HTPP) enables non-invasive, fast and standardized evaluations of a large number of plants for size, development, and certain physiological variables. Many research groups recognize the potential of HTPP and have made significant investments in HTPP infrastructure, or are considering doing so. To make optimal use of limited resources, it is important to plan and use these facilities prudently and to interpret the results carefully. Here we present a number of points that users should consider before purchasing, building or utilizing such equipment. They relate to (1) the financial and time investment for acquisition, operation, and maintenance, (2) the constraints associated with such machines in terms of flexibility and growth conditions, (3) the pros and cons of frequent non-destructive measurements, (4) the level of information provided by proxy traits, and (5) the utilization of calibration curves. Using data from an Arabidopsis experiment, we demonstrate how diurnal changes in leaf angle can impact plant size estimates from top-view cameras, causing deviations of more than 20% over the day. Growth analysis data from another rosette species showed that there was a curvilinear relationship between total and projected leaf area. Neglecting this curvilinearity resulted in linear calibration curves that, although having a high r2 (> 0.92), also exhibited large relative errors. Another important consideration we discussed is the frequency at which calibration curves need to be generated and whether different treatments, seasons, or genotypes require distinct calibration curves. In conclusion, HTPP systems have become a valuable addition to the toolbox of plant biologists, provided that these systems are tailored to the research questions of interest, and users are aware of both the possible pitfalls and potential involved.

Accuracy of gradient diffusion method for susceptibility testing of dalbavancin and comparators.

OBJECTIVES: This multicenter study aimed to assess the performances of gradient diffusion (GD) method in comparison to broth microdilution (BMD) method for susceptibility testing of dalbavancin, daptomycin, vancomycin, and teicoplanin. METHODS: Minimum Inhibitory Concentrations (MICs) were retrospectively determined concomitantly by BMD and GD methods, for 93 staphylococci and enterococci isolated from clinical samples. BMD was considered as the gold standard. Essential (EA) and categorical agreements (CA) were calculated. Discordant categorical results were categorized as major (ME) and very major errors (VME). RESULTS: EA and CA were 95.7% and 96.8%, 82.8% and 100%, 97.8% and 96.8%, and 94.6% and 95.7% for dalbavancin, daptomycin, vancomycin, and teicoplanin respectively. Concerning dalbavancin, 3 ME without any VME were observed and discrepancies were low (≤ to 2 two-fold dilutions) between both methods. VME were noted in 1 and 3 cases for vancomycin and teicoplanin, respectively, and resulted from 1 two-fold dilution discrepancy in each case. EA was lower for daptomycin. When they were discrepant, BMD MICs were systematically higher than GD ones. Nevertheless, no categorical discrepancy was noted. CONCLUSIONS: GD appears as an acceptable and convenient alternative for dalbavancin, vancomycin, and teicoplanin MICs determination. Our study also emphasizes how achieving accurate daptomycin MICs remains challenging.

Recognition of pleural mesothelioma by mucin-1(950-958)/human leukocyte antigen A*0201-specific CD8+ T-cells.

Recent clinical investigations have demonstrated that T-cell-based immunotherapy of malignant pleural mesothelioma (MPM) could represent an alternative to the other therapeutic strategies. However, its development suffers from the lack of identified tumour antigenic targets. Mucin (MUC)1, which is expressed and recognised by cytotoxic T-cells in numerous cancer types, has not been investigated as a potential immune target in MPM. Thus, the objective of this study was to analyse MUC1 expression by MPM cells and to determine whether this antigen can be the target of cytotoxic CD8+ T-cells (cytotoxic T-lymphocytes (CTLs)). We first evaluated the expression and glycosylation of MUC1 by MPM cell lines using different MUC1-specific monoclonal antibodies. We then obtained a CTL clone specific for a MUC1 peptide (residues 950-958) presented by human leukocyte antigen (HLA)-A*0201 and studied its interferon-γ and cytotoxic response to MPM cell lines. We found that all MPM cell lines expressed MUC1 protein at the cell surface with different glycosylation profiles. We also observed that HLA-A*0201+ MPM cell lines are recognised and lysed by a HLA-A*0201/MUC1(950-958)-specific CTL clone independently of the MUC1 glycosylation profile. Thus, MUC1 expression and antigen presentation by MPM cells may represent an attractive target for immunotherapeutic treatment of MPM despite its hyperglycosylated profile.

A 5-aza-2'-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumour with a limited response to conventional therapy. The aim of this study was to evaluate the anticancer effect of a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-azaCdR), and two histone deacetylase inhibitors, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA). Human mesothelioma cells were treated with each epigenetic drug, either alone or in combinations. The cytotoxic effects on treated cells and the expression of specific tumour antigens were evaluated. The recognition of treated cells by a specific CD8+ T-cell clone was also measured. Additionally, the effect of combined treatments was tested in a murine model of mesothelioma. We showed that VPA and SAHA synergised with 5-azaCdR to kill MPM cells and induce tumour antigen expression in the remaining living tumour cells. As a consequence, tumour cells expressing these antigens were recognised and lysed by specific CD8+ cytotoxic T-cells. In vivo, treatment with 5-azaCdR/VPA inhibited tumour growth, and promoted lymphocyte infiltration and an immune response against tumour cells. Appropriate epigenetic drug combinations, in addition to inducing mesothelioma cell death, also affect the immunogenic status of these cells. This property could be exploited in clinical investigations to develop MPM treatments combining chemotherapeutic and immunotherapeutic approaches.

Jasmonic acid does not mediate root growth responses to wounding in Arabidopsis thaliana.

Jasmonic acid (JA) is a crucial plant defence signalling substance that has recently been shown to mediate herbivory-induced root growth reduction in the ecological model species Nicotiana attenuata. To clarify whether JA-induced reduction of root growth might be a general response increasing plant fitness under biotic stress, a suite of experiments was performed with the model plant Arabidopsis thaliana. JA bursts were elicited in leaves of A. thaliana in different ways. Root growth reduction was neither induced by foliar application of herbivore oral secretions nor by direct application of methyl jasmonate to leaves. Root growth reduction was observed when leaves were infected with the pathogen Pseudomonas syringae pv. tomato, which persistently induces the JA signalling pathway. Yet, high resolution growth analyses of this effect in wild type and JA biosynthesis knock-out mutants showed that it was elicited by the bacterial toxin coronatine that suggests ethylene- but not JA-induced root growth reduction in A. thaliana. Overall, the results demonstrate that the reaction of root growth to herbivore-induced JA signalling differs among species, which is discussed in the context of different ecological defence strategies among species.

PK/PD targets of amikacin and gentamicin in ICU patients.

OBJECTIVES: We aimed to evaluate the probability to achieve PK-PD targets in patients with sepsis hospitalized in the intensive care unit (ICU) after a single dose of 30mg/kg of amikacin or 8mg/kg of gentamicin. PATIENTS AND METHODS: This single-center prospective study included 138 ICU patients with severe sepsis or septic shock with an indication for intravenous amikacin (N=89) or gentamicin (N=49). Maximum concentration (Cmax) was measured 30 minutes after infusion completion. PK/PD objectives were respectively Cmax≥60mg/L and ≥30mg/L for amikacin and gentamicin for empirical therapy, and a Cmax/MIC ratio≥8, as per French guidelines. RESULTS: The median Simplified Acute Physiology Score II was 43 and ICU case fatality rate was 34.8%. A causative bacterial agent was identified in 94 patients (68.1%). Three pathogens had acquired aminoglycoside resistance and 15 were naturally resistant. The targeted Cmax for the first dose was achieved in 53 patients (59.6%) receiving amikacin, and one (2.2%) patient receiving gentamicin. Cmax/MIC ratio≥8 was obtained in all patients infected with susceptible pathogens (N=72). Factors associated with Cmax≥60mg/L of amikacin in multivariate analysis were dose per kg of adapted body weight (OR=1.39, P<0.001) and renal clearance estimated with CKD-EPI formula (OR=0.98, P=0.003). CONCLUSIONS: Despite high doses, amikacin and gentamicin first Cmax remain dramatically low in ICU patients. However, an adequate Cmax/MIC ratio was reached in all patients.

Should we reconsider cefazolin for treating staphylococcal meningitis? A retrospective analysis of cefazolin and cloxacillin cerebrospinal fluid levels in patients treated for staphylococcal meningitis.

OBJECTIVES: To assess the meningeal penetration of cefazolin and cloxacillin in individuals treated for methicillin-susceptible staphylococcal meningitis. METHODS: We retrospectively identified individuals treated for Staphylococcus meningitis with measurements of cefazolin or cloxacillin concentrations in cerebrospinal fluid (CSF) using a validated assay of liquid chromatography coupled with mass spectrometry at the Nantes University Hospital between January 2009 and October 2019. Staphylococcus meningitis was defined by a compatible clinical presentation and a microbiological confirmation (positive CSF culture or positive specific PCR). Medical charts were retrospectively reviewed to collect microbiological and clinical data, and to assess therapeutic success. RESULTS: Among the 17 included individuals, eight (47%) were treated with cefazolin and nine (53%) with cloxacillin. Median daily dosages of cefazolin and cloxacillin were 8 g (range 6-12 g) and 12 g (range 10-13 g), respectively. Cefazolin and cloxacillin were mainly administered by continuous infusion. Eleven individuals (65%) were men, median (interquartile range (IQR)) age was 54 years (50; 70), 14 (82%) had postoperative meningitis and 3 (18%) had haematogenous meningitis. Median (IQR) antibiotic CSF concentrations were 2.8 mg/L (2.1; 5.2) and 0.66 mg/L (0.5; 0.9) for cefazolin and cloxacillin groups, respectively. Cloxacillin was discontinued in two individuals for therapeutic failure. CONCLUSIONS: Patients with staphylococcal meningitis treated with high-dose continuous intravenous infusion of cefazolin achieved therapeutic concentrations in CSF. Cefazolin appears to be a therapeutic candidate that should be properly evaluated in this indication.

Herbivore-induced jasmonic acid bursts in leaves of Nicotiana attenuata mediate short-term reductions in root growth.

Root growth in Nicotiana attenuata is transiently reduced after application of oral secretions (OS) of Manduca sexta larvae to wounds in leaves. Feeding of M. sexta or OS elicitation is known to result in jasmonic acid (JA) and ethylene bursts, and activates a suite of defence responses. Because both plant hormones are known to strongly reduce root growth, their activation might account for the observed reduction of root growth following herbivory. To test this hypothesis, we measured primary root growth with digital image sequence processing at high temporal resolution in antisense-lipoxygenase 3 (asLOX3) and inverted repeat-coronatin-insensitive 1 (irCOI1) seedlings which are impaired in JA biosynthesis and perception, respectively, and wild-type (WT) seedlings. Higher root growth rates in irCOI1 compared with WT were observed after OS elicitation. The dynamics of wound-induced root growth reduction coincide with the dynamics of root growth reduction induced by external application of methyl JA. In an experiment with 1-methylcyclopropen (1-MCP), a potent ethylene receptor blocker, no wounding-specific difference between growth of 1-MCP-treated plants and non-treated plants was observed, suggesting that wound-induced endogenous JA and not ethylene mediates the wounding-specific reduction in root growth. Yet, inhibiting the ethylene response by applying 1-MCP led to markedly increased root growth compared with that of control plants, indicating that ethylene normally suppresses plant growth in N. attenuata seedlings.

Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-linked mental retardation.

Investigation of chromosomal rearrangements in patients with mental retardation (MR) is particularly informative in the search for novel genes involved in MR. We report on a family with a genomic duplication at Xq25 identified by oligo array-CGH. Further characterization showed a partial tandem duplication of GRIA3 extending from exon 1 to exon 12. This duplication is present in two brothers with MR and on one allele in their sister with normal phenotype and completely skewed X-chromosome inactivation. The duplication is inherited from the mother, whose cognitive level is low and X-chromosome inactivation is random. This is the second family with partial duplication of GRIA3 associated with MR. GRIA3 expression studies in our case demonstrated a new mechanism for GRIA3 dysfunction with the presence of aberrant GRIA3 transcripts carrying multi-exon duplications leading to a frameshift. Our study gives additional support to the implication of GRIA3 in X-linked MR.

Switching from abacavir/lamivudine plus nevirapine to abacavir/lamivudine/dolutegravir in virologically controlled HIV-infected adults (SWAD study).

INTRODUCTION: The metabolic pathways of dolutegravir suggest a potential predator effect of nevirapine on dolutegravir pharmacokinetics and switching from a nevirapine- to a dolutegravir-containing regimen could lead to a lower and suboptimal exposure to dolutegravir several weeks after the switch in case of persistent inducer effect. PATIENTS AND METHOD: Prospective, pilot, single-arm, open-label, non-comparative, bicentric study to evaluate the pharmacokinetics, virologic outcomes, safety, and patient satisfaction of switching from abacavir/lamivudine and nevirapine to a single tablet of abacavir/lamivudine/dolutegravir. The primary endpoint was the maintenance of virologic suppression (HIV-1 RNA<50 copies/mL) at week 12. Secondary endpoints were virologic suppression at week 48, safety and tolerability, patient satisfaction, and pharmacokinetic interaction between nevirapine and dolutegravir. Fifty-three adults on stable abacavir/lamivudine and nevirapine regimen for a median duration of 6years and virologically suppressed for 9.6years were included. RESULTS: Dolutegravir reached steady state by week 4/week 12 when expected by day 5/day 10. All subjects maintained plasma HIV-RNA˂50 copies/mL at week 12 and week 48. Abacavir/lamivudine/dolutegravir was well-tolerated, with two cases of serious adverse events deemed unrelated to study drugs (coronary syndrome in both cases), and one discontinuation for renal impairment at week 24 with a slight improvement after dolutegravir discontinuation. Level of treatment satisfaction remained high after the switch. CONCLUSION: The transient predator effect of nevirapine on dolutegravir had no clinical consequences after switching from nevirapine to dolutegravir, neither on safety nor maintenance of virologic suppression. It also had no consequences on patient satisfaction.

Apoptotic pulsed dendritic cells induce a protective immune response against Toxoplasma gondii.

Infection with the intracellular protozoan parasite Toxoplasma gondii may cause severe sequelae in foetuses and life-threatening neuropathy in immunocompromised patients. We recently reported that vaccination with T. gondii-pulsed dendritic cells induces protective humoral and cellular immune responses against this intracellular pathogen in CBA/J mice. We assessed the feasibility of using a nonlive vaccine, by inducing the apoptosis of T. gondii-pulsed dendritic cells before injecting them into mice. Apoptosis was induced by culturing cells to confluence. We investigated whether these apoptotic T. gondii-pulsed dendritic cells elicited an immune response in vivo. Some studies have shown that immunization with apoptotic cells leads to the activation of innate and adaptive immune mechanisms. Our results are consistent with apoptotic cells having immunomodulatory properties in a model of parasite infection. We showed that the adoptive transfer of T. gondii-pulsed apoptotic dendritic cells elicited humoral and cellular Toxoplasma-specific immune responses with a Th1/Th2 profile, and conferred specific protection. The protective immune response induced was independent of inducible HSP70 production by apoptotic dendritic cells.

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRbeta-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique.

Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRbeta) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRbeta-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRbeta-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRbeta-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRbeta-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRbeta-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRbeta-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.