Pediatric diffusion tensor imaging: normal database and observation of the white matter maturation in early childhood

Recent advances in diffusion tensor imaging (DTI) have made it possible to reveal white matter anatomy and to detect neurological abnormalities in children. However, the clinical use of this technique is hampered by the lack of a normal standard of reference. The goal of this study was to initiate the establishment of a database of DTI images in children, which can be used as a normal standard of reference for diagnosis of pediatric neurological abnormalities. Seven pediatric volunteers and 23 pediatric patients (age range: 0-54 months) referred for clinical MR examinations, but whose brains were shown to be normal, underwent anatomical and DTI acquisitions on a 1.5 T MR scanner. The white matter maturation, as observed on DTI color maps, was described and illustrated. Changes in diffusion fractional anisotropy (FA), average apparent diffusion constant (ADC(ave)), and T2-weighted (T2W) signal intensity were quantified in 12 locations to characterize the anatomical variability of the maturation process. Almost all prominent white matter tracts could be identified from birth, although their anisotropy was often low. The evolution of FA, shape, and size of the white matter tracts comprised generally three phases: rapid changes during the first 12 months; slow modifications during the second year; and relative stability after 24 months. The time courses of FA, ADC(ave), and T2W signal intensity confirmed our visual observations that maturation of the white matter and the normality of its architecture can be assessed with DTI in young children. The database is available online and is expected to foster the use of this promising technique in the diagnosis of pediatric pathologies.     

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab).

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration (C(max)) for the latter, while the time to peak (T(max)) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C(max) by 18% and AUC by 21%, and slightly delayed T(max) from 5 to 6h. During fractional dosing, morning and evening C(max) reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC(0-24 h) on the last day to AUC(infinity) on the first day, was 82.1% (confidence limits 71.7-94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC(0-24 h, s.s.) of 5.55+/-1.78 and 5.71+/-1.08 microg h/ml).     

Translocation t(12;13)(p13.3;q12.2) is Not Restricted to Lymphoid Malignancies; Report of a Further Case with Hypereosinophilia

We report two cases of t(12;13)(p13;q12). One was found in a lymphoid disorder, as previously described, while the second was observed in a myeloproliferative syndrome with hypereosinophilia. As t(12;13) has already been described in association with hypereosinophilia in a case of acute lymphoblastic leukaemia, we suggest that the association of t(12;13) with hypereosinophilia is not random.     

The co-occurrence of gambling with substance use and conduct disorder among youth in the United States

The co-occurrence of gambling with substance use and conduct disorder was examined in a representative U.S. household sample of 2,274 youth 14-21 years old. The findings show that problem gambling occurs within a problem-behavior syndrome with other substance-use behaviors and conduct disorder. Male gender, being black, and being Hispanic were found to be significant in predicting problem gambling over and above the effects of all four substance use and conduct disorder variables. Clinical interventions for one specific problem behavior in youth should consider assessing the other problem behaviors as well.     

Latent hit series hidden in high-throughput screening data

Recently a novel method termed compound set enrichment (CSE) has been described that uses the activity distribution of a structural class of compounds to identify hit series from primary screening data. This report describes how this method can be used to identify such hit series, even when no hits according to conventional hit-calling methods for a given structural class are present in the data set. Such series, which were called latent hit series, were identified prospectively in a cell-based screening campaign and also in a series of retrospective analyses of publicly available data sets from PubChem. The assay used for the prospective case study was developed to identify compounds modulating protein translation directed from the internal ribosome entry site (IRES) of the encephalomyocarditis virus (EMCV) genomic RNA. The assay was designed with the ability to detect two assay readouts. The first assay readout monitors compound effects on IRES-directed translation, and the second readout monitors the cell viability and general effect on protein expression. By applying CSE separately to both of them, six validated latent hit series with apparently no effects on cell viability were identified. For each of these series, further testing of new compounds enabled identification of additional hits, also apparently with no effect on cell viability. These validated latent hit series would have been missed by a conventional cutoff-based hit-calling approach. This prospective study further supports CSE as a method for the analysis of high-throughput screening experiments.     

Macrophages induce differentiation of plasma cells through CXCL10/IP-10

In tonsils, CD138⁺ plasma cells (PCs) are surrounded by CD163⁺ resident macrophages (Mϕs). We show here that human Mϕs (isolated from tonsils or generated from monocytes in vitro) drive activated B cells to differentiate into CD138⁺CD38⁺⁺ PCs through secreted CXCL10/IP-10 and VCAM-1 contact. IP-10 production by Mϕs is induced by B cell–derived IL-6 and depends on STAT3 phosphorylation. Furthermore, IP-10 amplifies the production of IL-6 by B cells, which sustains the STAT3 signals that lead to PC differentiation. IP-10–deficient mice challenged with NP-Ficoll show a decreased frequency of NP-specific PCs and lower titers of antibodies. Thus, our results reveal a novel dialog between Mϕs and B cells, in which IP-10 acts as a PC differentiation factor.Plasma cells (PCs) include short-lived PCs found in the extrafollicular foci of peripheral lymphoid organs and long-lived PCs in the bone marrow. Short-lived PCs account for the initial immune response after antigen (Ag) encounter, whereas long-lived PCs can produce antibodies (Abs) for years and thus provide life-long protection (Kunkel and Butcher, 2003; Shapiro-Shelef and Calame, 2005; Radbruch et al., 2006; Hiepe et al., 2011). Our understanding of the mechanisms underlying the rapid formation of Ab-secreting PCs during early B cell responses remains incomplete (Oracki et al., 2010). B cell activation is initiated after engagement of the BCR by a specific Ag in both T cell–dependent (TD) and T cell–independent (TI) manners (Mond et al., 1995; Fagarasan and Honjo, 2000). Most long-lived PCs in the bone marrow are derived from TD responses involving germinal center reactions. Interestingly, large numbers of PCs and plasmablasts generated in both TD and TI responses die within a few days of being produced (Mond et al., 1995; Smith et al., 1996; García de Vinuesa, 1999; Shapiro-Shelef and Calame, 2005). However, emerging evidence indicates that long-lived Ab responses can also be induced by some TI challenges (Alugupalli et al., 2004; Hsu et al., 2006; Obukhanych and Nussenzweig, 2006). The TI response is critical for the host to provide prompt protection against invading pathogens and their products, such as viral glycoproteins and bacterial polysaccharides which stimulate IgG and IgA production in the absence of CD40L signals (Mond et al., 1995). One of the APCs, DCs, could also induce TI class switching through the secretion of BLyS and APRIL (Litinskiy et al., 2002).To maximize the probability of mounting a rapid and appropriate response, B cells encounter Ags in lymphoid organs, including lymph nodes, spleen, Peyer’s patches, and tonsils (Batista and Harwood, 2009). In lymph nodes, large Ags such as particulates, immune complexes, and viruses that travel through the subcapsular sinus are picked up by resident macrophages (Mϕs) and presented to follicular B cells (Carrasco and Batista, 2007; Junt et al., 2007; Phan et al., 2009). The recognition of Ags on the surfaces of APCs by B cells results in efficient formation of an immune synapse (Harwood and Batista, 2010; Pierce and Liu, 2010), which has been proven to be much more active and dynamic than that predicted from the response of B cells to Ags in solution (Fleire et al., 2006). The question remains whether APCs also provide “second” signals directing differentiation of PCs, in addition to the initiation of BCR signaling.After engagement of BCR signaling, the differentiation process of B cells into PCs depends on a combination of signals, including Ags, soluble mediators (such as IL-2, IL-3, IL-4, IL-6, IL-10, IL-15, IL-21, IFN-α, TNF, BAFF, and APRIL), pathogen-associated molecule patterns, and signals from T cells and APCs (Fairfax et al., 2008). Terminally differentiated PCs are quiescent cells that express CD138 (syndecan-1; Chilosi et al., 1999; Medina et al., 2002). Unlike the generation of CD138⁻CD38⁺⁺CD20⁻ plasmablasts, the mechanisms leading to terminal differentiation of B cells into CD138⁺CD38⁺⁺CD20⁻ PCs in humans remain to be better characterized (Arpin et al., 1995; Litinskiy et al., 2002; Huggins et al., 2007).In this study, we demonstrate that human Mϕs drive activated B cells to undergo proliferation and differentiation toward CD138⁺CD38⁺⁺ terminally differentiated PCs, through the chemokine IP-10/CXCL10. The data reveal an amplification loop where B cell IL-6 induces Mϕs to secrete IP-10, which further boosts the B cell autocrine secretion of IL-6, leading to PC differentiation in a TI manner.     

Current state of scanning micromanipulator applications with the carbon dioxide laser

OBJECTIVES: The development of the scanning system AcuBlade has considerably enhanced carbon dioxide laser energy delivery, improving cutting and ablation modes. The scanning system can be applied with the 2 available high-powered pulsed waves, SuperPulse and UltraPulse. This study was conducted to determine whether there are any differences in phonosurgery between the SuperPulse and UltraPulse lasing applications with regard to thermal diffusion into the surrounding tissues, healing time, and clinical results. METHODS: Thirteen patients with bilateral and similar vocal fold lesions underwent operation--one side in SuperPulse mode and the other side in UltraPulse mode. The parameters for phonosurgery were depth of 0.2 mm, 10 W, single pulse, and 0.10 second for SuperPulse, and 2 passes, 10 W, single pulse, and 0.10 second for UltraPulse. RESULTS: Incisions were sharper with UltraPulse, making the surgery easier, but at the first postoperative follow-up visit, after 8 to 10 days, no differences were observed in the presentation, the healing, or the vibration of the 2 vocal folds. Coagulation along the incision line was 25 microm for SuperPulse and 15 microm for UltraPulse (median values). CONCLUSIONS: In comparison with SuperPulse, the UltraPulse carbon dioxide laser made the procedure easier, but did not improve the clinical outcome.     

Treatment outcome of creatine transporter deficiency: international retrospective cohort study

Metabolic Brain Disease - To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment...     

When polymerase chain reaction does not help: cytomegalovirus pneumonitis associated with very low or undetectable viral load in both blood and bronchoalveolar lavage samples after lung transplantation

Cytomegalovirus (CMV) pneumonitis occurs frequently among solid organ transplant recipients and is classically associated with significant viral replication in both blood and bronchoalveolar lavage (BAL) samples. We present a case of a 64‐year‐old lung transplant recipient who presented with CMV pneumonitis that was diagnosed based on the association of viral inclusion in the BAL sample, rapid response to ganciclovir, and absence of other infectious etiology. Surprisingly, we observed very low or undetectable viral load both in blood and BAL samples. Diagnosis of CMV pneumonitis should rely on the association of clinical, pathological, radiological, and microbiological signs, while quantitative nucleic acid amplification testing should be interpreted with caution.     

Impact of renal dysfunction and glucometabolic status on one month mortality after acute myocardial infarction

Patients with impaired glucometabolic status or renal function have a higher mortality after acute myocardial infarction. It is unclear whether this higher risk is independent or related to the quality of care. In a prospective registry, stress hyperglycaemia (SH) was defined as glucose level>140 mg/dl. Renal function was assessed by the glomerular filtration rate (GFR): normal (>/=60), mild (30-60) and severe dysfunction (<30 ml/min/1.72 m(2)). The level of risk was assessed by the TIMI risk index and the quality of care by the rate of use of five guidelines-recommended treatments. Among the 1388 patients included, 23% had diabetes, 16% had SH, renal function was normal in 55%, mildly impaired in 35% and severely impaired in 9.5%. At one month, the mortality rate was higher in patients with SH (18%) as compared with diabetics (9%) or those with normal glucometabolic status (5%). Similarly, the mortality rate was higher in those with impaired renal function. Multivariable analysis identified SH, GFR group, TIMI risk index, ST segment elevation MI and quality of care as independent predictors of one-month mortality. In patients with acute MI, SH and GFR<30 ml/min/m(2) are independent predictors of mortality after adjustment for the level of risk and acute care.