Diffusion tensor imaging and fiber tractography of C6 rat glioma

PURPOSE: To apply diffusion tensor images using 30 noncollinear directions for diffusion-weighted gradient schemes to characterize diffusion tensor imaging (DTI) features associated with C6 glioma-bearing rat brains, and ideally visualize fiber tractography datasets. MATERIALS AND METHODS: Fiber tractographies of normal male Fischer 344 rat brains were constructed from DTI datasets acquired with a 30 noncollinear diffusion gradient scheme. Cultured C6 cell were intracranially injected into the cortex of male Fischer 344 rats. The time course of the tumor growth was monitored with DTI and fiber tractography using diffusion-weighting gradients in 30 noncollinear directions. RESULTS: Fiber tractographies through the corpus callosum (CC) were easily visualized with the 30-direction gradient scheme, and the fiber trajectories of the motor cortex and striatum were well represented in normal rats. Fiber tractography indicated that the neuronal fibers of the CC were compressed or disappeared by growing C6 glioma, which affected surrounding brain tissue. CONCLUSION: We have demonstrated in this study that fiber tractography with the 30 noncollinear diffusion gradient scheme method can be used to help provide a better understanding regarding the influence of a tumor on the surrounding regions of normal brain tissue in vivo.     

Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment

Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or because the host lacks the corresponding MHC I ligands for the receptors. Such NK cells nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating receptors. To address whether NK cell responsiveness is set only during the NK cell differentiation process, we transferred mature NK cells from wild-type (WT) to MHC I–deficient hosts or vice versa. Remarkably, mature responsive NK cells from WT mice became hyporesponsive after transfer to MHC I–deficient mice, whereas mature hyporesponsive NK cells from MHC I–deficient mice became responsive after transfer to WT mice. Altered responsiveness was evident among mature NK cells that had not divided in the recipient animals, indicating that the cells were mature before transfer and that alterations in activity did not require cell division. Furthermore, the percentages of NK cells expressing KLRG1, CD11b, CD27, and Ly49 receptors specific for H-2^b were not markedly altered after transfer. Thus, the functional activity of mature NK cells can be reset when the cells are exposed to a changed MHC environment. These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease.An important role of NK cells is to eliminate cells that extinguish or diminish expression of self-MHC class I molecules, which commonly occurs as a result of viral infection or cellular transformation (Herberman et al., 1975; Kiessling et al., 1975; Biron et al., 1999; Diefenbach and Raulet, 2002). This capacity arises because NK cells express stimulatory and inhibitory receptors that engage ligands on normal cells. The majority of inhibitory receptors belong to the KIR (in human), Ly49 (in mouse), and CD94/NKG2A (both in human and mouse) families and are specific for MHC I molecules (Raulet et al., 1997; Moretta et al., 2001; Lanier, 2005). When an NK cell encounters a normal cell, engagement of the inhibitory receptors conveys signals that counteract stimulatory signaling. Lysis occurs when inhibition is lost because the target cell lacks one or more self-MHC molecules or when target cells express high levels of stimulatory ligands that override inhibition (Raulet and Vance, 2006).NK cells vary in the number and specificity of MHC-specific inhibitory receptors that they express (Raulet et al., 1997). Recent studies demonstrate that NK cells vary in basal responsiveness to stimulatory receptor engagement depending on the number of expressed inhibitory receptors specific for self-MHC molecules (Yu et al., 2007; Brodin et al., 2009; Joncker et al., 2009). Cells with several self-MHC–specific receptors exhibit the greatest basal responsiveness and thus mediate the greatest activity against target cells that lose MHC. Cells with no self-MHC–specific receptors are the most hyporesponsive, to the extent that they fail to attack otherwise normal cells lacking MHC molecules. These data suggest that the responsiveness set point of individual NK cells is tuned depending on the balance of inhibitory and stimulatory ligands that each NK cell encounters on neighboring cells in the normal environment (Joncker and Raulet, 2008).An important unanswered question is whether the basal responsiveness of NK cells is set only once during NK cell development or, alternatively, can be readjusted when the fully mature NK cell is exposed to a changing MHC environment. Readjustments of NK cell responsiveness, if they occur, may account for instances under which NK cells fail to eliminate tumors or pathogen-infected cells and will be important to address when testing therapies designed to augment or suppress NK cell activity in the context of disease.     

Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome

Prader-Willi syndrome is a neurodevelopmental disorder that is characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia (leading to obesity in early childhood), learning problems, and behavioral difficulties. A paternal 15q11-q13 deletion is found in approximately 70% of patients with Prader-Willi syndrome, approximately 25% have uniparental maternal disomy 15, and the remaining 2% to 5% have imprinting defects. The proximal deletion breakpoint in the 15q11-q13 region occurs at 1 of 2 sites located within either of 2 large duplicons allowing for the identification of 2 deletion subgroups. The larger, type I (TI) deletion involves breakpoint 1, which is close to the centromere, whereas the smaller, type II (TII) deletion involves breakpoint 2, located approximately 500 kilobases distal to breakpoint 1. Breakpoint 3 is located at the distal end of the 15q11-q13 region and common to both typical deletion subgroups. Analyses of the genetic subtypes of Prader-Willi syndrome to date have primarily compared individuals with typical deletion and uniparental maternal disomy 15 without grouping the individuals with a deletion into TI or TII. Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters. We previously presented the first assessment of clinical differences in individuals with Prader-Willi syndrome categorized as having type I or II deletions. Adaptive behavior, obsessive-compulsive behaviors, reading, math, and visual-motor integration assessments were generally poorer in individuals with Prader-Willi syndrome and the TI deletion compared with subjects with Prader-Willi syndrome with the TII deletion or uniparental maternal disomy 15. Four genes (NIPA1, NIPA2, CYFIP1, and GCP5) have been identified in the chromosomal region between breakpoints 1 and 2 and are implicated in compulsive behavior and lower intellectual ability observed in individuals with Prader-Willi syndrome with TI versus TII deletions. We quantified messenger-RNA levels of these 4 genes in actively growing lymphoblastoid cells derived from 8 subjects with Prader-Willi syndrome with the TI deletion (4 males, 4 females; mean: age 25.2 +/- 8.9 years) and 9 with the TII deletion (3 males, 6 females; mean age: 19.5 +/- 5.8 years). Messenger-RNA levels were correlated with validated psychological and behavioral scales administered by trained psychologists blinded to genotype status. Messenger RNA from NIPA1, NIPA2, CYFIP1, and GCP5 was reduced but detectable in the subjects with Prader-Willi syndrome with the TI deletion, supporting biallelic expression. For the most part, messenger-RNA values were positively correlated with assessment parameters, indicating a direct relationship between messenger-RNA levels and better assessment scores, with the highest correlation for NIPA2. The coefficient of determination indicated the quantity of messenger RNA of the 4 genes explained from 24% to 99% of the variation of the behavioral and academic parameters measured. By comparison, the coefficient of determination for deletion type alone explained 5% to 50% of the variation in the assessed parameters. Understanding the influence of gene expression on behavioral and cognitive characteristics in humans is in the early stage of research development. Additional research is needed to identify the function of these genes and their interaction with gene networks to clarify the potential role they play in central nervous system development and function.     

The challenges of using medication event monitoring technology with pediatric transplant patients

This study investigated the advantages and challenges of using Medication Electronic Monitoring System (MEMS) technology to examine adherence among pediatric kidney transplant patients. Twenty-nine patients participated in the study, with a mean age of 14.03 yr (SD = 3.34, range 8-19 yr). Patients were given a MEMS bottle and cap to be used with their primary immunosuppressant medication over a three-month period. Issues related to study eligibility, recruitment, and participant maintenance were recorded. Patients completed the Debriefing Form regarding their experiences with the MEMS. Many younger patients were on liquid medications affecting the feasibility of this technology across ages. Acceptance of this technology proved difficult, as many patients either declined upfront or dropped out because they did not want to use the MEMS. Of the final sample, 41% found transferring medication into the MEMS bottle difficult and 27.2% reported that the MEMS was a burden and/or difficult to transport. Another 22% of the patients reported that using the MEMS changed their routine, and 10.2% worried about missing their medications. Pediatric transplant centers should be cautious about solely relying on MEMS to examine adherence until more research is conducted on the feasibility, acceptance, and utility of this technology.     

Infrainguinal atherectomy: a retrospective review of a single-center experience

By decreasing plaque burden, atherectomy provides an alternative to angioplasty and stenting as a means of revascularizing patients with peripheral arterial disease. A new atherectomy device (SilverHawk) has recently been approved by the Food and Drug Administration, but the results with its use are unclear. We analyzed a series of consecutive patients undergoing atherectomy. We retrospectively reviewed the charts of 35 patients undergoing infrainguinal (IF) atherectomy in 38 limbs. The Trans-Atlantic Inter-Society Consensus (TASC) classification and Society of Vascular Surgery runoff scores were calculated. Time to event analysis was performed using Kaplan-Meier estimates. Risk factors affecting patency were analyzed with a multivariate Cox model. Mean patient age was 70 +/- 9.6 years. Indications for intervention were claudication (26%), rest pain (21%), and tissue loss (53%). Femoropopliteal (FP) atherectomy was performed in 68% and tibial atherectomy in 32%. For FP lesions, the TASC distribution was A, 42%; B, 23%; C, 4%; and D, 15%. The average lesion treatment length was 9.4 +/- 10.6 cm (range 1-40), and the runoff score was 5.1 +/- 3.5. For tibial lesions, the TASC distribution was A, 0%; B, 17%; C, 8%; and D, 75%. The average lesion treatment length was 9.2 +/- 6.0 cm (range 2-20), with a runoff score of 5.4 +/- 2.4. A total of 39% of patients had prior IF interventions. Adjunctive angioplasty of the atherectomized lesion was performed in 55% of cases, stenting in 0%, and adjunctive therapy for tandem lesions in 39%. The postoperative ankle-brachial index increased by 0.30 +/- 0.14 and toe pressures increased by 40 +/- 32.4 mm Hg. Mean follow-up was 10 +/- 8 months (range 0.3-23). During the studied period, seven patients required major limb amputation and five open surgical revascularization. Total primary and secondary patency rates were 66% and 70% at 1 year, respectively. Primary and secondary patency rates for FP atherectomy were 68% and 73% at 1 year, respectively. The limb salvage rate was 74% at 6 months. Patients with prior interventions in the atherectomized segment had an almost 10-fold decrease in primary patency. Atherectomy produces acceptable results, similar to those in reported series of conventional balloon angioplasty/stenting. Patients with prior IF interventions had a nearly 10-fold decrease in primary patency. A greater than sixfold decrease in patency rates was noted in patients who underwent simultaneous inflow or outflow procedures, but this finding did not reach statistical significance (p = 0.082). Future studies should focus on cost comparisons with other treatments such as angioplasty and stenting, and prospective randomized trials should be performed to compare these treatment alternatives.     

Overview on the Evaluation of the Elastic Properties of Non-Carbon Nanotubes by Theoretical Approaches

Low-dimensional structures, such as nanotubes, have been the focus of research interest for approximately three decades due to their potential for use in numerous applications in engineering and technology. In addition to extensive investigation of carbon nanotubes, those composed of elements other than carbon, the so-called non-carbon nanotubes, have also begun to be studied, since they can be more suitable for electronic and optical nano-devices than their carbon counterparts. As in the case of carbon nanotubes, theoretical (numerical and analytical) approaches have been established predominantly to study non-carbon nanotubes. So far, most of work has dealt with the investigation of the structural and electrical properties of non-carbon nanotubes, paying less attention to the evaluation of their mechanical properties. As the understanding of the mechanical behaviour of the constituents is fundamental to ensure the effective performance of nanotube-based devices, this overview aims to analyse and systematize the literature results on the elastic properties of inorganic non-carbon nanotubes.     

Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02029443","term_id":"NCT02029443"}}NCT02029443, {"type":"clinical-trial","attrs":{"text":"NCT02475681","term_id":"NCT02475681"}}NCT02475681, {"type":"clinical-trial","attrs":{"text":"NCT02970318","term_id":"NCT02970318"}}NCT02970318 and {"type":"clinical-trial","attrs":{"text":"NCT02337829","term_id":"NCT02337829"}}NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477696","term_id":"NCT02477696"}}NCT02477696) prospectively assess differences in CV toxicity between the two agents.     

Single-stage off-pump repair of coarctation of the aorta and ventricular septal defects in children

Open in a separate window OBJECTIVESThe appropriate approach for surgical repair of coarctation of the aorta with a ventricular septal defect (VSD) remains controversial. This study evaluated the outcomes of primary repair of VSDs with periventricular device closure without cardiopulmonary bypass through a left thoracotomy in patients without arch hypoplasia.METHODSWe selected 21 patients aged <1 year, including 7 neonates, who underwent repair of coarctation of the aorta with periventricular device closure of a VSD.RESULTSThe median occluder size was 6 (range, 5–8) mm. The median mechanical ventilation time was 14 (range, 2–68) h, and the median duration of hospital stay was 11 (range, 7–16) days. No reoperations were required to correct VSD shunting, and the median residual shunt size was 1 (range, 1–2) mm. The median follow-up period was 13 (range, 4–31) months. No late deaths were reported, and no haemodynamically significant pressure gradient at the anastomotic site was observed. The median distal aortic arch z-score was 0.39 (range, −0.1–to 0.9). Only 1 patient had a permanent pacemaker implanted towards the end of the follow-up period.CONCLUSIONSPeriventricular device closure can be used safely for closure of VSD in children with coarctation of the aorta without a hypoplastic aortic arch, even in neonates, to reduce the risk of prolonged cardiopulmonary bypass. This hybrid approach can be performed with a low incidence of rhythm disturbances and residual shunting. However, a meticulous assessment of the VSD anatomy is essential to avoid any unfavourable events.     

Elastic Moduli of Non-Chiral Singe-Walled Silicon Carbide Nanotubes: Numerical Simulation Study

Silicon carbide nanotubes (SiCNTs) have generated significant research interest due to their potential use in the fabrication of electronic and optoelectronic nanodevices and biosensors. The exceptional chemical, electrical and thermal properties of SiCNTs are beneficial for their application in high-temperature and harsh-environments. In view of the limited thermal stability of carbon nanotubes, they can be replaced by silicon carbide nanotubes in reinforced composites, developed for operations at high temperatures. However, fundamentally theoretical studies of the mechanical properties of the silicon carbide nanotubes are at an early stage and their results are still insufficient for designing and exploiting appropriate nanodevices based on SiCNTs and reinforced composites. In this context, the present study deals with the determination of Young’s and shear moduli of non-chiral single-walled silicon carbide nanotubes, using a three-dimensional finite element model.     

SnS2 Nanosheets as a Template for 2D SnO2 Sensitive Material: Nanostructure and Surface Composition Effects

Two-dimensional nanosheets of semiconductor metal oxides are considered as promising for use in gas sensors, because of the combination of a large surface-area, high thermal stability and high sensitivity, due to the chemisorption mechanism of gas detection. In this work, 2D SnO₂ nanosheets were synthesized via the oxidation of template SnS₂ nanosheets obtained by surfactant-assisted one-pot solution synthesis. The 2D SnO₂ was characterized using transmission and scanning electron microscopy (TEM, SEM), X-ray diffraction (XRD), low-temperature nitrogen adsorption, X-ray photoelectron spectroscopy (XPS) and IR spectroscopy. The sensor characteristics were studied when detecting model gases CO and NH₃ in dry (RH₂₅ = 0%) and humid (RH₂₅ = 30%) air. The combination of high specific-surface-area and increased surface acidity caused by the presence of residual sulfate anions provides a high 2D SnO₂ sensor’s signal towards NH₃ at a low temperature of 200 °C in dry air, but at the same time causes an inversion of the sensor response when detecting NH₃ in a humid atmosphere. To reveal the processes responsible for sensor-response inversion, the interaction of 2D SnO₂ with ammonia was investigated using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) in dry and humid air at temperatures corresponding to the maximum “positive” and maximum “negative” sensor response.