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The adsorption and dynamical behavior of the muonated cyclohexadienyl radical (C6H6Mu) in NaY zeolite, formed by muonium (Mu) addition on adsorbed benzene, was investigated by the muon spin resonance (μSR) technique, primarily at loadings of 2−3 C6H6 molecules per supercage of NaY. The dynamics of this radical are expected to be the same as its isotopic analogue, C6H7, for which there are no similar data available. Both TF-μSR and ALC-μSR spectra were recorded, with the most detailed information provided by the positions and line widths of the avoided level crossing resonances. In concert with 2H NMR, neutron diffraction and molecular dynamics studies of the parent benzene molecule, as well as current theoretical calculations, the dominant adsorption site for the C6H6Mu radical is believed to be the SII Na cation, within a supercage, which gives rise to three observed ALC lines, corresponding to two different orientations for the muon (proton) of the CHMu methylene group: pointing toward (endo) and away ...

Resisted sprint training is performed in a horizontal direction and involves similar muscles, velocities, and ranges of motion (ROM) to those of normal sprinting. Generally, sleds are attached to the athletes through a lead (3 m) and harness; the most common attachment points are the shoulder or waist. At present, it is not known how the different harness point's impact on the kinematics and kinetics associated with sled towing (ST). The aim of the current investigation was to examine the kinetics and kinematics of shoulder and waist harness attachment points in relation to the acceleration phase of ST. Fourteen trained men completed normal and ST trials, loaded at 10% reduction of sprint velocity. Sagittal plane kinematics from the trunk, hip, knee, and ankle were measured, together with stance phase kinetics (third footstrike). Kinetic and kinematic parameters were compared between harness attachments using one-way repeated-measures analysis of variance. The results indicated that various kinetic differences were present between the normal and ST conditions. Significantly greater net horizontal mean force, net horizontal impulses, propulsive mean force, and propulsive impulses were measured (p < 0.05). Interestingly, the waist harness also led to greater net horizontal impulse when compared with the shoulder attachment (p < 0.001). In kinematic terms, ST conditions significantly increased peak flexion in hip, knee, and ankle joints compared with the normal trials (p < 0.05). Results highlighted that the shoulder harness had a greater impact on trunk and knee joint kinematics when compared with the waist harness (p < 0.05). In summary, waist harnesses seem to be the most suitable attachment point for the acceleration phase of sprinting. Sled towing with these attachments resulted in fewer kinematic alterations and greater net horizontal impulse when compared with the shoulder harness. Future research is necessary in order to explore the long-term adaptations of these acute changes.

International audience; Although bone formation around and within implants has been intensively studied, the role of pores and pore geometry is still debated. Notwithstanding studies reporting the formation of bone and bone components within pores as small as a few micrometers ('micropores'), bone ingrowth is believed to only occur in pores larger than 100 mu m ('macropores'). A thorough analysis of 10 different porous beta-tricalcium phosphate cylinders (empty set: 8 mm; L: 13 mm) implanted for 2-24 weeks in an ovine model demonstrates ingrowth of mineralized tissue (MT) in pores as small as 1 mu m. This tissue contained calcium phosphate, collagen, and interconnected cells. It formed within the first 3-4 weeks of implantation, extended over several hundred micrometers within the ceramic, and contributed to the majority of the early MT formation (including bone) in the defect. The indentation stiffness of the MT-ceramic composite was significantly higher than that of bone and MT-free ceramic. The presented results substantiate the importance of micropores for optimal bone healing, particularly at early implantation times

Leprosy: Ancient and Modern In medieval Europe, leprosy was greatly feared: Sufferers had to wear bells and were shunned and kept isolated from society. Although leprosy largely disappeared from Europe in the 16th century, elsewhere in the world almost a quarter of a million cases are still reported annually, despite the availability of effective drugs. Schuenemann et al. (p. 179 , published online 13 June; see the 14 June News story by Gibbons , p. 1278 ) probed the origins of leprosy bacilli by using a genomic capture-based approach on DNA obtained from skeletal remains from the 10th to 14th centuries. Because the unique mycolic acids of this mycobacterium protect its DNA, for one Danish sample over 100-fold, coverage of the genome was possible. Sequencing suggests a link between the middle-eastern and medieval European strains, which falls in line with social historical expectations that the returning expeditionary forces of antiquity originally spread the pathogen. Subsequently, Europeans took the bacterium westward to the Americas. Overall, ancient and modern strains remain remarkably similar, with no apparent loss of virulence genes, indicating it was most probably improvements in social conditions that led to leprosy's demise in Europe.

PURPOSE: To establish a consensus in relation to case selection, conduct of therapy, and outcomes that are associated with focal therapy for men with localized prostate cancer. MATERIAL AND METHODS: Urologic surgeons, radiation oncologists, radiologists, and histopathologists from North America and Europe participated in a consensus workshop on focal therapy for prostate cancer. The consensus process was face to face within a structured meeting, in which pertinent clinical issues were raised, discussed, and agreement sought. Where no agreement was possible, this was acknowledged, and the nature of the disagreement noted. RESULTS: Candidates for focal treatment should have unilateral low- to intermediate-risk disease with clinical stage

Renal infarction is a rare finding in children. Associations between SARS-CoV-2 infections and thromboembolic events including renal infarcts have been described in adults. Although a similar association in children has not yet been described with this pandemic, the pediatric literature is still evolving with the recognition of new manifestations including the post-infectious Multisystem Inflammatory Syndrome in Children (MIS-C). We report the rare event of multiple renal infarcts in a 6-year-old boy manifesting several features of MIS-C 9 weeks following a self-limiting febrile illness characteristic of COVID-19. An underlying Factor V Leiden mutation was identified in this child but felt to be insufficient on its own to explain his clinical presentation. As SARS-CoV-2 testing was delayed, the failure to identify viral RNA or antibodies may not exclude the virus' potential role in precipitating the infarct in this host. Given that renal infarcts have been described in adult patients with COVID-19, reporting this perplexing case where SARS-CoV-2 may have played a role, may help identify this potential complication.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

The editors of Societies would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2013. [...]

AbstractThe epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

Dasatinib (SPRYCEL®) is the most potent BCR-ABL inhibitor and is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Previous studies have demonstrated the efficacy and safety of dasatinib 70 mg BID for patients with CML-AP who are intolerant or resistant to imatinib. In the phase III CA180-035 study, patients with CML-AP, blast phase CML, or Ph+ ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary trial objective was to compare major hematologic response (MaHR) rates between the two schedules. Secondary objectives included a comparison of major cytogenetic response (MCyR) rates, time to and duration of responses, progression-free survival (PFS), overall survival (OS), and safety profiles between the two schedules. Previous analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, 2-year results from the subgroup with CML-AP (n=317) recruited from 97 international sites are reported. Among patients randomized to QD (n=158) or BID (n=159) treatment with dasatinib, rates of MaHR and MCyR were similar (MaHR: 66% vs 68%; MCyR: 39% vs 43%, respectively; Table). Excluding patients that were BCR-ABL positive, Ph negative (n=3), rates of MCyR were nearly identical. Most MaHRs were achieved within 4 months of therapy and most MCyRs were achieved within 6 months. Based on Kaplan-Meier analyses, an estimated 65% vs 60% of patients had maintained a durable MaHR in QD and BID groups, respectively, at 24 months. Estimated PFS rates were 51% vs 55% and OS rates were 63% vs 72%, respectively. Although dasatinib was generally well tolerated with both dose schedules, QD treatment was associated with an improved safety profile compared with BID treatment. Only small increases in AE rates were observed compared with 1-year data. Cytopenias were the most common AEs and for QD vs BID treatment, rates of grade 3/4 events were 59% vs 69% for neutropenia and 64% vs 67% for thrombocytopenia. Fewer drug-related fluid retention events (including pleural effusion, superficial edema, and peripheral edema) were reported in the QD (34%) vs BID (48%) group. In particular, significantly fewer patients experienced a pleural effusion with QD vs BID treatment (p<0.001, all grades). No grade 4 pleural effusions occurred. Pleural effusions were manageable and led to treatment discontinuation in only 5% (QD) and 9% (BID) of patients. Grade 3/4 nonhematologic AEs were reported in less than 7% of all QD and BID patients and included dyspnea (3% vs 7%) and diarrhea (3% in both groups). Median durations of dasatinib therapy were 15 months (QD) and 12 months (BID), and median values of mean daily doses were 138 mg and 110 mg, respectively. Fewer dose reductions (38% vs 50%) and interruptions (64% vs 74%) occurred in the QD group. At the time of analysis, 34% of the QD group and 35% of the BID group remained on study, with a median duration of therapy of 23 months in both groups. Overall, extended follow-up from the CA180-035 study confirms earlier findings and demonstrates that in patients with CML-AP with imatinib resistance or intolerance, dasatinib 140 mg QD has equivalent efficacy to dasatinib 70 mg BID but with an improved safety profile. Similar durable responses were observed with both schedules. Table | | Patients (%) | |:---------------------------------- | ------------ | ----------- | | | QD (n=158) | BID (n=159) | | MaHR | 66 | 68 | | MCyR | 39 | 43 | | MCyR (excluding BCR-ABL+ Ph−, n=3) | 38 | 43 | | 24-month PFS | 51 | 55 | | 24-month OS | 63 | 72 | | Neutropenia, grade 3/4 | 59 | 69 | | Thrombocytopenia, grade 3/4 | 64 | 67 | | Pleural effusion (drug-related) | | | | All grades | 20 | 39 | | Grade 3 | 7 | 6 | | Interruption | 38 | 50 | | Reduction | 64 | 74 |