Do radiolucent lines and stress shielding of the humeral shaft really matter in shoulder arthroplasty?

The purpose of this study is to evaluate at a mid-term follow up, the radiological survival of an uncemented humeral stem in shoulder arthroplasty. One hundred and twenty-six replacements including hemi (HA), total (TSA) and reverse (RSA) implanted from 1999 to 2008 were reviewed at a mean follow up of 7.2 years (48-144 months). The same uncemented triconical stem (SMR, Lima Corporate) was implanted. There were: 23 HSA, 43 TSA, 60 RSA. An independent observer evaluated all the patients with Constant Score. A radiologic analysis by an expert radiologist and an orthopaedic surgeon was performed: humeral component-bone interface was divided in seven zones. They judged a mobilisation if a migration or tilt of the humeral implant or if≥ 2 mm radiolucent line in at least three zones was present. Chi-squared test, Fisher test and analysis of variance were performed and a p<0.05 was considered statistically significant. No major radiological signs of loosening and no tilt or migration of the humeral component were found. Only 23 (18.2%) patients had no RL around the humeral implant. In the remaining 103 (81.7%) implants: 96 (76.1%) presented RL less than 2 mm, particularly 75 (59.5%) in less than 3 zones and 21 (16.6%) in more than 3 zones. Of the remaining 7 (5.5%) implants the presence of RL of 2 mm or greater in only one zone was seen. Apart from sepsis no revision was performed for humeral component loosening. Although a high rate of RL, uncemented humeral stem has an excellent survivorship at a mid-term follow up. Relationship between presence, position and depth of RL and internal stress shielding is commonly observed but does not appear t

A previously unreported function of beta1B integrin isoform in caspase-8-dependent integrin-mediated keratinocyte death

Integrins regulate adhesive cell-matrix interactions and mediate survival signals. On the other hand, unligated or free cytoplasmic fragments of integrins induce apoptosis in many cell types (integrin-mediated death). We have previously shown that b1 integrins expression protects keratinocyte stem cells from anoikis, while the role of the b1B integrin isoform has never been clarified. Here we report that suspended keratinocytes undergo apoptosis via the activation of caspase-8, independently of Fas/Fas Ligand system. Indeed, anti-b1 integrin neutralizing antibodies induced apoptosis in short-hairpin-RNA-Fas-Associated-Death-Domain treated cells. Moreover, before and during suspension, caspase-8 directly associated with b1 integrin, that in turn internalized and progressively degraded, shedding the cytoplasmic domain. b1B was expressed only in the cytoplasm in a perinuclear fashion and remained unaltered during suspension. At 24 hrs, as b1A located close to the nucleus, b1B co-localized with b1A and co-immunoprecipitated with caspase-8. Caspase-8 was activated earlier in b1B integrin transfected keratinocytes, and these cells underwent a higher rate of apoptosis than mock cells. By contrast, caspase-8 was not activated in siRNA b1B transfected cells. These results indicate that when b1A is unligated, b1B is responsible for “integrin-mediated death” in human keratinocytes

A Genome-Wide Screening and SNPs-to-Genes Approach to Identify Novel Genetic Risk Factors Associated with Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer’s disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel SNPs-to-genes approach and functional annotation analysis. We identified two novel potential loci for FTD. Suggestive SNPs reached p-values ~10-7 and OR > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation, and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-GWAS. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis

Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients

Introduction: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. Methods: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aβ)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. Discussion: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

Ventricular volume expansion in presymptomatic genetic frontotemporal dementia

Objective: To characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. Methods: Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers. Results: A total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings. Conclusions: Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD

Accounting Problems Under the Excess Profits Tax

DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV- 1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8(+) T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.Funding Agencies|Research Council of Norway; Odd Fellow</p

Ventricular volume expansion in presymptomatic genetic frontotemporal dementia

OBJECTIVE: To characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. METHODS: Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers. RESULTS: A total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings. CONCLUSIONS: Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD

Role of MAPT mutations and haplotype in frontotemporal lobar degeneration in Northern Finland

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) consists of a clinically and neuropathologically heterogeneous group of syndromes affecting the frontal and temporal lobes of the brain. Mutations in microtubule-associated protein tau (<it>MAPT</it>), progranulin (<it>PGRN</it>) and charged multi-vesicular body protein 2B (<it>CHMP2B</it>) are associated with familial forms of the disease. The prevalence of these mutations varies between populations. The H1 haplotype of <it>MAPT </it>has been found to be closely associated with tauopathies and with sporadic FTLD. Our aim was to investigate <it>MAPT </it>mutations and haplotype frequencies in a clinical series of patients with FTLD in Northern Finland.</p> <p>Methods</p> <p><it>MAPT </it>exons 1, 2 and 9–13 were sequenced in 59 patients with FTLD, and <it>MAPT </it>haplotypes were analysed in these patients, 122 patients with early onset Alzheimer's disease (eoAD) and 198 healthy controls.</p> <p>Results</p> <p>No pathogenic mutations were found. The H2 allele frequency was 11.0% (<it>P </it>= 0.028) in the FTLD patients, 9.8% (<it>P </it>= 0.029) in the eoAD patients and 5.3% in the controls. The H2 allele was especially clustered in patients with a positive family history (<it>P </it>= 0.011) but did not lower the age at onset of the disease. The ApoE4 allele frequency was significantly increased in the patients with eoAD and in those with FTLD.</p> <p>Conclusion</p> <p>We conclude that although pathogenic <it>MAPT </it>mutations are rare in Northern Finland, the <it>MAPT </it>H2 allele may be associated with increased risks of FTLD and eoAD in the Finnish population.</p

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011