Application to a short-stem hip implant

Today, different implant designs exist in the market; however, there is not a clear understanding of which are the best implant design parameters to achieve mechanical optimal conditions. Therefore, the aim of this project was to investigate if the geometry of a commercial short stem hip prosthesis can be further optimized to reduce stress shielding effects and achieve better short- stemmed implant performance. To reach this aim, the potential of machine learning techniques combined with parametric Finite Element analysis was used. The selected implant geometrical parameters were: total stem length (L), thickness in the lateral (R1) and medial (R2) and the distance between the implant neck and the central stem surface (D). The results show that the total stem length was not the only parameter playing a role in stress shielding. An optimized implant should aim for a decreased stem length and a reduced length of the surface in contact with the bone. The two radiuses that characterize the stem width at the distal cross-section in contact with the bone were less influential in the reduction of stress shielding compared with the other two parameters; but they also play a role where thinner stems present better results

Multiscale Modeling of Bone Healing

Bone is a living part of the body that can, in most situations, heal itself after fracture. However, in some situations, healing may fail. Compromised conditions, such as large bone defects, aging, immuno-deficiency, or genetic disorders, might lead to delayed or non-unions. Treatment strategies for those conditions remain a clinical challenge, emphasizing the need to better understand the mechanisms behind endogenous bone regeneration. Bone healing is a complex process that involves the coordination of multiple events at different length and time scales. Computer models have been able to provide great insights into the interactions occurring within and across the different scales (organ, tissue, cellular, intracellular) using different modeling approaches [partial differential equations (PDEs), agent-based models, and finite element techniques]. In this review, we summarize the latest advances in computer models of bone healing with a focus on multiscale approaches and how they have contributed to understand the emergence of tissue formation patterns as a result of processes taking place at the lower length scales

Short-run dynamics of income disparities and regional cycle synchronization in the U.S.

Since the 1990s, the issue of regional income convergence and its long-term tendencies has been thoroughly and heatedly discussed. Much less attention, however, has been devoted to the short-run dynamics of regional convergence. In particular, three important aspects have not yet been adequately addressed. First, it is indeed essential to understand whether regional disparities manifest a tendency to move systematically along the national cycle. Then, if this happens to be the case, it becomes crucial to know whether 1) these movements are pro- or counter-cyclical,2) the cyclical evolution of the disparities is a consequence of differences in the timing with which the business cycle is felt in regions or it is motivated by the amplitude differences across local cyclical swings. In this paper, we shed light on these issues using data on personal income for the 48 coterminous U.S. states between 1969 and 2008. Our results indicate that income disparities do not move randomly in the short run but follow a distinct cyclical pattern, moving either pro- or counter-cyclically depending on the period of analysis. These patterns are probably explained by the changes in the direction of capital and labor flows that favor developed or poorer states in different periods. As for the underlying mechanism, it appears that the short-run evolution of the disparities in recent years is largely a consequence of differences in the timing with which the business cycle is felt across states rather than the outcome of amplitude differences across local cyclical swings

Circulating MicroRNAs in Elderly Type 2 Diabetic Patients

The circulating microRNAs (miRNAs) associated with type 2 diabetes (T2D) in elderly patients are still being defined. To identify novel miRNA biomarker candidates for monitoring responses to sitagliptin in such patients, we prospectively studied 40 T2D patients (age > 65) with HbA1c levels of 7.5–9.0% on metformin. After collection of baseline blood samples (t0), the dipeptidyl peptidase-IV (DPP-IV) inhibitor (DPP-IVi) sitagliptin was added to the metformin regimen, and patients were followed for 15 months. Patients with HbA1c0.5% after 3 and 15 months of therapy were classified as “responders” (group R, n = 34); all others were classified as “nonresponders” (group NR, n = 6). Circulating miRNA profiling was performed on plasma collected in each group before and after 15 months of therapy (t0 and t15). Intra- and intergroup comparison of miRNA profiles pinpointed three miRNAs that correlated with responses to sitagliptin: miR-378, which is a candidate biomarker of resistance to this DPP-IVi, and miR-126-3p and miR-223, which are associated with positive responses to the drug. The translational implications are as immediate as evident, with the possibility to develop noninvasive diagnostic tools to predict drug response and development of chronic complications

The Power Spectrum of Flux Limited X-Ray Galaxy Cluster Surveys

We compute the redshift space power spectrum of two X-ray cluster samples: the X-ray Brightest Abell Cluster Sample (XBACS) and the Brightest Cluster Sample (BCS) using the method developed by Feldman, Kaiser & Peacock. The power spectrums derived for these samples are in agreement with determinations of other optical and X-ray cluster samples. For XBACS we find the largest power spectrum amplitude expected given the high richness of this sample ($R \ge 2$). In the range 0.05 \uk < k < 0.4 \uk the power spectrum shows a power law behavior $P(k)\propto k^{n}$ with an index $n\simeq-1.2$. In a similar range 0.04 \uk < k < 0.3 \uk BCS power spectrum has a smaller amplitude with index $n\simeq-1.0$. We do not find significant evidence for a peak at k \simeq 0.05 \uk suggesting that claims such of feature detections in some cluster samples could relay on artificial inhomogeneities of the data. We compare our results with power spectrum predictions derived by Moscardini et al. within current cosmological models (LCDM and OCDM). For XBACS we find that both models underestimate the amplitude of the power spectrum but for BCS there is reasonably good agreement at k\gsim 0.03 \uk for both models.Comment: 9 pages (LateX, mn.sty), 9 figures, accepted for publication in MNRA

Increased release and activity of matrix metalloproteinase-9 in patients with mandibuloacral dysplasia type A, a rare premature ageing syndrome

Mandibuloacral dysplasia type A (MADA; OMIM 248370), a rare disorder caused by mutation in the LMNA gene, is characterized by post-natal growth retardation, craniofacial and skeletal anomalies (mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, low bone mass and joint contractures), cutaneous changes and partial lipodystrophy. Little is known about the molecular mechanisms by which LMNA mutations produce bone alterations. An altered bone extracellular matrix (ECM) remodelling could play a pivotal role in this disorder and influence part of the typical bone phenotype observed in patients. Therefore, we have focused our investigation on matrix metalloproteinases (MMPs), which are degradative enzymes involved in ECM degradation and ECM remodelling, thus likely contributing to the altered bone mineral density and bone metabolism values seen in five MADA patients. We evaluated the serum levels of several MMPs involved in bone development, remodelling and homeostasis, such as MMP-9, -2, -3, -8 and -13, and found that only the 82 kDa active enzyme forms of MMP-9 are significantly higher in MADA sera compared with healthy controls (n = 16). The serum level of MMP-3 was instead lower in all patients. No significant differences were observed between controls and MADA patients for the serum levels of MMP-2, -8 and -13 and of tissue inhibitor of metalloproteinase 2, a natural inhibitor of MMP-9. Similarly, normal serum levels of tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta were detected. These data suggest a possible involvement of MMP-9 in MADA disease, underlying the potential use in diagnosis and therapy

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population

The initial GWAS was funded by the International Serious Adverse Events Consortium (iSAEC). The iSAEC is a non-profit organization dedicated to identifying and validating DNA variants useful in predicting the risk of drug-related serious adverse events. The Consortium brings together the pharmaceutical industry, regulatory authorities and academic centres to address clinical and scientific issues associated with the genetics of drug-related serious adverse events. The iSAEC’s current funding members include: Abbott, Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda and the Wellcome Trust. Mas Chaponda was funded by a 3 year Wellcome Trust training fellowship WT078857MA administered through the University of Liverpool. Malawi-Liverpool-Wellcome Trust Clinical Research Programme is funded through a Core Programme Grant award from the Wellcome Trust. Munir Pirmohamed is a National Institute for Health Research Senior Investigator, and also wishes to thank the MRC Centre for Drug Safety Science for support. The DART study was supported by the UK Medical Research Council (grant number G0600344), the UK Department for International Development and the Rockefeller Foundation. Andrew P. Morris is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). Louise Y. Takeshita is funded by a PhD fellowship from CNPq (National Council for Scientific and Technological Development, Brazil). Panos Deloukas’ work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research

L'ADHD materno influenza la risposta al trattamento in bambini con DCD?

Il fil rouge del presente elaborato di tesi si basa sulla corrente di pensiero che vede una possibile interazione dinamica e articolata tra i fattori di rischio e le variabili protettive nello sviluppo infantile. I disturbi del comportamento in età evolutiva sono molto frequenti e rappresentano il principale motivo di consultazione presso i servizi di salute mentale dell’infanzia e dell’adolescenza. Bambini con queste patologie presentano un significativo peggioramento del funzionamento in ambito familiare, sociale e scolastico; infatti sono considerati tra i disturbi a più alto dispendio economico (Loeber et al., 2000). Nello specifico in ambito familiare, i modelli di attaccamento con il caregiver sono predittori di comportamento adattivo o disadattivo del bambino e sono connessi alla gravità e alla continuità dei problemi. Diversi disturbi psichici nei genitori sono stati associati all’aumento del rischio di insorgenza di psicopatologia nei figli. La letteratura, in particolare, ha messo in evidenza il ruolo della depressione in madri di bambini con diagnosi di Disturbo Oppositivo-Provocatorio o Disturbo della Condotta. Lo scopo del nostro studio, invece, è stato quello di indagare se madri con Disturbo da Deficti di Attenzione/Iperattività possano influenzare l’esito del trattamento multimodale, come il Coping Power Program, su un campione clinico di soggetti in età evolutiva. La possibile presenza di ADHD (Attention-Deficit/Hyperactivity Disorder) nelle madri di 66 bambini, diagnosticati con DOP, DC e ADHD, è stata misurata utilizzando una nuova scala di screening, e non di diagnosi, ipotizzata da Eich (2012), il quale ha selezionato, all’interno della SCL-90-R, nove possibili items considerati caratteristici dell’ADHD nell’adulto. Eich, attraverso un’analisi fattoriale esplorativa su questi 9 items, ha individuato tre fattori significativi definiti: “Nervousness”, “Impaired Cognition” e “Irritabilità”; nei nostri risultati, dopo aver fatto un’analisi statistica utilizzando Mplus 4.2, solamente il fattore “Nervousness” correla significativamente con il cambiamento della CBCL externalizing, scala che valuta come misura di out come il comportamento del bambino. Anche la regressione logistica mostra come solo il fattore “Nervousness” predice una minore risposta al trattamento, valutata dal clinico utilizzando la CGI

Microvesicles: Novel Biomarkers for Neurological Disorders

Microvesicles (MVs) are released by most cell types in physiological conditions, but their number is often increased upon cellular activation or neoplastic transformation. This suggests that their detection may be helpful in pathological conditions to have information on activated cell types and, possibly, on the nature of the activation. This could be of paramount importance in districts and tissues that are not accessible to direct examination, such as the central nervous system. Increased release of MVs has been described to be associated to the acute or active phase of several neurological disorders. While the subcellular origin of MVs (exosome or ectosomes) is basically never addressed in these studies because of technical limitations, the cell of origin is always identified. Endothelium- or platelet-derived MVs, detected in plasma or serum, are linked to neurological pathologies with a vascular or ischemic pathogenic component, and may represent a very useful marker to support therapeutic choices in stroke. In neuroinflammatory disorders, such as multiple sclerosis, MVs of oligodendroglial, or microglial origin have been described in the cerebrospinal fluid and may carry, in perspective, additional information on the biological alterations in their cell of origin. Little specific evidence is available in neurodegenerative disorders and, specifically, MVs of neural origin have never been investigated in these pathologies. Few data have been reported for neuroinfection and brain trauma. In brain tumors, despite the limited number of studies performed, results are very promising and potentially close to clinical translation. We here review all currently available data on the detection of MVs in neurological diseases, limiting our search to exclusively human studies. Current literature and our own data indicate that MVs detection may represent a very promising strategy to gain pathogenic information, identify therapeutic targets, and select specific biomarkers for neurological disorders