Combined Peridynamics and Discrete Multiphysics to Study the Effects of Air Voids and Freeze-Thaw on the Mechanical Properties of Asphalt

This paper demonstrates the use of peridynamics and discrete multiphysics to assess micro crack formation and propagation in asphalt at low temperatures and under freezing conditions. Three scenarios are investigated: (a) asphalt without air voids under compressive load, (b) asphalt with air voids and (c) voids filled with freezing water. The first two are computed with Peridynamics, the third with peridynamics combined with discrete multiphysics. The results show that the presence of voids changes the way cracks propagate in the material. In asphalt without voids, cracks tend to propagate at the interface between the mastic and the aggregate. In the presence of voids, they ‘jump’ from one void to the closest void. Water expansion is modelled by coupling Peridynamics with repulsive forces in the context of Discrete Multiphysics. Freezing water expands against the voids’ internal surface, building tension in the material. A network of cracks forms in the asphalt, weakening its mechanical properties. The proposed methodology provides a computational tool for generating samples of ‘digital asphalt’ that can be tested to assess the asphalt properties under different operating conditions.     

The Effectiveness of Osseodensification Drilling Protocol for Implant Site Osteotomy: A Systematic Review of the Literature and Meta-Analysis

Many different osteotomy procedures has been proposed in the literature for dental implant site preparation. The osseodensification is a drilling technique that has been proposed to improve the local bone quality and implant stability in poor density alveolar ridges. This technique determines an expansion of the implant site by increasing the density of the adjacent bone. The aim of the present investigation was to evaluate the effectiveness of the osseodensification technique for implant site preparation through a literature review and meta-analysis. The database electronic research was performed on PubMed (Medline) database for the screening of the scientific papers. A total of 16 articles have been identified suitable for the review and qualitative analysis—11 clinical studies (eight on animals, three on human subjects), four literature reviews, and one case report. The meta-analysis was performed to compare the bone-to-implant contact % (BIC), bone area fraction occupied % (BAFO), and insertion torque of clockwise and counter-clockwise osseodensification procedure in animal studies. The included articles reported a significant increase in the insertion torque of the implants positioned through the osseodensification protocol compared to the conventional drilling technique. Advantages of this new technique are important above all when the patient has a strong missing and/or low quantity of bone tissue. The data collected until the drafting of this paper detect an improvement when the osseodensification has been adopted if compared to the conventional technique. A significant difference in BIC and insertion torque between the clockwise and counter-clockwise osseodensification procedure was reported, with no difference in BAFO measurements between the two approaches. The effectiveness of the present study demonstrated that the osseodensification drilling protocol is a useful technique to obtain increased implant insertion torque and bone to implant contact (BIC) in vivo. Further randomized clinical studies are required to confirm these pieces of evidence in human studies.     

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL-positive and -negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA-739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34(+) cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.     

On social polarization and ordinal variables: the case of self-assessed health

Social polarization refers to the measurement of the distance between different social groups, defined on the basis of variables such as race, religion, or ethnicity. We propose two approaches to measuring social polarization in the case where the distance between groups is based on an ordinal variable, such as self-assessed health status. The first one, the ‘stratification approach’, amounts to assessing the degree of non-overlapping of the distributions of the ordinal variable between the different population subgroups that are distinguished. The second one, the ‘antipodal approach’, considers that the social polarization of an ordinal variable will be maximal if the individuals belonging to a given population subgroup are in the same health category, this category corresponding either to the lowest or to the highest health status. An empirical illustration is provided using the 2009 cross-sectional data of the European Union Statistics on Income and Living Conditions (EU-SILC). We find that Estonia, Latvia, and Ireland have the highest degree of social polarization when the ordinal variable under scrutiny refers to self-assessed health status and the (unordered) population subgroups to the citizenship of the respondent whereas Luxembourg is the country with the lowest degree of social polarization in health.     

Low-Dose Acetazolamide in the Treatment of Premenstrual Dysphoric Disorder: A Case Series

The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms.     

Erythrocyte glutathione transferase activity: a possible early biomarker for blood toxicity in uremic diabetic patients

Erythrocyte glutathione transferase (e-GST) displays increased activity in patients with renal damage and positive correlation with homocysteine (Hcy) in patients under maintenance hemodialysis. Here, we determined e-GST, Hcy, and erythrocyte catalase (e-CAT) in 328 patients affected by type 2 diabetes mellitus (T2DM), 61 diabetic non-nephropathic patients and 267 affected by diabetes and by chronic kidney disease (CKD) under conservative therapy subdivided into four stages according to K-DOQI lines. e-GST activity was significantly higher in all T2DM patients compared to the control group (7.90 ± 0.26 vs. 5.6 ± 0.4 U/g_Hb), and we observed an enhanced activity in all subgroups of CKD diabetic patients. No significant correlation or increase has been found for e-CAT in all patients tested. Mean Hcy in diabetic patients is higher than that in healthy subjects (33.42 ± 1.23 vs. 13.6 ± 0.8 μM), and Hcy increases in relation to the CKD stage. As expected, a significant correlation was found between e-GST and Hcy levels. These findings suggest that e-GST hyperactivity is not caused directly by diabetes but by its consequent renal damage. e-GST, as well as Hcy, may represent an early biomarker of renal failure.     

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the “minor pocket,” previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR^−/− mice compared with WT mice. Furthermore, treatment of C5aR^−/− mice with DF2593A did not produce any further antinociceptive effect compared with C5aR^−/− mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain.Inflammatory and neuropathic pain are the most prevalent types of pathological pain and represent important health problems. Whereas inflammatory pain is one of the classic symptoms of the inflammatory process, neuropathic pain arises from any of multiple nerve lesions or diseases, with symptoms including hyperalgesia or allodynia (1, 2). Some of the most powerful painkillers, including opioids and nonsteroidal anti-inflammatory drugs, are only partially effective and prolonged exposure can cause unwanted effects (3, 4). As a result, there is continuous effort to identify novel therapeutics for pain control with alternative biological mechanisms and that elicit fewer side effects.Inflammatory mediators, including cytokines/chemokines, play a critical role in the pathogenesis of inflammatory and neuropathic pain (5, 6). Emerging evidences suggest that C5a, the anaphylatoxin produced by complement activation, has potent nociceptive activity in several models of inflammatory and neuropathic pain by interacting with its selective receptor C5aR (7, 8). C5aR belongs to the class A subfamily of the seven-transmembrane (TM) G protein-coupled receptors (GPCR) (9) and is widely expressed in immune cells, including neutrophils (polymorphonuclear cells, PMN), monocytes, microglia, and in nonimmune cells, including neurons in the CNS and dorsal root ganglia (10, 11).Evidence for a role of C5a in nociception sensitization has been obtained in several models of inflammatory pain. For example, C5a was produced at the inflammatory sites and elicited mechanical hyperalgesia by activating the C5aR on infiltrated PMN (7). Direct intraplantar injection of C5a in mice elicited both heat and mechanical hyperalgesia by sensitizing primary afferent C-nociceptors (12, 13). Local activation of C5aR has been also implicated in the pathogenesis of postsurgical pain, a model of postoperative pain (13). Finally, local administration of PMX-53, a C5aR antagonist, attenuated mechanical hyperalgesia induced by carrageenan, zymosan, or lipopolysaccharide (7). In addition to the peripheral role of C5a/C5aR in inflammatory pain, up-regulated levels of C5 and C5aR have been found in spinal cord microglia in animals subjected to spared nerve injury (SNI), a model of neuropathic pain (8). Indeed, C5-null mice or the infusion of PMX-53 into the intrathecal space reduced neuropathic pain hypersensitivity in the SNI model (8). Collectively, these data suggest that a neuroimmune interaction in the periphery and spinal cord through activation of the complement cascade and the production of C5a contributes to the genesis of both inflammatory and neuropathic pain.As for other peptidergic GPCRs, the efforts to identify small molecular weight C5aR antagonists have led to a limited number of molecules, mostly lacking adequate potency and selectivity (14). The most promising candidate so far described, PMX-53, is a cyclic peptidomimetic antagonist designed to mimic the C-terminal portion of C5a (15). Despite the encouraging results obtained in preclinical studies, as for many peptide drugs, the development of PMX-53 has been limited by its short half-life and unfavorable bioavailability (16). In the present study, we report the successful design of a nonpeptidic C5a allosteric small molecular weight inhibitor driven by the structural information on a minor pocket spanning between TM1, -2, -3, -6, and -7 that is highly conserved across the GPCR family and that has been recently proposed as a key motif for the intracellular activation process. Reparixin was previously reported as a neutral allosteric inhibitor of CXCR1 and CXCR2 that binds the TM in a region that overlaps the minor pocket (17, 18). Combining the information from independent sources on structural and functional features of allosteric sites in homologous chemokine receptors, this paper intends to provide what is, to our knowledge, the first example of de novo design of a new class of allosteric small molecular weight inhibitors of a GPCR not belonging to the chemokine receptor family, C5aR. The preclinical candidate, DF2593A, is a potent and orally active C5a noncompetitive allosteric inhibitor with significant antinociceptive effects in a wide range of inflammatory and neuropathic pain models.