Heterogeneity of yield strain in low-density versus high-density human trabecular bone

Understanding the off-axis behavior of trabecular yield strains may lend unique insight into the etiology of fractures since yield strains provide measures of failure independent of elastic behavior. We sought to address anisotropy of trabecular yield strains while accounting for variations in both density and anatomic site and to determine the mechanisms governing this behavior. Cylindrical specimens were cored from vertebral bodies (n=22, BV/TV=0.11±0.02) and femoral necks (n=28, BV/TV=0.22±0.06) with the principal trabecular orientation either aligned along the cylinder axis (on-axis, n=22) or at an oblique angle of 15° or 45° (off-axis, n=28). Each specimen was scanned with micro-CT, mechanically compressed to failure, and analysed with nonlinear micro-CT-based finite element analysis. Yield strains depended on anatomic site (p=0.03, ANOVA), and the effect of off-axis loading was different for the two sites (p=0.04)—yield strains increased for off-axis loading of the vertebral bone (p=0.04), but were isotropic for the femoral bone (p=0.66). With sites pooled together, yield strains were positively correlated with BV/TV for on-axis loading (R²=58%, p<0.0001), but no such correlation existed for off-axis loading (p=0.79). Analysis of the modulus-BV/TV and strength-BV/TV relationships indicated that, for the femoral bone, the reduction in strength associated with off-axis loading was greater than that for modulus, while the opposite trend occurred for the vertebral bone. The micro-FE analyses indicated that these trends were due to different failure mechanisms for the two types of bone and the different loading modes. Taken together, these results provide unique insight into the failure behavior of human trabecular bone and highlight the need for a multiaxial failure criterion that accounts for anatomic site and bone volume fraction.     

Efficacy of Setarud (IMod), a novel drug with potent anti-toxic stress potential in rat inflammatory bowel disease and comparison with dexamethasone and infliximab

The inflammatory bowel disease (IBD) is an idiopathic, immune-mediated and chronic intestinal condition. In the present study, the effect of Setarud (IMOD), a novel natural drug with known immunomodulatory, anti-inflammatory and antioxidant properties was investigated in experimental colitis in rats and compared with the dexamethasone and infliximab. Immunologic colitis was induced by intracolonic administration of a mixture of trinitrobenzene sulfonic acid (TNBS) and absolute ethanol in male Wistar rats. Animals were divided into 6 groups of sham (normal group), control (vehicle-treated), positive control (dexamethasone 1 mg/kg/day given orally and infliximab 5 mg/kg/day given subcutaneously) and 3 Setarud-treated groups (13.3, 20, 30 mg/kg/day given intraperitoneally). The treatment continued for 14 consecutive days and then animals were decapitated on the day 15 and distal colons were removed for macroscopic, microscopic, and biochemical assays. Biochemical markers, including TNF-alpha, IL-1beta, ferric reducing/antioxidant power (FRAP), myeloperoxidase (MPO) activity and thiobarbitoric acid-reactive substance (TBARS) were measured in the homogenate of colonic tissue. A remarkable reduction in macroscopic and histological damage scores was observed in the animals treated with Setarud. These findings were confirmed by decreased levels of TNF-alpha, interleukin-1beta, MPO activity and TBARS, and raised levels of FRAP in the colon tissue. These observations confirmed the immunomodulatory, anti-inflammatory and antioxidant properties of Setarud in experimental colitis, which was comparable to those of dexamethasone and infliximab.     

Altered Glucose Homeostasis in Mice with Liver-specific Deletion of Src Homology Phosphatase 2

The Src homology 2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, although its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of insulin receptor substrate (IRS)1/2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced ERK activation was dramatically attenuated, yet there was no effect on the putative ERK site on IRS1 (Ser⁶¹²) or on S6 kinase 1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.     

Dissociation of the Octameric Enolase from S. Pyogenes - One Interface Stabilizes Another

Most enolases are homodimers. There are a few that are octamers, with the eight subunits arranged as a tetramer of dimers. These dimers have the same basic fold and same subunit interactions as are found in the dimeric enolases. The dissociation of the octameric enolase from S. pyogenes was examined, using NaClO₄, a weak chaotrope, to perturb the quaternary structure. Dissociation was monitored by sedimentation velocity. NaClO₄ dissociated the octamer into inactive monomers. There was no indication that dissociation of the octamer into monomers proceeded via formation of significant amounts of dimer or any other intermediate species. Two mutations at the dimer-dimer interface, F137L and E363G, were introduced in order to destabilize the octameric structure. The double mutant was more easily dissociated than was the wild type. Dissociation could also be produced by other salts, including tetramethylammonium chloride (TMACl) or by increasing pH. In all cases, no significant amounts of dimers or other intermediates were formed. Weakening one interface in this protein weakened the other interface as well. Although enolases from most organisms are dimers, the dimeric form of the S. pyogenes enzyme appears to be unstable.     

Abdominal pain as presentation of Takayasu's arteritis in an adolescent male patient

We describe a boy with chronic abdominal pain, nausea and vomiting, and weight loss. The imaging was compatible with Takayasu's arteritis. Chronic mesenteric ischemia was the etiology of the patient's symptoms.     

Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells

Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by STI571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.     

New findings in the study on the intercalation of bisdaunorubicin and its monomeric analogues with naked and nucleus DNA

DNA is a target molecule for anthracycline anticancer drugs. We have used new anthracycline derivatives, bisdaunorubicin (WP631) and its monomeric analogues (WP700 serie), and look if there was a relation between the drug binding affinity to naked DNA and to cell nucleus in the cell with its cytotoxicity. Circular dichroism (CD) and fluorescence were used to follow the interaction of anthracycline derivatives with naked DNA and cell nuclei. WP631 interacts with DNA at two distinct stoichiometries, 6:1 and 3:1 base pair (bp)/WP631 molecule (3:1 and 1.5:1 per anthracycline rings). Monomeric daunorubicin (DNR) with its amino sugar N-bound to amino- and nitro-substituted benzyl moiety, representing p-xylenyl linker present in WP631 bisintercalator, is much more binding to DNA than DNR or WP631. These findings are supported by the study of drug binding by nuclei of K562 cells. Around 70% of WP700 intercalate to nucleus DNA in the steady-state, while only 45% of DNR intercalate DNA in the cell. The binding of WP631 by K562 cells is even less effective ( approximately 20%). WP 700 compounds, which are very similar to each other in their binding to DNA, self-association and cell accumulation, differ very distinctly in their cytotoxicity power. The most effective compounds are amino-benzyl derivatives of WP 700 series. The nitro-benzyl compounds have very low toxicity, even if they bind to DNA with similar power with that of the amino derivatives. The comparison of the all data clearly indicates no relation between cytotoxicity of the drug and its ability to intercalate DNA.     

Risk factors of leishmanin-skin test positivity in transmission of Leishmania infantum in the center of Tunisia

This work aims to estimate prevalence and evaluate risk factors of leishmanin-skin test positivity. A cross-sectional leishmanin skin test study was carried out on a sample of 3190 healthy volunteers living in the gouvernorates of Kairouan and Kasserine. Age standardized prevalence of leishmanin-skin test positivity was 45.9% (CI95% = [43.9-47.9]) confirming the hyper endemicity of this region. The rate of leishmanin-skin test positivity ranged from 75.9% (CI95% = [71.9-79.5]) in Zaghdoud (Kairouan) to 6.5% (CI95% = [3.7-11.01) in Abdeladhim (Kasserine). There is no significant difference between men and women suggesting a similar exposure to infection. In the districts of Zaghdoud, Sidi Amor, El Hajeb and chbika, age specific rates showed a rapid increasing positive prevalence with age reaching a proportion exceeding 80% after the age of 15 years. However, the age specific prevalence from other delegations showed a progressive increasing trend with age, with a low rate for younger children and a plateau of 75% after 45 years. Multivariate analysis of leishmanin-skin test positivity risk factors showed that only district and age are determinants of this infection.