Miracle-dz/UniFAR-FTUs huggingface dataset:
Improved healing of large segmental defects in the rat femur by reverse dynamization in the presence of bone morphogenetic protein-2.

BACKGROUND Large segmental defects in bone do not heal well and present clinical challenges. This study investigated modulation of the mechanical environment as a means of improving bone healing in the presence of bone morphogenetic protein (BMP)-2. Although the influence of mechanical forces on the healing of fractures is well established, no previous studies, to our knowledge, have described their influence on the healing of large segmental defects. We hypothesized that bone-healing would be improved by initial, low-stiffness fixation of the defect, followed by high-stiffness fixation during the healing process. We call this reverse dynamization. METHODS A rat model of a critical-sized femoral defect was used. External fixators were constructed to provide different degrees of stiffness and, importantly, the ability to change stiffness during the healing process in vivo. Healing of the critical-sized defects was initiated by the implantation of 11 μg of recombinant human BMP (rhBMP)-2 on a collagen sponge. Groups of rats receiving BMP-2 were allowed to heal with low, medium, and high-stiffness fixators, as well as under conditions of reverse dynamization, in which the stiffness was changed from low to high at two weeks. Healing was assessed at eight weeks with use of radiographs, histological analysis, microcomputed tomography, dual x-ray absorptiometry, and mechanical testing. RESULTS Under constant stiffness, the low-stiffness fixator produced the best healing after eight weeks. However, reverse dynamization provided considerable improvement, resulting in a marked acceleration of the healing process by all of the criteria of this study. The histological data suggest that this was the result of intramembranous, rather than endochondral, ossification. CONCLUSIONS Reverse dynamization accelerated healing in the presence of BMP-2 in the rat femur and is worthy of further investigation as a means of improving the healing of large segmental bone defects. CLINICAL RELEVANCE These data provide the basis of a novel, simple, and inexpensive way to improve the healing of critical-sized defects in long bones. Reverse dynamization may also be applicable to other circumstances in which bone-healing is problematic.
Gene rearrangement in acute non‐lymphoblastic leukaemia: correlation with morphological and immunophenotypic characteristics of blast cells

The presence of Ig and TCR gene rearrangement has been reported to occur in ANLL. However, most of the studies have been performed in short series of patients and, in general, not all rearranging genes have been included. We have investigated the configuration of immunoglobulin (Ig) and T-cell receptor loci (TCR) in a series of 160 untreated patients with de novo acute non-lymphoblastic leukaemia (ANLL) and correlated the results with the morphological and immunophenotypic characteristics of blast cells. IGH gene rearrangement was detected in 16/160 cases analysed (10%) and IGK was rearranged in half of them. The incidence of cases displaying TCRB, TCRG and TCRD rearrangements was 5.6%, 13.8% and 13%, respectively. Concomitant recombinatorial events including different Ig and/or TCR genes were frequently detected. Gene rearrangement was not related to the stage of cell differentiation within the myeloid lineage assessed both by morphological and immunophenotypic criteria. Regarding the correlation with the presence of lymphoid related markers, the only relevant association was between the expression of CD7 antigen and TCRG and TCRD gene rearrangement. Our results show that the incidence of gene rearrangement in ANLL may be slightly higher than previously suspected, and that it is not associated with early stages of cell differentiation nor to the expression of lymphoid markers.
Drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma: Current state of the art

Transarterial chemoembolization (TACE) represents the current gold standard for hepatocellular carcinoma (HCC) patients in intermediate stage. Conventional TACE (cTACE) is performed with the injection of an emulsion of a chemotherapeutic drug with lipiodol into the artery feeding the tumoral nodules, followed by embolization of the same vessel to obtain a synergistic effect of drug cytotoxic activity and ischemia. Aim of this review is to summarize the main characteristics of drug-eluting beads (DEB)-TACE and the clinical results reported so far in the literature. A literature search was conducted using PubMed until June 2017. In order to overcome the drawbacks of cTACE, namely lack of standardization and unpredictability of outcomes, non-absorbable embolic microspheres charged with cytotoxic agents (DEBs) have been developed. DEBs are able to simultaneously exert both the therapeutic components of TACE, either drug-carrier function and embolization, unlike cTACE in which applying the embolic agent is a second moment after drug injection. This way, risk of systemic drug release is minimal due to both high-affinity carrier activity of DEBs and absence of a time interval between injection and embolization. However, despite promising results of preliminary studies, clear evidence of superiority of DEB-TACE over cTACE is still lacking. A number of novel technical devices are actually in development in the field of loco-regional treatments for HCC, but only a few of them have entered the clinical arena. In absence of well-designed randomized-controlled trials, the decision on whether use DEB-TACE or cTACE is still controversial.
Evaluation of Pipeline Flex delivery system for the treatment of unruptured aneurysms

ABSTRACT Introduction: Refinements in endovascular technology have revolutionized the treatment of intracranial aneurysms (IAs) with the development of flow-diversion technology. The first generation of the Pipelin Embolization Device (PED) has demonstrated its safety and efficacy. However, the deployment technique was a difficult task that often led to complex maneuvers. The Pipeline Flex Embolization Device (PED Flex) is the second generation and its introduction has arrived with high expectations due to a completely redesigned delivery system that intends to overcome deployment difficulties seen in the previous generation. Areas covered: Preclinical studies, mechanism of action of flow-diverters, technical aspects and deployment system of the PED Flex, and clinical outcomes with both PED generations. Expert commentary: Flow diversion has allowed us to treat lesions that would be otherwise challenging for surgical clipping or unsuitable for other endosaccular strategies. Although the experience with PED Flex is limited, initial results suggest its safety and short-term efficacy.
Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way

Nicotine can stimulate the progression of non-small cell lung cancer (NSCLC) through nicotinic acetylcholine receptors (nAChRs). The persistent proliferation of cancer cells is one of the key effects of nicotinic signaling. The present study aimed to clarify the mechanism of nicotine-induced proliferation in NSCLCs at the receptor subtype level. We have previously reported that there are various subtypes of nicotinic receptors expressed in NSCLC cell lines. In the present study, we demonstrated that blocking α7nAChRs agonized by nicotine could suppress the proliferation of H1299 cells in vitro and decrease H1299 tumor xenograft growth in nude mice. During this process, the expression of vimentin was also markedly attenuated, concomitant with the decreased expression of α7nAChR. These results were ascertained by knocking down the α7nAChR gene to abolish receptor functioning. Furthermore, under the stimulation of nicotine, the MEK/ERK signaling pathway was found to be inhibited when cells were treated with an antagonist of α7nAChR or an inhibitor of MEK. Collectively the results indicate that the changes in proliferation and vimentin expression of H1299 cells in response to α7nAChR stimulation are mediated by the MEK/ERK pathway. These findings demonstrate that α7nAChR plays an important role in H1299 cell proliferation, tumor growth and expression of vimentin. Therefore, blocking α7nAChRs in NSCLC may be a potential adjuvant therapy for the targeted treatment of NSCLC.
Activin‐βc reduces reproductive tumour progression and abolishes cancer‐associated cachexia in inhibin‐deficient mice

Activins are involved in the regulation of a diverse range of physiological processes including development, reproduction, and fertility, and have been implicated in the progression of cancers. Bioactivity is regulated by the inhibin α‐subunit and by an activin‐binding protein, follistatin. The activin‐βC subunit was not considered functionally significant in this regard due to an absence of phenotype in knockout mice. However, activin‐βC forms heterodimers with activin‐βA and activin‐C antagonizes activin‐A in vitro. Thus, it is proposed that overexpression, rather than loss of activin‐βC, regulates activin‐A bioactivity. In order to prove biological efficacy, inhibin α‐subunit knockout mice (α‐KO) were crossed with mice overexpressing activin‐βC (ActC++). Deletion of inhibin leads to Sertoli and granulosa cell tumours, increased activin‐A, and cancer‐associated cachexia. Therefore, cachexia and reproductive tumour development should be modulated in α‐KO/ActC++ mice, where excessive activin‐A is the underlying cause. Accordingly, a reduction in activin‐A, no significant weight loss, and reduced incidence of reproductive tumours were evident in α‐KO/ActC++ mice. Overexpression of activin‐βC antagonized the activin signalling cascade; thus, the tumourigenic effects of activin‐A were abrogated. This study provides proof of the biological relevance of activin‐βC. Being a regulator of activin‐A, it is able to abolish cachexia and modulate reproductive tumour development in α‐KO mice.
Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells

Ikaros is a transcription factor that regulates lymphocyte development from the level of the haematopoietic stem cell. Lack of Ikaros reduces the ability of progenitor cells to commit to the T‐cell lineage, resulting in reduced numbers of early thymic T‐cell progenitors and mature T cells. Mature CD4 T cells that lack Ikaros have defects in proliferation, T helper cell differentiation, cytokine expression and the ability to become anergic. A role for Ikaros in the naive T cell has not yet been identified. The receptors interleukin‐7 receptor α (IL‐7Rα) and l‐selectin are important for ensuring survival and proper homing of naive T cells, respectively. Here we show that lack of Ikaros leads to reduced expression of these receptors in naive T cells, which impacts their ability to home and survive in response to IL‐7. We define the mechanism underlying this phenotype as a requirement for Ikaros in maintenance of expression of Foxo1, a transcriptional regulator that is required for their expression. We also demonstrate that CD4 T cells lacking Ikaros are significantly crippled in their ability to become induced regulatory T cells, a phenotype also linked to reduced Foxo1 expression. Finally, we show that restoring Ikaros function to Ikaros‐deficient CD4 T cells increases levels of Foxo1 message. Together, these studies define, for the first time, a role for Ikaros in naive T cells and establish it as the first transcriptional regulator required for maintaining levels of Foxo1 gene expression in these cells.
Role for cellular Src kinase in myoblast proliferation

In this study, a role for cellular Src in muscle cell proliferation and differentiation was investigated. Pharmacological inhibition of Src‐class kinases repressed proliferation and promoted differentiation of the C2C12 muscle cell line, even when the cells were cultured under growth‐inducing conditions of high serum. Pharmacological inhibition of Src‐class kinases also affected cellular components that regulate proliferation and differentiation in muscle; cyclin D1 levels were reduced while, myogenin was increased. Suppression of cyclin D1 and enhancement of myogenin levels also occurred upon expression of a dominant negative Src, corroborating a role for Src kinases in regulating proliferation and differentiation. Inhibition of Src‐family kinases also blocked fibroblast growth factor (FGF) induced proliferation but, notably, did not reverse the effect of FGF to inhibit differentiation. Evidence for the Src‐class kinase Src in myoblast mitogenesis was obtained by determining the pattern of protein expression and activity for this kinase. Under all conditions examined, Src's expression and enzymatic activity were high in cultures of myoblasts and down‐regulated during differentiation. Importantly, Src's activity was rapidly stimulated by mitogen‐containing serum and attenuated when myoblasts were switched to low serum‐containing differentiation medium. These data indicate that Src is important for maintaining muscle cell proliferation. J. Cell. Physiol. 193: 328–339, 2002. © 2002 Wiley‐Liss, Inc.
A preparative method for isolation of fucoxanthin from Eisenia bicyclis by centrifugal partition chromatography.

INTRODUCTION Eisenia bicyclis (Kjellman) Setchell (Laminariaceae) is a common brown alga that inhabits around the coast of Korea, Japan and China. It contains fucoxanthin, a major carotenoid of brown algae which shows a variety of pharmaceutical functions. OBJECTIVE The aim of this investigation was the quantification and preparative isolation of fucoxanthin from fresh E. bicyclis using a new separation scheme, centrifugal partition chromatography (CPC). METHODOLOGY The fucoxanthin fraction (Fuco fraction) was prepared by solvent partition method from the acetone extract of fresh E. bicyclis. Fuco fraction was used for CPC using a two-phase solvent system of n-hexane-ethyl acetate-ethanol-water (5:5:7:3, v/v/v/v). The flow rate of mobile phase was 2 mL/min with descending mode while rotating at 1000 rpm. The eluate was monitored at 410 nm. The content and structure of fucoxanthin in the CPC fraction were confirmed with HPLC, UV, APCI/MS and NMR spectra. RESULTS A preparative CPC yielded 20 mg of fucoxanthin (87% recovery from Fuco fraction) in a two-step separation from 516 mg of Fuco fraction containing 4.59% fucoxanthin. The purity of the isolated fucoxanthin was about 81% in the first CPC step and over 98% in the second CPC step based on the calibration curve. The isolated fucoxanthin was identified as all-trans-fucoxanthin with APCI/MS (parent ion at m/z 641 [M + H - H(2) O](+) ) and (1) H, (13) C and 2-D NMR spectra. CONCLUSION High-purity fucoxanthin was successfully isolated from fresh E. bicyclis, suggesting further potential applications in the industrial use of this valuable carotenoid.
Sentinel lymph node biopsy in breast cancer after neoadjuvant chemotherapy. A pilot study.

AIMS Sentinel lymph node biopsy (SLN) seems to represent a reliable method for early breast cancer staging, offering an alternative to complete axillary dissection. METHODS The identification of sentinel node(s), their localization and the predictive capacity of SLN were analysed in 42 patients who had neoadjuvant chemotherapy for breast cancer. Dextran labelled with (99m)Tc was injected close to the tumor. The radioactive uptake in the axilla was detected by scintigraphic images and by a hand-held probe guided the SLN. RESULTS One or more sentinel nodes were identified in 41 patients (97.6%). We could accurately predict axillary lymph nodes status in 93% of the cases. CONCLUSIONS SLN can predict the status of the axilla in patients who have received primary chemotherapy.
Induction of fetal hemoglobin synthesis with recombinant human erythropoietin in anemic patients with heterozygous beta-thalassemia during pregnancy.

OBJECTIVE Recombinant human erythropoietin (rhEPO) increases fetal hemoglobin synthesis in nonpregnant thalassaemic patients. We used rhEPO in 4 pregnant patients with heterozygous beta-thalassemia and anemia to study its effect on erythropoiesis, F cell production, and HbF synthesis. METHODS Patients were treated with a combination therapy of rhEPO and iron. The effect on HbF synthesis was assessed by the percentage of F reticulocytes, F cells, and total HbF, erythropietis by reticulocyte count, and hemoglobin measurements and iron status by ferritin levels, transferrin saturation, and percentage of hypochromic red cells. RESULTS RhEPO caused an increase of F reticulocytes (1.5 to 10.5 fold), F cells (5.0 to 7.7 fold), and HbF (1.4 to 2.2 fold). All patients showed an increase of young, immature reticulocytes and had elevated reticulocytes at the end of therapy. Hemoglobin increased with a range from 0.3 to 1.5 g/dL. Transferrin saturation and ferritin levels were normal at the end of the study. There was an increase of the percentage of hypochromic red cells, indicating functional iron deficiency after rhEPO administration despite supplemental iron. CONCLUSIONS RhEPO stimulates both HbF synthesis and erythropoiesis in pregnant patients with heterozygous beta-thalassemia and anemia. Since it is known that high HbF levels ameliorate thalassemia symptoms in nonpregnant patients, use of rhEPO for the treatment of severe anemia in thalassaemic patients during pregnancy might be further evaluated.
Cerebrospinal fluid IgG, IgA, IgM, IgD, and IgE levels in central nervous system disorders

Using a radioimmunoassay, we evaluated the cerebrospinal fluid content of IgG, IgA, IgM, IgD, and IgE in multiple sclerosis, viral meningitis, and tumors. Abnormal immunoglobulin levels occurred in all conditions, reaching 13 times the norm for IgM in multiple sclerosis and 5 times the norm in aseptic meningitis. Striking increases also occurred with IgA, IgM, and IgE in benign and malignant (both primary and metastatic) tumors of the CNS. Furthermore, the immunoglobulin-protein ratio was calculated. In aseptic meningitis and multiple sclerosis, the ratio was significant as compared to the norms.
MELAS: Clinical features, biochemistry, and molecular genetics

We studied 23 patients with clinically defined mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS), 25 oligosymptomatic or asymptomatic maternal relatives, and 50 mitochondrial disease control subjects for the presence of a previously reported heteroplasmic point mutation at nt 3,243 in the transfer RNALeu(UUR) gene of mitochondrial DNA. We found a high concordance between clinical diagnosis of MELAS and transfer RNALeu(UUR) mutation, which was present in 21 of the 23 patients with MELAS, all 11 oligosymptomatic and 12 of 14 asymptomatic relatives, but in only five of 50 patients without MELAS. The proportion of mutant genomes in muscle ranged from 56 to 95% and was significantly higher in the patients with MELAS than in their oligosymptomatic or asymptomatic relatives. In subjects in whom both muscle and blood were studied, the percentage of mutations was significantly lower in blood and was not detected in three of 12 asymptomatic relatives. The activities of complexes I + III, II + III, and IV were decreased in muscle biopsies harboring the mutation, but there was no clear correlation between percentage of mutant mitochondrial DNAs and severity of the biochemical defect.
Stress resistance and lifespan are increased in C. elegans but decreased in S. cerevisiae by mafr-1/maf1 deletion

Maf1 is a conserved effector of the mechanistic target of rapamycin (mTOR), an aging promoting kinase. However, whether Maf1 is required for lifespan extension caused by mTOR inhibition, such as dietary restriction (DR) or calorie restriction (CR) remains elusive. Here we show that deletion of maf1 in the budding yeast S. cerevisiae but not mafr-1 in C. elegans prevents DR or CR to extend lifespan. Interestingly, mafr-1 deletion increases stress tolerance and extends lifespan. MAFR-1 is phosphorylated in a mTOR-dependent manner and mafr-1 deletion alleviates the inhibition of tRNA synthesis caused by reduced mTOR activity. We find that the opposite effect of mafr-1 deletion on lifespan is due to an enhancement of stress response, including oxidative stress response, mitochondrial unfolded protein response (UPRmt) and autophagy. mafr-1 deletion also attenuates the paralysis of a C. elegans model of Alzheimer's disease. Our study reveals distinct mechanisms of lifespan regulation by Maf1 and MAFR-1.
Initial resuscitation guided by the Surviving Sepsis Campaign recommendations and early echocardiographic assessment of hemodynamics in intensive care unit septic patients: A pilot study*

Objective: To compare therapeutic interventions during initial resuscitation derived from echocardiographic assessment of hemodynamics and from the Surviving Sepsis Campaign guidelines in intensive care unit septic patients. Design and Setting: Prospective, descriptive study in two intensive care units of teaching hospitals. Methods: The number of ventilated patients with septic shock who were studied was 46. Transesophageal echocardiography was first performed (T1 < 3 hrs after intensive care unit admission) to adapt therapy according to the following predefined hemodynamic profiles: fluid loading (index of collapsibility of the superior vena cava ≥36%), inotropic support (left ventricular fractional area change <45% without relevant index of collapsibility of the superior vena cava), or increased vasopressor support (right ventricular systolic dysfunction, unremarkable transesophageal echocardiography study consistent with sustained vasoplegia). Agreement for treatment decision between transesophageal echocardiography and Surviving Sepsis Campaign guidelines was evaluated. A second transesophageal echocardiography assessment (T2) was performed to validate therapeutic interventions. Results: Although transesophageal echocardiography and Surviving Sepsis Campaign approaches were concordant to manage fluid loading in 32 of 46 patients (70%), echocardiography led to the absence of blood volume expansion in the remaining 14 patients who all had a central venous pressure <12mm Hg. Accordingly, the agreement was weak between transesophageal echocardiography and Surviving Sepsis Campaign for the decision of fluid loading (&kgr;: 0.37 [0.16;0.59]). With a cut-off value <8 mm Hg for central venous pressure, &kgr; was 0.33 [−0.03;0.69]. Inotropes were prescribed based on transesophageal echocardiography assessment in 14 patients but would have been decided in only four patients according to Surviving Sepsis Campaign guidelines. As a result, the agreement between the two approaches for the decision of inotropic support was weak (&kgr;: 0.23 [−0.04;0.50]). No right ventricular dysfunction was observed. No patient had anemia and only three patients with transesophageal echocardiography documented left ventricular systolic dysfunction had a central venous oxygen saturation <70%. Conclusions: A weak agreement was found in the prescription of fluid loading and inotropic support derived from early transesophageal echocardiography assessment of hemodynamics and Surviving Sepsis Campaign guidelines in patients presenting with septic shock.
Nasal infestation by Linguatula serrata in a dog in the UK: a case report.

A two-year-old, female neutered, cross-breed dog imported from Romania was diagnosed with nasal infestation of Linguatula serrata after she sneezed out an adult female. The dog was presented with mucopurulent/sanguinous nasal discharge, marked left-sided exophthalmia, conjunctival hyperaemia and chemosis. Computed tomography and left frontal sinusotomy revealed no further evidence of adult parasites. In addition, there was no evidence of egg shedding in the nasal secretions or faeces. Clinical signs resolved within 48 hours of sinusotomy, and with systemic broad-spectrum antibiotics and non-steroidal anti-inflammatory drugs. Recommendations are given in this report regarding the management and follow-up of this important zoonotic disease.