Impact of the medial displacement calcaneal osteotomy on foot biomechanics: a systematic literature review.

INTRODUCTION: Progressive collapsing foot deformity (PCFD), formally known as "adult-acquired flatfoot deformity" (AAFFD), is a complex foot deformity consisting of multiple components. If surgery is required, joint-preserving procedures, such as a medial displacement calcaneal osteotomy (MDCO), are frequently performed. The aim of this systematic review is to provide a summary of the evidence on the impact of MDCO on foot biomechanics. MATERIALS AND METHODS: A systematic literature search across two major sources (PubMed and Scopus) without time limitation was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) criteria. Only original research studies reporting on biomechanical changes following a MDCO were included. Exclusion criteria consisted of review articles, case studies, and studies not written in English. 27 studies were included and the methodologic quality graded according to the QUACS scale and the modified Coleman score. RESULTS: The 27 included studies consisted of 18 cadaveric, 7 studies based on biomechanical models, and 2 clinical studies. The impact of MDCO on the following five major parameters were assessed: plantar fascia (n = 6), medial longitudinal arch (n = 9), hind- and midfoot joint pressures (n = 10), Achilles tendon (n = 5), and gait pattern parameters (n = 3). The quality of the studies was moderate to good with a pooled mean QUACS score of 65% (range 46-92%) for in-vitro and a pooled mean Coleman score of 58 (range 56-65) points for clinical studies. CONCLUSION: A thorough knowledge of how MDCO impacts foot function is key in properly understanding the postoperative effects of this commonly performed procedure. According to the evidence, MDCO impacts the function of the plantar fascia and Achilles tendon, the integrity of the medial longitudinal arch, hind- and midfoot joint pressures, and consequently specific gait pattern parameters.

Odor-Reduced HDPE-Lignin Blends by Use of Processing Additives.

The comprehensive use of natural polymers, such as lignin, can accelerate the replacement of mineral oil-based commodities. Promoting the material recovery of the still underutilized technical lignin, polyolefin-lignin blends are a highly promising approach towards sustainable polymeric materials. However, a limiting factor for high-quality applications is the unpleasant odor of technical lignin and resulting blends. The latter, especially, are a target for potential odor reduction, since heat- and shear-force intense processing can intensify the smell. In the present study, the odor optimization of kraft and soda HDPE-lignin blends was implemented by the in-process application of two different processing additives-5% of activated carbon and 0.7% of a stripping agent. Both additives were added directly within the compounding process executed with a twin screw extruder. The odor properties of the produced blends were assessed systematically by a trained human panel performing sensory evaluations of the odor characteristics. Subsequently, causative odor-active molecules were elucidated by means of GC-O and 2D-GC-MS/O while OEDA gave insights into relative odor potencies of single odorants. Out of 70 different odorants detected in the entirety of the sample material, more than 30 sulfur-containing odorants were present in the kraft HDPE-lignin blend, most of them neo-formed due to high melt temperatures during extrusion, leading to strong burnt and sulfurous smells. The addition of activated carbon significantly decreased especially these sulfurous compounds, resulting in 48% of overall odor reduction of the kraft blend (mean intensity ratings of 5.2) in comparison to the untreated blend (10.0). The applied stripping agent, an aqueous solution of polymeric, surface-active substances adsorbed onto a PP carrier, was less powerful in reducing neo-formed sulfur odorants, but led to a decrease in odor of 26% in the case of the soda HDPE-lignin blend (7.4). The identification of single odorants on a molecular level further enabled the elucidation of odor reduction trends within single compound classes. The obtained odor reduction strategies not only promote the deodorization of HDPE-lignin blends, but might be additionally helpful for the odor optimization of other natural-fiber based materials.

Odor and Constituent Odorants of HDPE-Lignin Blends of Different Lignin Origin.

The still-rising global demand for plastics warrants the substitution of non-renewable mineral oil-based resources with natural products as a decisive step towards sustainability. Lignin is one of the most abundant natural polymers and represents an ideal but hitherto highly underutilized raw material to replace petroleum-based resources. In particular, the use of lignin composites, especially polyolefin-lignin blends, is currently on the rise. In addition to specific mechanical property requirements, a challenge of implementing these alternative polymers is their heavy odor load. This is especially relevant for lignin, which exhibits an intrinsic odor that limits its use as an ingredient in blends intended for high quality applications. The present study addressed this issue by undertaking a systematic evaluation of the odor properties and constituent odorants of commercially available lignins and related high-density polyethylene (HDPE) blends. The potent odors of the investigated samples could be attributed to the presence of 71 individual odorous constituents that originated primarily from the structurally complex lignin. The majority of them was assignable to six main substance classes: carboxylic acids, aldehydes, phenols, furan compounds, alkylated 2-cyclopenten-1-ones, and sulfur compounds. The odors were strongly related to both the lignin raw materials and the different processes of their extraction, while the production of the blends had a lower but also significant influence. Especially the investigated soda lignin with hay- and honey-like odors was highly different in its odorant composition compared to lignins resulting from the sulfurous kraft process predominantly characterized by smoky and burnt odors. These observations highlight the importance of sufficient purification of the lignin raw material and the need for odor abatement procedures during the compounding process. The molecular elucidation of the odorants causing the strong odor represents an important procedure to develop odor reduction strategies.

Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation.

Noninfectious lung injury and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with significant morbidity and mortality. Azithromycin is widely used in allogeneic HCT recipients for pulmonary chronic GVHD, although current data appear controversial. We induced GVHD and noninfectious lung injury in lethally irradiated B6D2F1 mice by transplanting bone marrow and splenic T cells from allogeneic C57BL/6 mice. Experimental groups were treated with oral azithromycin starting on day 14 until the end of week 6 or week 14 after transplantation. Azithromycin treatment resulted in improved survival and decreased lung injury; the latter characterized by improved pulmonary function, reduced peribronchial and perivascular inflammatory cell infiltrates along with diminished collagen deposition, and a decrease in lung cytokine and chemokine expression. Azithromycin also improved intestinal GVHD but did not affect liver GVHD at week 6 early after transplantation. At week 14, azithromycin decreased liver GVHD but had no effect on intestinal GVHD. In vitro, allogeneic antigen-presenting cell (APC)- dependent T cell proliferation and cytokine production were suppressed by azithromycin and inversely correlated with relative regulatory T cell (Treg) expansion, whereas no effect was seen when T cell proliferation occurred APC independently through CD3/CD28-stimulation. Further, azithromycin reduced alloreactive T cell expansion but increased Treg expansion in vivo with corresponding downregulation of MHC II on CD11c(+) dendritic cells. These results demonstrate that preventive administration of azithromycin can reduce the severity of acute GVHD and noninfectious lung injury after allo-HCT, supporting further investigation in clinical trials.

Safety and feasibility of long term administration of recombinant human granulocyte-colony stimulating factor in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuronal disease resulting in a loss of the upper and lower motor neurons and subsequent death within three to four years after diagnosis. Mouse models and preliminary human exposure data suggest that the treatment with granulocyte-colony stimulating factor (G-CSF) has neuro-protective effects and may delay ALS progression. As data on long-term administration of G-CSF in patients with normal bone marrow (BM) function are scarce, we initiated a compassionate use program including 6 ALS patients with monthly G-CSF treatment cycles. Here we demonstrate that G-CSF injection was safe and feasible throughout our observation period up to three years. Significant decrease of mobilization efficiency occurred in one patient and a loss of immature erythroid progenitors was observed in all six patients. These data imply that follow-up studies analyzing BM function during long-term G-CSF stimulation are required.

Steroid treatment alters adhesion molecule and chemokine expression in experimental acute graft-vs.-host disease of the intestinal tract.

OBJECTIVE: Acute graft-vs.-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT) that is characterized by high morbidity and mortality. Systemic treatment with steroids has been the mainstay of first-line therapy of aGVHD, although controlled experimental data in this context are limited. MATERIALS AND METHODS: Using a haploidentical murine BMT model, steroid effects on hepatic and intestinal inflammation during aGVHD have been investigated. Lethally irradiated B6D2F1 mice received bone marrow cells and splenocytes from either syngeneic (B6D2F1) or allogeneic (C57BL/6) donors. RESULTS: Intraperitoneal administration of prednisolone (2 mg/kg body weight every day) early after onset of GVHD from day +10 until day +42 resulted in reduced clinical GVHD severity and improved survival of allogeneic recipients. Although the liver was barely affected by prednisolone treatment, aGVHD-related histopathologic injury of the gastrointestinal tract was strongly reduced in association with diminished expression of interferon-γ, tumor necrosis factor, CXCL 9-11, CCL2-3, mucosal addressin cell adhesion molecule-1, and intercellular adhesion molecule-1. Prednisolone-induced reduction of adhesion molecule expression in the gut manifested earlier than seen for cytokines or chemokines. Interestingly, when starting steroid treatment on day +28, the course of GVHD was unchanged and no major differences in cyto- or chemokine expression in gastrointestinal tract or liver on day +42 were seen. CONCLUSIONS: When started early after GVHD onset, prednisolone-related beneficial effects can affect aGVHD target organs differently, involving divergent regulation of inflammation and leukocyte migration. Specifically, a change in adhesion properties between leukocytes and endothelial cells in the gastrointestinal tract may be one of the initial steps in a cascade of steroid-related aGVHD-attenuating events.

Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease.

Pulmonary graft-versus-host disease (pGVHD) is a major complication after allogeneic bone marrow transplantation (BMT), which involves donor leukocyte migration into the lung along chemokine gradients, leading to pulmonary dysfunction and respiratory insufficiency. As broad spectrum chemokine inhibitor (BSCI) NR58-3.14.3 suppresses leukocyte migration in response to various chemokines, including CCL2, CCL3, CCL5, we investigated the effects of NR58-3.14.3 on the evolution of pGVHD. Lethally irradiated B6D2F1 mice received BMT from syngeneic (B6D2F1) or allogeneic (C57BL/6) donors, and animals were treated with either NR58-3.14.3 or vehicle control from day -1 to day +14. At week 6, in allogeneic recipients that received BSCI, inflammatory cell infiltrates in the lung were decreased, and reduced histopathologic changes translated into improved pulmonary function when compared to allo-controls. Acute GVHD of the liver was also diminished, whereas no differences were seen in the gut. Alloantigen-dependent splenic T cell expansion and systemic TNF-alpha and IFN-gamma levels were comparable in NR58-3.14.3-treated animals and allo-controls. No suppressive effect of NR58-3.14.3 on CTL cytotoxicity was found, and diminished cellular infiltrates in lung and liver were most likely due to decreased migration of mononuclear cells. Therefore, novel approaches involving BSCIs may provide a promising tool in the management of pGVHD.

Pulmonary function changes in experimental graft-versus-host disease of the lung.

Pulmonary graft-versus-host disease (p-GVHD) is a serious complication after allogeneic stem cell transplantation (allo-SCT) of high morbidity and high mortality. We characterized breathing patterns and pulmonary function changes in correlation to lung histopathology and survival by using a well-established murine model of p-GVHD. Lethally irradiated B6D2F1 mice received SCT from either syngeneic B6D2F1 or allogeneic C57BL/6 animals. Within 6 weeks, severe p-GVHD developed in allogeneic recipients characterized by progressive interstitial, alveolar, peribronchial, and periluminal inflammatory cell infiltration, whereas in syngeneic recipients lung histology remained normal. Allogeneic recipients demonstrated decreased minute ventilation (MV), reduced peak inspiratory and expiratory flow rates as early as 1 week after SCT. In addition, allo-SCT resulted in restrictive pulmonary function changes as early as 7 days after transplantation and in progressive airflow obstruction within 6 weeks. Decreased breathing abilities and pulmonary function changes of allogeneic recipients were associated with increased mortality and the severity of acute graft-versus-host disease (aGVHD). These findings show that p-GVHD can be characterized by changes in pulmonary function and functional respiratory insufficiency. Furthermore, our data strengthen the understanding, that the lung is a critical target organ of aGVHD.

Detection and quantification of functionally defined hematopoietic progenitor cells and tissue specific mRNA within the peripheral blood of myeloma patients after administration of granulocyte colony-stimulating factor and erythropoietin.

OBJECTIVE: Hematopoietic progenitor cells (HPC) as well as tissue committed stem cells expressing mRNA specific to various somatic tissues are thought to be part of the CD34+ bone marrow compartment. In this study, we explore and quantify their mobilization in patients with multiple myeloma undergoing chemotherapy upon administration of granulocyte colony-stimulating factor (G-CSF) plus/minus erythropoietin (EPO). PATIENTS AND METHODS: HPC were quantified by flow cytometry and functional assays within the blood of healthy donors and myeloma patients before and after chemotherapy followed by G-CSF or G-CSF + EPO given subcutaneously. The mRNA expression was studied by quantitative polymerase chain reaction (PCR). Cytokines and peripheral blood protease levels were measured by an enzyme-linked immunosorbent assay. RESULTS: EPO did not significantly alter the number of HPC mobilized by G-CSF alone, and mRNA specific for liver, brain, muscle and kidney was detected in both treatment groups. Quantitative PCR analysis revealed a 2.7-fold increased expression of glial fibrillary acidic protein after G-CSF + EPO administration compared to G-CSF alone (P = 0.003). The concentration of G-CSF rose from 62 +/- 22 pg/mL and 48 +/- 10 pg/mL to 28 +/- 9 ng/mL and 85 +/- 10 ng/mL after 10 d of treatment with G-CSF and G-CSF + EPO, respectively. The concentration of neutrophil elastase (NE) rose only in the G-CSF group by a factor 1.5. CONCLUSION: The alteration of G-CSF and NE levels as well as the expression of tissue committed RNA after the administration of EPO in addition to G-CSF indicate that different growth factors mobilize different stem cells that might potentially be used for the support of tissue repair in future treatment protocols.

The absence of donor-derived IL-13 exacerbates the severity of acute graft-versus-host disease following allogeneic bone marrow transplantation.

Acute graft versus host disease (aGVHD) after allogeneic bone marrow transplantation (allo-BMT) predominantly involves a Th1-type cytokine response. Interestingly, the Th2-cytokine, Interleukin-13 (IL-13), produced by alloreactive donor T cells in vitro was recently shown to correlate with clinical aGVHD severity. Using an established mouse model, we show that the systemic cytokine milieu following allo-BMT with IL-13-/- donors is characterized by decreases in serum Th2 cytokines and an increase in serum TNFalpha, and ultimately correlates with higher aGVHD mortality compared to allogeneic controls. In vitro studies further demonstrate that both exogenous and T cell-derived IL-13 can regulate TNFalpha production by macrophages following lipopolysaccharide stimulation. Thus, donor-derived IL-13 may have a role in modulating inflammatory cytokine release that is associated with aGVHD.

Bone morphogenetic protein (BMP)-7 but not BMP-2 and BMP-4 improves maintenance of primitive peripheral blood-derived hematopoietic progenitor cells (HPC) cultured in serum-free medium supplemented with early acting cytokines.

BMPs regulate the developmental program of hematopoiesis. We demonstrate an increased expression of the BMP receptors Ia and II on cultured CD34+ cells and examine the impact of BMP-2, -4 and -7 on postnatal HPC cultured with stem cell factor, flt3-ligand and interleukin-3 (SF3). The addition of BMP-2 at 5, 25 and 50 ng/m to serum-free medium with SF3 yielded a 1.4- to 1.2-fold increase of CD34+ cells after seven days, but no effect on CFC or LTC-IC was observed. BMP-4 at 25 ng/ml induced a 2.9-fold expansion of colony-forming cells (CFC) within 1 week followed by a decrease to pre-culture values on day 14. The number of long-term culture initiating cells (LTC-IC) decreased by the factor 40 from day 0 to day 14. BMP-7 at 5-50 ng/ml had not effect on the expansion of CD34+ cells and CFC, but improved at 5 ng/ml the survival of LTC-IC significantly as compared to SF3 alone. In summary, BMP-2, -4 and -7 have no effect on the proliferation of CD34+ cells and CFC cultured with serum-free medium and SF3. However, BMP-7 but not BMP-2 and BMP-4 prevents the loss of primitive hematopoietic progenitor cells cultured in SFM plus SF3.

Differentiation of hematopoietic progenitor cells towards the myeloid and B-lymphoid lineage by hepatocyte growth factor (HGF) and thrombopoietin (TPO) together with early acting cytokines.

OBJECTIVES: The effect of stem cell factor (SCF), flt3-ligand (FL), and interleukin (IL)-3 (SF3) in combination with hepatocyte growth factor (HGF), thrombopoietin (TPO), and Hyper-IL-6 on maintenance and differentiation of early human peripheral blood-derived progenitor cells was investigated. METHODS: Single sorted CD34(+) 38(-) cells were cultured with various combinations of these growth factors in order to identify the most effective cytokine combination. Then, lineage-depleted cells were stimulated for 7 d in bulk culture before they were assessed by flow cytometry and in functional assays. RESULTS: The highest number of clones in the single-cell assay was obtained after culture with SF3 + TPO + HGF. Cell expansion with SF3 + TPO + HGF yielded an increase of the total cell number (11-fold), the number of CD34(+) cells (sevenfold), colony forming cells (CFC; 13-fold), granulocytes (CD15/66b(+); 45-fold) and B-cells (CD19/20(+); 55-fold). However, the number of long-term culture initiating cells (LTC-IC) decreased from 779 +/- 338 per 1 x 10(5) CD34(+) cells on day 0 to 253 +/- 115 on day 7. In parallel, the number of pluripotent mouse repopulating cells decreased by the factor 11, and no significant change in the proportion of human myeloid or lymphoid cells found in the mouse bone marrow was noted. CONCLUSION: The observation that mature cells of different lineages are generated and that transplantable multipotent hematopoietic cells are lost during culture suggests the differentiation of early hematopoietic progenitors toward lineage committed cells by the tested cytokines. The detection of cells expressing B-lymphoid markers after culture indicates a possible role in the propagation of B-cells.

Expression and function of homing-essential molecules and enhanced in vivo homing ability of human peripheral blood-derived hematopoietic progenitor cells after stimulation with stem cell factor.

Hematopoietic stem cell (HSC) homing from blood to bone marrow is a multistep process involving rolling, extravasation, migration, and finally adhesion in the correct microenvironment. With view to the hematopoietic recovery after clinical stem cell transplantation, we investigated the effect of stem cell factor (SCF) on the expression and the adhesive function of the alpha4beta1 and alpha5beta1 integrins very-late antigen (VLA)-4 and VLA-5 on peripheral blood-derived hematopoietic progenitor cells. After SCF stimulation, the expression of VLA-4 and VLA-5 on CD34+/c-kit+ cells obtained from healthy donors increased from 54% to 90% and from 3% to 82%, respectively. For patient-derived cells, the increase was 67% to 90% and 12% to 46%. The proportion of mononuclear cells adhering to the fibronectin fragment CH296 increased by stimulation with SCF from 14% to 23%. Accordingly, functional studies showed an approximate 30% increase of adherent long-term culture-initiating cell. The improvement of the homing abilities of SCF-stimulated HSC was confirmed by transplantation into sublethally irradiated nonobese diabetic-scid/scid mice. Six weeks after the transplantation, in eight of eight animals receiving human HSC with the addition of SCF, a profound multilineage hematopoietic engraftment was detected, whereas in the control group receiving only HSC, none of eight animals engrafted. Our data provide the first in vivo evidence that stimulation with cytokines improves the homing ability of transplanted human hematopoietic progenitor cells.