[Established classification systems of posterior malleolar fractures : A systematic literature review]. / Etablierte Klassifikationssysteme der posterioren Malleolus-Fraktur : Eine systematische Literaturübersicht.

BACKGROUND: Posterior malleolar fractures are found in almost 50% of all ankle fractures. The high clinical relevance of these joint fractures is explained by the significantly worse clinical and functional outcome. There is still a lack of unified opinion regarding the classification and treatment of these fractures. OBJECTIVE: The aim of this article is to provide a systematic literature review of clinical studies that investigated posterior malleolar fractures and classified them using one of the three established classifications according to Haraguchi, Bartonicek/Rammelt, or Mason. MATERIAL AND METHODS: PubMed was searched without time limits. The systematic literature search was performed according to the current criteria of Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). The methodological quality of the included studies was quantified using the modified Coleman score. RESULTS: A total of 27 studies with a total of 2220 patients were included in this systematic literature review. Trimalleolar fractures showed a significantly less favorable prognosis than other ankle fractures. The quality of reduction was the most important prognostic factor for the clinical outcome. CONCLUSION: None of the three classifications examined has become established in the literature. Most of the classifications are weak or should not be used with respect to a derivable treatment algorithm or a prognosis with respect to the outcome. Only the classification according to Bartonicek/Rammelt is suitable to become established in the literature and in clinical practice due to its derivable treatment algorithm.

The Peptide/Antibody-Based Surface Decoration of Calcium Phosphate Nanoparticles Carrying siRNA Influences the p65 NF-κB Protein Expression in Inflamed Cells In Vitro.

Earlier studies with nanoparticles carrying siRNA were restricted to investigating the inhibition of target-specific protein expression, while almost ignoring effects related to the nanoparticle composition. Here, we demonstrate how the design and surface decoration of nanoparticles impact the p65 nuclear factor-kappa B (NF-κB) protein expression in inflamed leucocytes and endothelial cells in vitro. We prepared silica-coated calcium phosphate nanoparticles carrying encapsulated siRNA against p65 NF-κB and surface-decorated with peptides or antibodies. We show that RGD-decorated nanoparticles are efficient in down-regulating p65 NF-κB protein expression in endothelial cells as a result of an enhanced specific cellular binding and subsequent uptake of nanoparticles. In contrast, nanoparticles decorated with IgG (whether specific or not for CD69) are efficient in down-regulating p65 NF-κB protein expression in T-cells, but not in B-cells. Thus, an optimized nanoparticle decoration with xenogenic IgG may stimulate a specific cellular uptake. In summary, the composition of siRNA-loaded calcium phosphate nanoparticles can either weaken or stimulate p65 NF-κB protein expression in targeted inflamed leucocytes and endothelial cells. In general, unveiling such interactions may be very useful for the future design of anti-p65 siRNA-based nanomedicines for treatment of inflammation-associated diseases.

Nanoparticles Carrying NF-κB p65-Specific siRNA Alleviate Colitis in Mice by Attenuating NF-κB-Related Protein Expression and Pro-Inflammatory Cellular Mediator Secretion.

Ulcerative colitis is a disease that causes inflammation and ulcers in the colon and which is typically recurrent, and NF-κB proteins are important players during disease progression. Here, we assess the impact of silica-coated calcium phosphate nanoparticles carrying encapsulated siRNA against NF-κB p65 on a murine model of colitis. To this end, nanoparticles were injected intravenously (2.0 mg siRNA/kg body weight) into mice after colitis induction with dextran sulfate sodium or healthy ones. The disease activity index, the histopathological impact on the colon, the protein expression of several NF-κB-associated players, and the mediator secretion (colon tissue, blood) were analyzed. We found that the nanoparticles effectively alleviated the clinical and histopathological features of colitis. They further suppressed the expression of NF-κB proteins (e.g., p65, p50, p52, p100, etc.) in the colon. They finally attenuated the local (colon) or systemic (blood) pro-inflammatory mediator secretion (e.g., TNF-α, IFN-ß, MCP-1, interleukins, etc.) as well as the leucocyte load of the spleen and mesenteric lymph nodes. The nanoparticle biodistribution in diseased animals was seen to pinpoint organs containing lymphoid entities (appendix, intestine, lung, etc.). Taken together, the nanoparticle-related silencing of p65 NF-κB protein expression could well be used for the treatment of ulcerative colitis in the future.

Silica-coated calcium phosphate nanoparticles for gene silencing of NF-κB p65 by siRNA and their impact on cellular players of inflammation.

The transcription factor NF-κB and its signaling cascade both play key roles in all inflammatory processes. The most critical member of the NF-κB transcription factor family is p65. We investigated the role of cationic silica-coated calcium phosphate nanoparticles (spherical, diameter by SEM 50-60 nm; zeta potential about +26 mV; stabilized by polyethyleneimine) carrying encapsulated siRNA against NF-κB p65 and their influence on inflamed cells. The nanoparticles were taken up by cells of the blood compartment involved in the inflammatory response, particularly by monocytes, and to a lesser extent by endothelial cells and B-cells, but not by T-cells. The particles were found in endolysosomes where they were dissolved at low pH and released the siRNA into the cytoplasm. This was confirmed by dissolution experiments of model nanoparticles in simulated endolysosomal medium (pH 4.7) and by intracellular co-localization studies of double-labeled nanoparticles (using a negatively charged model peptide for siRNA). The encapsulated functional siRNA reverted the p65 gene and protein expression in inflamed monocytes, the main cells in immune response and surveillance, almost back to the non-inflammatory condition. Additionally, the nanoparticles suppressed the pro-inflammatory cytokine expression profiles (TNF-α, IL-6, IFN-ß) in inflamed J774A.1 monocytes. Taken together, such nanoparticles can be applied for the treatment of inflammatory diseases.

Chemoradiotherapy by intensity-modulated radiation therapy with simultaneous integrated boost in locally advanced or oligometastatic non-small-cell lung cancer-a two center experience.

PURPOSE: Integrating moderate hypofractionation to the macroscopic tumor with elective nodal irradiation while sparing the organs at risk (OAR) in chemoradiotherapy of locally advanced non-small-cell lung cancer. METHODS: From 2010-2018, treatment, patient and tumor characteristics of 138 patients from two radiation therapy centers were assessed. Chemoradiotherapy by intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) to the primary tumor and macroscopic lymph node metastases was used. RESULTS: A total of 124 (90%) patients received concurrent chemotherapy. 106 (76%) patients had UICC (Union for International Cancer Control) stage ≥IIIB and 21 (15%) patients had an oligometastatic disease (UICC stage IV). Median SIB and elective total dose was 61.6 and 50.4 Gy in 28 fractions, respectively. Furthermore, 64 patients (46%) had an additional sequential boost to the primary tumor after the SIB-IMRT main series: median 6.6 Gy in median 3 fractions. The median cumulative mean lung dose was 15.6 Gy (range 6.2-29.5 Gy). Median follow-up and radiological follow-up for all patients was 18.0 months (range 0.6-86.9) and 16.0 months (range 0.2-86.9), respectively. Actuarial local control rates at 1, 2 and 3 years were 80.4, 68.4 and 57.8%. Median overall survival and progression-free survival was 30.0 months (95% confidence interval [CI] 23.5-36.4) and 12.1 months (95% CI 8.2-16.0), respectively. Treatment-related toxicity was moderate. Radiation-induced pneumonitis grade 2 and grade 3 occurred in 13 (9.8%) and 3 (2.3%) patients. CONCLUSIONS: Chemoradiotherapy using SIB-IMRT showed promising local tumor control rates and acceptable toxicity in patients with locally advanced and in part oligometastatic lung cancer. The SIB concept, resulting in a relatively low mean lung dose, was associated with low numbers of clinically relevant pneumonitis. The overall survival appears promising in the presence of a majority of patients with UICC stage ≥IIIB disease.

Functional Outcomes of Revision Osteosynthesis after Failure of Surgical Treatment of Patellar Fractures.

Patellar fractures account for approximately 1% of all skeletal fractures. These fractures are rare; however, because of the crucial function of the patella in the extensor mechanism of the knee, they may lead to serious impairment. New data are revealing functional impairment remains common even with improved surgical techniques. The aim of this study was to assess the functional outcomes of patients after revision surgery in cases of secondary fracture dislocation or persistent articular incongruity. This study included 16 patients with a mean age of 51.8 years (range: 16-85 years) with a mean follow-up of 35.1 months. According to the AO/OTA classification, 15 patients had a C-type fracture, including 10 patients with C3 fracture. Thirteen patients were initially treated with tension band wiring via K-wires or cannulated screws. Revision surgery was performed because of persistent articular incongruity in five patients and secondary fracture dislocation or refracture in 11 patients. We analyzed pain (visual analog scale [0-10]), satisfaction, range of motion (ROM), Böstman's score, Lysholm's score, and knee injury and osteoarthritis outcome score (KOOS) after revision surgery and could extract follow-up data from 15 patients. Mean pain score at rest was 0.57 (range: 0-3.5) and on exertion 2.79 (range: 0-8). The measurement of the ROM of the affected knee compared with that of the opposite knee revealed complete extension. Mean flexion was 123 degrees, in the corresponding knee it was 136 degrees (p = 0.05). The mean postoperative Böstman's and Lysholm's scores were 25.11 (good, maximum: 30) and 78.67 (moderate, maximum: 100), respectively. KOOS was as follows: symptoms, 66.8 points; pain, 77.55 points; activity of daily living (ADL), 75.67 points; and quality of life, 56.25 points. The results of this study suggested that early revision surgery after failure of primary osteosynthesis with secondary anatomic reconstruction and good radiological results leads to satisfactory functional outcomes with persistent functional deficits.

5-Azacytidine modulates CpG methylation levels of EZH2 and NOTCH1 in myelodysplastic syndromes.

PURPOSE: Molecular mechanisms of response to hypomethylating agents in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) still remain largely unknown. Therefore, the effects of 5-Azacytidine (Aza) on clonal architecture and DNA methylation were investigated in this study. METHODS: Using next-generation sequencing (NGS), 30 myeloid leukemia-associated genes were analyzed in 15 MDS/CMML patients with excellent response to Aza. Effects on methylation levels were analyzed by quantitative methylation analysis using pyrosequencing for the global methylation marker LINE-1 in patients and myeloid cell lines. Various myeloid cell lines and a healthy cohort were screened for methylation levels in 23 genes. Selected targets were verified on the MDS/CMML cohort. RESULTS: The study presented here showed a stable variant allele frequency and stable global methylation levels in responding patients. A significant demethylation of EZH2 and NOTCH1 was revealed in patients with Aza response. CONCLUSIONS: A response to Aza is not associated with eradication of malignant clones, but rather with a stabilization of the clonal architecture. We suggest changes in CpG methylation levels of EZH2 and NOTCH1 as potential targets of epigenetic response to Aza treatment which may also serve as useful biomarkers after clinical evaluation.

Lysosomal acid lipase deficiency - early diagnosis is the key.

Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease that may present from infancy to late adulthood depending on residual enzyme activity. While the severe form manifests as a rapidly progressive disease with near universal mortality within the first 6 months of life, milder forms frequently go undiagnosed for prolonged periods and typically present with progressive fatty liver disease, enlarged spleen, atherogenic dyslipidemia and premature atherosclerosis. The adult variant of LAL-D is typically diagnosed late or even overlooked due to the unspecific nature of the presenting symptoms, which are similar to common changes observed in the context of the metabolic syndrome. This review is aimed at delineating clinically useful scenarios in which pediatric or adult medicine clinicians should be aware of LAL-D as a differential diagnosis for selected patients. This is particularly relevant as a potentially life-saving enzyme replacement therapy has become available and the diagnosis can easily be ruled out or confirmed using a dried blood spot test.

Magnetic Nanoparticles Interact and Pass an In Vitro Co-Culture Blood-Placenta Barrier Model.

Magnetic nanoparticles are interesting tools for biomedicine. Before application, critical prerequisites have to be fulfilled. An important issue is the contact and interaction with biological barriers such as the blood-placenta barrier. In order to study these processes in detail, suitable in vitro models are needed. For that purpose a blood-placenta barrier model based on the trophoblast-like cell line BeWo and primary placenta-derived pericytes was established. This model was characterized by molecular permeability, transepithelial electrical resistance and cell-cell-contact markers. Superparamagnetic iron oxide nanoparticles (SPIONs) with cationic, anionic or neutral surface charge were applied. The localization of the nanoparticles within the cells was illustrated by histochemistry. The time-dependent passage of the nanoparticles through the BeWo/pericyte barrier was measured by magnetic particle spectroscopy and atomic absorption spectroscopy. Cationically coated SPIONs exhibited the most extensive interaction with the BeWo cells and remained primarily in the BeWo/pericyte cell layer. In contrast, SPIONs with neutral and anionic surface charge were able to pass the cell layer to a higher extent and could be detected beyond the barrier after 24 h. This study showed that the mode of SPION interaction with and passage through the in vitro blood-placenta barrier model depends on the surface charge and the duration of treatment.

Iron overload and non-alcoholic fatty liver disease.

Approximately one third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of disturbed iron homeostasis as indicated by elevated serum ferritin with normal or mildly elevated transferrin saturation. Mild hepatic iron deposition is the typical histological finding in these subjects and the term "dysmetabolic iron overload syndrome (DIOS)" is now used to describe this syndrome. From a clinical point of view, excess iron likely aggravates the natural course of NAFLD with regard to liver-related endpoints and extrahepatic disease complications although sound evidence is still lacking. The detrimental effect of iron is attributed to its capability to catalyse the formation of toxic hydroxyl radicals resulting in cellular damage. Conversely, reduction of body iron restores insulin sensitivity, and epidemiological evidence suggests that it delays the onset of complications such as T2DM, cardiovascular disease and also advanced liver disease. Iron accumulation in NAFLD is mainly due to inhibition of iron mobilisation from hepatocytes and Kupffer cells. Impaired iron export is related to inflammation and metabolic derangements that appear to impact on iron regulators, such as hepcidin, ferroportin and to a lesser degree on transferrin receptor, ferritin or copper. This review summarizes the current understanding of the role of iron in NAFLD.

Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study.

BACKGROUND: Chronic pain is common in children and adolescents and is often associated with severe functional disability and mood disorders. The pharmacological treatment of chronic pain in children and adolescents can be challenging, ineffective, and is mostly based on expert opinions and consensus. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been used as an adjuvant for treatment of adult chronic pain and has been shown, in some instances, to improve pain and decrease opioid-requirement. We examined the effects of subanesthetic ketamine infusions on pain intensity and opioid use in children and adolescents with chronic pain syndromes treated in an outpatient setting. METHODS: Longitudinal cohort study of consecutive pediatric patients treated with subanesthetic ketamine infusions in a tertiary outpatient center. Outcome measurements included self-reported pain scores (numeric rating scale) and morphine-equivalent intake. RESULTS: Over a 15-month period, 63 children and adolescents (median age 15, interquartile range 12-17 years) with chronic pain received 277 ketamine infusions. Intravenous administration of subanesthetic doses of ketamine to children and adolescents on an outpatient basis was safe and not associated with psychotropic effects or hemodynamic perturbations. Overall, ketamine significantly reduced pain intensity (p < 0.001) and yielded greater pain reduction in patients with complex regional pain syndrome (CRPS) than in patients with other chronic pain syndromes (p = 0.029). Ketamine-associated reductions in pain scores were the largest in postural orthostatic tachycardia syndrome (POTS) and trauma patients and the smallest in patients with chronic headache (p = 0.007). In 37% of infusions, patients had a greater than 20 % reduction in pain score. Conversely, ketamine infusions did not change overall morphine-equivalent intake (p = 0.3). CONCLUSIONS: These data suggest that subanesthetic ketamine infusion is feasible in an outpatient setting and may benefit children and adolescents with chronic pain. Further, patients with CRPS, POTS, and a history of trauma-related chronic pain are more likely to benefit from this therapeutic modality.

SP-PLP-EPR study of chain-length-dependent termination in free-radical polymerization of n-dodecyl methacrylate, cyclohexyl methacrylate, and benzyl methacrylate: evidence of "composite" behavior.

The chain-length dependence of the termination rate coefficient in n-dodecyl methacrylate (DMA), cyclohexyl methacrylate (CHMA), and benzyl methacrylate (BzMA) bulk free-radical homopolymerizations at ambient pressure and at temperatures from -20 to 0 degrees C is deduced using the recently developed technique of SP-PLP-EPR: pulsed-laser polymerization (PLP) in which time-resolved EPR measurement of radical concentration, cR, is made following each single pulse (SP) of an excimer laser. The decay of cR results from termination of radicals of almost identical size. Their chain length, i, increases linearly with time, t, after applying a SP. The rate coefficient, kt(i,i), for termination of two radicals of size i is determined by fitting the experimental cR vs t data. This process demonstrates that (at least) two power-law exponents are necessary to describe kt(i,i) over the extended chain-length range of i = 1 to 1000. This is consistent with the so-called "composite model" , which uses power-law exponents alpha(S) and alpha(L) to describe termination of radicals either shorter or longer, respectively, than a crossover chain length, ic. The fourth parameter obtained from fitting the SP-PLP-EPR data with this model is kt(1,1), the termination rate coefficient for two radicals of degree of polymerization 1. Previous DMA experiments are reanalyzed while new experimental results are reported and analyzed for CHMA and BzMA. The parameter values for CHMA and BzMA termination at 0 degrees C are almost identical-kt(1,1) approximately 3 x 10(7) L mol(-1) s(-1), alpha(S) approximately 0.50, ic approximately 90, and alpha(L) approximately 0.21-and they are close to those for DMA at 0 degrees C: kt(1,1) approximately 1 x 10(7) L mol(-1) s(-1), alpha(S) approximately 0.64, ic approximately 50, and alpha(L) approximately 0.18. The results fully support the composite model in that the chain-length dependence is more pronounced for shorter than for longer radicals, i.e., alpha(S) > alpha(L). Moreover, the power-law exponent that characterizes termination of long-chain radicals is close to the theoretical value of alpha(L) = 0.16. In fact all parameter values-including the small differences between DMA and CHMA/BzMA-are more-or-less in accord with expectations based on polymer dynamics. Furthermore, our results suggest that termination of methacrylate radicals with large cyclic or long n-alkyl substituents may be affected by steric shielding of the radical functionality.