Search

The sphingolipid ceramide is intimately involved in the growth, differentiation, senescence, and death of normal and cancerous cells. Mitochondria are increasingly appreciated to play a key role in ceramide-induced cell death. Recent work showed the C16-pyridinium ceramide analogue LCL-30 to induce cell death in vitro by mitochondrial targeting. The aim of the current study was to translate these results to an in vivo model. We found that LCL-30 accumulated in mitochondria in the murine colorectal cancer cell line CT-26 and reduced cellular ATP content, leading to dose- and time-dependent cytotoxicity. Although the mitochondrial levels of sphingosine-1-phosphate (S1P) became elevated, transcription levels of ceramide-metabolising enzymes were not affected. In mice, LCL-30 was rapidly absorbed from the peritoneal cavity and cleared from the circulation within 24 h, but local peritoneal toxicity was dose-limiting. In a model of subcutaneous tumour inoculation, LCL-30 significantly reduced the proliferative activity and the growth rate of established tumours. Sphingolipid profiles in tumour tissue also showed increased levels of S1P. In summary, we present the first in vivo application of a long-chain pyridinium ceramide for the treatment of experimental metastatic colorectal cancer, together with its pharmacokinetic parameters. LCL-30 was an efficacious and safe agent. Future studies should identify an improved application route and effective partners for combination treatment.British Journal of Cancer (2008) 98, 98–105. doi:10.1038/sj.bjc.6604099 www.bjcancer.com Published online 20 November 2007 [ABSTRACT FROM AUTHOR]

Presents letters to the editor on topics in medicine. Severe acute respiratory syndrome (SARS), lay epidemiology, and fear; Atypical presentations of SARS; Admission cardiotocography; Hepatic artery chemotherapy and colorectal liver metastases; Question of whether VaxGen hides breakthrough infections; Inequities among the very poor in health care, and the effect of young age on care-seeking; Recombinant activated factor VII and perioperative blood loss; Churg-Strauss syndrome and the association with the use of leukotriene antagonists; Anxiety in cancer patients; Mortality, morbidity, and injury of children living with single parents; Mortality in parents after the death of a child; Staining for cell death; Private medical education in India; Thoughts on primary-care research; Randomized controlled trials and the quality of medical journals; The importance of language when speaking about mental depression in order to overcome negative attitudes toward people with mental disorders.

Purpose: The purpose of this study was to investigate biomechanical differences of medial patellofemoral ligament (MPFL) reconstruction, medial quadriceps tendon femoral ligament (MQTFL) reconstruction, and a combination of these techniques to restore lateral patellar constraint and contact pressures., Methods: Eight fresh frozen cadaver knees were mounted to a custom jig with physiological quadriceps tendon loading. Flexion angles and contact pressure (CP) were dynamically measured using Tekscan® pressure sensors and Polhemus® Liberty 6 degree of freedom (6DOF) positioning sensors in the following conditions: 1) intact 2) MPFL and MQTFL deficient, 3) MPFL reconstructed, 4) Combined MPFL + MQTFL reconstructed, and 5) MQTFL reconstructed. Lateral patellar translation was tested using horizontally directed 30 N force applied at 30° of knee flexion. The knees were flexed in dynamic fashion, and CP values were recorded for 10°, 20°, 30°, 50°, 70°, and 90° degrees of flexion. Group differences were assessed with ANOVA's followed by pairwise comparisons with Bonferroni correction., Results: MPFL (P = .002) and combined MPFL/MQTFL (P = .034) reconstruction significantly reduced patellar lateralization from +19.28% (9.78%, 28.78%) in the deficient condition to -17.57% (-27.84%, -7.29%) and -15.56% (-33.61%, 2.30%), respectively. MPFL reconstruction was most restrictive and MQTFL reconstruction the least -7.29% (-22.01%, 7.45%). No significant differences were found between the three reconstruction techniques. Differences in CP between the three reconstruction techniques were not significant (<.02 MPa) at all flexion angles., Conclusion: The present study found no significant difference for patellar lateralization and patellofemoral CP between MPFL, combined MPFL/MQTFL, and MQTFL reconstruction. All 3 techniques resulted in stronger lateral patellar constraint compared to the native state, while the MQTFL reconstruction emulated the intact state the closest., Clinical Relevance: Various surgical techniques for medial patellofemoral complex reconstruction can restore patellar stability with similar patellofemoral articular pressures., (Copyright © 2022 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Introduction: Within the last few decades, focused high-energy extracorporeal shockwave therapy (ESWT) has proven to be an effective alternative to standard of care revision surgery in delayed healing fractures or manifest non-unions in various anatomical regions., Materials and Methods: A retrospective multi-variant analysis of an open prospective, single-armed clinical study was conducted. Patients receiving focused high-energy ESWT for a delayed healing or an apparent non-union of a humeral fracture between January 1999 and December 2015 at a single trauma center were included in the study. Bony healing was defined as cortical continuity in three of four cortices and pain-free force loading and evaluated using CT scans and clinical examination at three- and six-month follow-ups after ESWT., Results: A total of 236 patients were included. N = 93 (43.8%) showed bony consolidation three months after ESWT and n = 105 (52.5%) after six months. Sub-group analysis showed significantly better healing for the proximal metaphyseal humerus (66.7% after six months, n = 42) compared to the diaphyseal region (48.1%, n = 133) and distal metaphyseal humerus (48.1%, n = 25). Regression analysis indicated significantly increased healing rates for patients of younger ages (p = 0.001) and a fracture diastasis of less than 5 mm (p = 0.002)., Conclusion: The findings of this study indicate that ESWT can be considered as a treatment option for a well-selected patient population despite the lower healing rates compared to other anatomical regions., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: Satraplatin is an oral platinum analog with proven clinical efficacy and a more favorable toxicity profile, although with increased hematotoxicity, when compared to cisplatin. Hence, we carried out a systematic biomarker analysis to identify hematological malignancies with high susceptibility to satraplatin., Materials and Methods: Half-maximal inhibitory concentrations (IC 50 ) for satraplatin and cisplatin were determined for 66 different cancer cell lines by CTG Luminescent Cell Viability Assay. In a second step, whole transcriptome RNA sequencing and whole-exome DNA sequencing technology followed by unbiased analysis of gene expression, gene mutation and copy number levels were performed and correlated with drug efficacy., Results: Satraplatin was significantly more active against hematological malignancies compared to solid organ cancer. In addition, satraplatin showed a significantly more potent antiproliferative activity compared to cisplatin in most lymphoma cell lines achieving sub micromolar IC 50 values. Single BCL2 apoptosis regulator (BCL2) gene mutation and 9p21 copy-number deletions including S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency were identified as key characteristics for high sensitivity to satraplatin., Conclusion: Satraplatin demonstrated a high cytotoxic activity in genetically well-defined hematological malignancies which is distinct from that of cisplatin. MTAP deficiency was identified as biomarker of enhanced satraplatin efficacy in hematological cancer-derived cell lines. These data in combination with the lipophilicity of satraplatin provide the rationale for targeting specific lymphatic entities such as primary central nervous system lymphoma and cutaneous T-cell lymphoma to improve clinical outcome., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Lesions of the lateral cutaneous femoral nerve are a reported complication of the direct anterior approach (DAA) for total hip arthroplasty (THA). Little is known about the incidence rates of this lesion. The goal of this study was to answer the following questions: (1) Is the true incidence rate of LFCN lesions after DAA THA known? (2) What are the reasons for the wide range of reported incidence rates in the literature? (3) Are surgeons increasingly aware of the significance of LFCN lesions?, Methods: A US Medical Library of Medicine database search was performed for DAA THA. In total, 1261 search results were screened for reported LFCN lesions., Results: Forty-five studies were included reporting LFCN lesions rates of 0-83%. Subgroup analysis for studies with (group A, 6 studies, n=1113 cases) and without (group B, 39 studies n=16,741) primary focus on the LFCN lesions was performed. Incidence in group A ranged from 14.8-81% (mean 31%) and 0-83% (mean 3.8%) in group B. The difference between the groups was significant (p=0.005). No uniform and time sensitive definition of postoperative LFCN lesions was found in the literature. An analysis of the publication year and the discovered incidence rate showed an increase of incidence rates [r s =0.521 (p<0.001, two-tailed)] over time., Conclusion: Despite the absence of a uniform definition: LFCN lesions after DAA THA are a frequent and, in the past, often underestimated complication., Level of Evidence: IV; systematic review of level II to level IV studies., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Purpose and Hypothesis: Although sex- and gender-specific analyses have been gaining more attention during the last years they have rarely been performed in orthopaedic literature. The primary purpose of this study was to investigate whether for injuries of the UCL the specific location of the rupture is influenced by sex. A secondary study question addressed the sex-independent effect of trauma intensity on the rupture site of the UCL., Methods: This study is a retrospective analysis of all patients with either a proximal or distal bony avulsion or with a mid-substance tear or ligament avulsion of the UCL treated surgically between 1992 and 2015 at two level-I trauma centres. Trauma mechanisms leading to the UCL injury were classified into the following categories: (1) blunt trauma (i.e., strains), (2) low-velocity injuries (e.g., fall from standing height, assaults), and (3) high-velocity injuries (e.g., sports injuries, motor vehicle accidents). After reviewing the surgical records, patients were divided into three groups, depending upon the ligament rupture site: (1) mid-substance tears, (2) proximal ligament or bony avulsions and (3) distal ligament or bony avulsions. Dependencies between the specific rupture site and the explanatory variables (sex, age, and trauma intensity) were evaluated using χ2 test and logistic regression analysis., Results: In total, 1582 patients (1094 males, 488 females) met the inclusion criteria. Mean age was 41 years (range: 9-90 years). Taking into account the effects of sex on trauma intensity (p<0.001) and of trauma intensity on rupture site (p<0.001), mid-substance tears occurred more frequently in women, whereas men were more prone to distal ligament or bony avulsions (p<0.001). In other words, sex and rupture site correlated due to the effects of sex on trauma intensity and of trauma intensity on rupture site, but taking into account those effects there still was a significant effect of sex on rupture site., Conclusions: The results of this study demonstrate that with regression analysis both sex and trauma intensity allow to predict rupture site in UCL injuries.

The decision of the Higher Regional Court of Düsseldorf from 01.09.2009 (20 U 121/08), given below in parts, confirms the decision of the Regional Court Duisburg from 01.04.2008 (4 O 300/07) published in Der Urologe issue 10.2008 (1355 ff). The hope expressed in the literature (e.g. Wienke/Janke, OM 4-2009, 461) that the decision of the Regional Court Duisburg would not be upheld on appeal, proved to be unwarranted.

The term interdisciplinary care is frequently used to indicate the often criticized division between inpatient and outpatient treatment. Interdisciplinary care in the actual sense in the form of integrated care necessarily requires the involvement of health insurance providers as the contractual partner.

Serotonin, a neurotransmitter with numerous functions in the central nervous system (CNS), is emerging as an important signaling molecule in biological processes outside of the CNS. Recent advances have implicated serotonin as a regulator of inflammation, proliferation, regeneration, and repair. The role of serotonin in tumor biology in vivo has not been elucidated. Using a genetic model of serotonin deficiency (Tph1(-/-)) in mice, we show serotonin to be crucial for the growth of s.c. colon cancer allografts in vivo. Serotonin does not enhance tumor cell proliferation but acts as a regulator of angiogenesis by reducing the expression of matrix metalloproteinase 12 (MMP-12) in tumor-infiltrating macrophages, entailing lower levels of angiostatin-an endogenous inhibitor of angiogenesis. Accordingly, serotonin deficiency causes slower growth of s.c. tumors by reducing vascularity, thus increasing hypoxia and spontaneous necrosis. The biological relevance of these effects is underscored by the reconstitution of serotonin synthesis in Tph1(-/-) mice, which restores allograft phenotype in all aspects. In conclusion, we show how serotonin regulates angiogenesis in s.c. colon cancer allografts by influencing MMP-12 expression in tumor-infiltrating macrophages, thereby affecting the production of circulating angiostatin.