Bekkenbanden voor acute stabilisatie van instabiele bekkenfracturen

Bekkenbanden zijn ontwikkeld voor de acute behandeling van instabiele bekkenringfracturen in de prehospitale fase. Deze behandeling is gericht op het beperken van het inwendig bloedverlies door het verkleinen van het bij bekkenfracturen toegenomen bekkenvolume en het stabiliseren van de fractuurdelen. Het effect van commercieel verkrijgbare bekkenbanden op de reductie van de symphysis pubisdiastase en de hemodynamische stabiliteit is aangetoond. Het langdurig gebruik van bekkenbanden wordt ontraden wegens toegenomen risico op het ontwikkelen van decubitus. Met name langdurige immobilisatie met een bekkenband op een traumaplank dient voorkomen te worden. In dit artikel wordt een aantal verschillende bekkenbanden besproken en wordt een casus gepresenteerd.Pelvic circumferential compression devices have been developed for initial treatment of unstable pelvic ring fractures in the prehospital situation. The treatment is aimed at achieving tamponade by reducing the increased pelvic volume and reducing the bleeding from fracture surfaces. The effect of commercially available pelvic circumferential compression devices on the reduction of symphysis pubis diastasis and the resuscitation has been proved. Prolonged use of these devices is complicated by the risk of development of pressure sores. Therefore prolonged immobilization on a spine board should be avoided. A number of different pelvic binders will be discussed in this article, which also presents a case

Indapamide-induced transient myopia with supraciliary effusion: case report.

BACKGROUND: Ingestion of sulphonamide-derived drugs has been reported to possibly have ocular side-effects. Authors aimed to present a rare case of indapamide-induced transient myopia with ciliary body edema and supraciliary effusion. CASE PRESENTATION: A 39 years old caucasian female patient presented at the Department of Neurology with headache and sudden bilateral loss of distant vision. Neurological assessment and cranial CT scans were unremarkable. For her hypertension, twice a day bisoprolol 2.5 mg and once a day indapamide 1.5 mg tablets were prescribed several days before. At her presenting, ophthalmic findings were as follows: visual acuity 0.08-7.25Dsph = 1.0 and 0.06-7.25Dsph = 1.0; IOP 25 mmHg and 24 mmHg, anterior chamber depth (ACD) 2.32 mm and 2.49 mm, lens thickness (L) 4.02 mm and 4.09 mm in the right and the left eye, respectively. By means of ultrasound biomicroscopy (UBM), thickened (720 / 700 micron) and detached ciliary body, its forward movement (ciliary body-cornea angle 108[prime] / 114[prime]) and forward rotated ciliary processes were seen. Angle opening distance (AOD500) were 300 / 314 microns. By the following days, the myopia gradually diminished, and a week after her first symptoms, her uncorrected visual acuity was 1.0 in both eyes, IOP 13 mmHg and 17 mmHg, ACD 3.68 mm and 3.66 mm, L 3.78 mm and 3.81 mm in the right and the left eye, respectively. Ciliary body edema and detachment disappeared (ciliary body thickness 225 / 230 micron), both of the ciliary body-cornea angle 134[prime] / 140[prime] and the AOD500 (650 / 640 microns) increased. At this point, the patient admitted that she had stopped taking indapamide two days before. CONCLUSIONS: Our case report is the third one in the literature to present indapamide-induced transient myopia, and the first to employ UBM for describing the characteristics of this rare condition. According to the findings, authors suggest that both ciliary muscle contraction and ciliary body edema may play role in the pathomechanism. UBM seems to be a useful tool in the differential diagnosis of acute myopia. Further, authors wish to draw attention to one of the potential adverse effects of this drug which was not listed by its package insert

Intratracheal synthetic CpG oligodeoxynucleotide causes acute lung injury with systemic inflammatory response

Bacterial genome is characterized by frequent unmethylated cytosine-phosphate-guanine (CpG) motifs. Deleterious effects can occur when synthetic oligodeoxynucleotides (ODN) with unmethylated CpG dinucleotides (CpG-ODN) are administered in a systemic fashion. We aimed to evaluate the effect of intratracheal CpG-ODN on lung inflammation and systemic inflammatory response. C57BL/6J mice received intratracheal administration of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 μM) or control ODN without CpG motif. Bronchoalveolar lavage (BAL) fluid was obtained 3 or 6 h or 1, 2, 7, or 14 days after the instillation and subjected to a differential cell count and cytokine measurement. Lung permeability was evaluated as the BAL fluid-to-plasma ratio of the concentration of human serum albumin that was injected 1 h before euthanasia. Nuclear factor (NF)-κB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 μM or higher concentration of CpG-ODN induced significant inflammatory cell accumulation into the airspace. The peak accumulation of neutrophils and lymphocytes occurred 1 and 2 days after the CpG-ODN administration, respectively. Lung permeability was increased 1 day after the 10 μM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-κB and upregulation of various inflammatory cytokines in BAL fluid and plasma. Histopathology of the lungs and liver revealed acute lung injury and liver damage with necrosis, respectively. Control ODN without CpG motif did not induce any inflammatory change. Since intratracheal CpG-ODN induced acute lung injury as well as systemic inflammatory response, therapeutic strategies to neutralize bacterial DNA that is released after administration of bactericidal agents should be considered

Lattice QCD at the physical point: Simulation and analysis details

We give details of our precise determination of the light quark masses m_{ud}=(m_u+m_d)/2 and m_s in 2+1 flavor QCD, with simulated pion masses down to 120 MeV, at five lattice spacings, and in large volumes. The details concern the action and algorithm employed, the HMC force with HEX smeared clover fermions, the choice of the scale setting procedure and of the input masses. After an overview of the simulation parameters, extensive checks of algorithmic stability, autocorrelation and (practical) ergodicity are reported. To corroborate the good scaling properties of our action, explicit tests of the scaling of hadron masses in N_f=3 QCD are carried out. Details of how we control finite volume effects through dedicated finite volume scaling runs are reported. To check consistency with SU(2) Chiral Perturbation Theory the behavior of M_\pi^2/m_{ud} and F_\pi as a function of m_{ud} is investigated. Details of how we use the RI/MOM procedure with a separate continuum limit of the running of the scalar density R_S(\mu,\mu') are given. This procedure is shown to reproduce the known value of r_0m_s in quenched QCD. Input from dispersion theory is used to split our value of m_{ud} into separate values of m_u and m_d. Finally, our procedure to quantify both systematic and statistical uncertainties is discussed.Comment: 45 page

Mitochondrial Localization of ABC Transporter ABCG2 and Its Function in 5-Aminolevulinic Acid-Mediated Protoporphyrin IX Accumulation

Accumulation of protoporphyrin IX (PpIX) in malignant cells is the basis of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy. We studied the expression of proteins that possibly affect ALA-mediated PpIX accumulation, namely oligopeptide transporter-1 and -2, ferrochelatase and ATP-binding cassette transporter G2 (ABCG2), in several tumor cell lines. Among these proteins, only ABCG2 correlated negatively with ALA-mediated PpIX accumulation. Both a subcellular fractionation study and confocal laser microscopic analysis revealed that ABCG2 was distributed not only in the plasma membrane but also intracellular organelles, including mitochondria. In addition, mitochondrial ABCG2 regulated the content of ALA-mediated PpIX in mitochondria, and Ko143, a specific inhibitor of ABCG2, enhanced mitochondrial PpIX accumulation. To clarify the possible roles of mitochondrial ABCG2, we characterized stably transfected-HEK (ST-HEK) cells overexpressing ABCG2. In these ST-HEK cells, functionally active ABCG2 was detected in mitochondria, and treatment with Ko143 increased ALA-mediated mitochondrial PpIX accumulation. Moreover, the mitochondria isolated from ST-HEK cells exported doxorubicin probably through ABCG2, because the export of doxorubicin was inhibited by Ko143. The susceptibility of ABCG2 distributed in mitochondria to proteinase K, endoglycosidase H and peptide-N-glycosidase F suggested that ABCG2 in mitochondrial fraction is modified by N-glycans and trafficked through the endoplasmic reticulum and Golgi apparatus and finally localizes within the mitochondria. Thus, it was found that ABCG2 distributed in mitochondria is a functional transporter and that the mitochondrial ABCG2 regulates ALA-mediated PpIX level through PpIX export from mitochondria to the cytosol

Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes

Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators

Paramedics' perceptions and experiences of pelvic injuries in prehospital situations

In recent years there has been an increase in pelvic injuries due to an increase in road traffic collisions (RTCs) (Chesters 2017). Two thirds of pelvic injuries are due to RTCs and the remainder are made up of pedestrian collisions, motorcycle accidents and falls from heights. Patients with fatal pelvic injuries more than likely die of exsanguinations and/or associated severe injuries (ibid.). Lee & Porter (2007) undertook a literature review to analyse the current practice of assessing and managing pelvic injuries in pre-hospital situations. They write that the mortality rates of patients with pelvic fractures are estimated between 7% and 19%, upon their arrival at hospital. The mortality rates of patients with ‘open book’ fractures can be as high as 50%. An ‘open book’ fracture can be defined as any serious fracture that causes the pelvic ring to open like a book. This is commonly seen in anterior injuries to the pelvis widening the pubic symphysis (Gerecht, Larrimore & Steuerwald 2014). Lee and Porter (2007) argue that paramedics can help reduce the retroperitoneal space that a patient can haemorrhage into, and therefore lower the mortality rates for patients with ‘open-book’ pelvic fractures. Given the high mortality rates associated with pelvic injuries and the role paramedics can play in reducing these outcomes, the aim of this narrative review is to synthesize existing literature about pelvic injury recognition, assessment and management in pre-hospital situations. The authors will also conclude upon any new insights or recommendations found following the review

Targeted therapy against Bcl-2-related proteins in breast cancer cells

INTRODUCTION: Bcl-2 and Bcl-xL confer resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We examined the relationship between the expression of Bcl-2 and Bcl-xL and chemosensitivity of breast cancer cells, with the aim of developing specific targeted therapy. METHODS: Four human breast cancer cell lines were examined, and the effects of antisense (AS) Bcl-2 and AS Bcl-xL phosphorothioate oligodeoxynucleotides (ODNs) on chemosensitivity were tested in vitro and in vivo. Chemosensitivity was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay, and the antitumor effect was assessed in vivo by the success of xenograft transplantation into athymic mice. RESULTS: Treatment with AS Bcl-2 and Bcl-xL ODNs resulted in a sequence-specific decrease in protein expression, compared with controls. Treatment of BT-474, ZR-75-1, and MDA-MB-231 cells with AS Bcl-2 increased chemosensitivity to doxorubicin (DOX), mitomycin C (MMC), paclitaxel (TXL), and docetaxel (TXT). Transfection of the Bcl-2 gene into MDA-MB-453 cells decreased sensitivity to DOX and MMC. Treatment of MDA-MB-231, BT-474, and ZR-75-1 cells with AS Bcl-xL increased chemosensitivity to DOX, MMC and taxanes to a smaller extent than AS Bcl-2. This occurred in the setting of increased Bax and cleaved poly(ADP-ribose) polymerase, as well as decreased Bcl-2 and pAkt. AS Bcl-2 ODNs induced splenomegaly in association with increased serum IL-12, which was attenuated by methylation of the CpG motifs of AS Bcl-2; however, methylated CpG failed to negate the increased antitumor effect of AS Bcl-2. Bcl-2 and Bcl-xL, to a smaller extent, are major determinants of chemosensitivity in breast cancer cells. CONCLUSION: Targeted therapy against Bcl-2 protein with the use of AS ODNs might enhance the effects of chemotherapy in patients with breast cancer

Gold Nanoparticle Delivery of Modified CpG Stimulates Macrophages and Inhibits Tumor Growth for Enhanced Immunotherapy

Gold nanoparticle accumulation in immune cells has commonly been viewed as a side effect for cancer therapeutic delivery; however, this phenomenon can be utilized for developing gold nanoparticle mediated immunotherapy. Here, we conjugated a modified CpG oligodeoxynucleotide immune stimulant to gold nanoparticles using a simple and scalable selfassembled monolayer scheme that enhanced the functionality of CpG in vitro and in vivo. Nanoparticles can attenuate systemic side effects by enhancing CpG delivery passively to innate effector cells. The use of a triethylene glycol (TEG) spacer on top of the traditional poly-thymidine spacer increased CpG macrophage stimulatory effects without sacrificing DNA content on the nanoparticle, which directly correlates to particle uptake. In addition, the immune effects of modified CpGAuNPs were altered by the core particle size, with smaller 15 nm AuNPs generating maximum immune response. These TEG modified CpG-AuNP complexes induced macrophage and dendritic cell tumor infiltration, significantly inhibited tumor growth, and promoted survival in mice when compared to treatments with free CpG

XIAP impairs Smac release from the mitochondria during apoptosis

X-linked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of caspases 3, 7 and 9, and mitochondrial Smac (second mitochondria-derived activator of caspase) release during apoptosis inhibits the activity of XIAP. In this study we show that cytosolic XIAP also feeds back to mitochondria to impair Smac release. We constructed a fluorescent XIAP-fusion protein by labelling NH2- and COOH-termini with Cerulean fluorescent protein (C-XIAP-C). Immunoprecipitation confirmed that C-XIAP-C retained the ability to interact with Smac and impaired extrinsically and intrinsically activated apoptosis in response to tumour necrosis factor-related apoptosis-inducing ligand/cycloheximide and staurosporine. In C-XIAP-C-expressing cells, cytochrome c release from mitochondria proceeded normally, whereas Smac release was significantly prolonged and incomplete. In addition, physiological expression of native XIAP prolonged or limited Smac release in HCT-116 colon cancer cells and primary mouse cortical neurons. The Smac-binding capacity of XIAP, but not caspase inhibition, was central for mitochondrial Smac retention, as evidenced in experiments using XIAP mutants that cannot bind to Smac or effector caspases. Similarly, the release of a Smac mutant that cannot bind to XIAP was not impaired by C-XIAP-C expression. Full Smac release could however be provoked by rapid cytosolic C-XIAP-C depletion upon digitonin-induced plasma membrane permeabilization. Our findings suggest that although mitochondria may already contain pores sufficient for cytochrome c release, elevated amounts of XIAP can selectively impair and limit the release of Smac