Effect of rofecoxib on platelet aggregation and blood loss in gynaecological and breast surgery compared with diclofenac

Background. Non‐selective cyclooxygenase (COX) inhibitors or non‐steroidal anti‐ inflammatory drugs (NSAIDs) are frequently omitted for perioperative pain relief because of potential side‐effects. COX‐2‐selective inhibitors may have a more favourable side‐effect profile. This study tested the hypothesis that the COX‐2‐selective inhibitor rofecoxib has less influence on platelet function than the NSAID diclofenac in gynaecological surgery. In addition, analgesic efficacy and side‐effects of the two drugs were compared. Methods. In this single‐centre, prospective, double‐blind, active controlled study, women undergoing vaginal hysterectomy (n=25) or breast surgery (n=25) under general anaesthesia received preoperatively 50 mg of rofecoxib p.o. followed 8 and 16 h later by two doses of placebo or three doses of diclofenac 50 mg p.o. at the same time points. We assessed arachidonic acid‐stimulated platelet aggregation before and 4 h after the first dose of study medication, estimated intraoperative blood loss, and haemoglobin loss until the first morning after surgery. Analgesic efficacy, use of rescue analgesics, and side‐effects were also recorded. Results. In the rofecoxib group, stimulated platelet aggregation was disturbed less (P=0.02), and estimated intraoperative blood loss (P=0.01) and the decrease in haemoglobin were lower (P=0.01). At similar pain ratings, the use of anti‐emetic drugs was less in the rofecoxib group (P=0.03). Conclusion. Besides having a smaller effect on platelet aggregation, one oral dose of rofecoxib 50 mg given before surgery provided postoperative analgesia similar to that given by three doses of diclofenac 50 mg and was associated with less use of anti‐emetics and less surgical blood loss in gynaecological surgery compared with diclofenac. Br J Anaesth 2004; 92: 523-3

Cement-augmented dorsal instrumentation of the spine as a safe adjunct to the multimodal management of metastatic pheochromocytoma: a case report

Malignant pheochromocytoma is a neuroendocrine tumor that originates from chromaffin tissue. Although osseous metastases are common, metastatic dissemination to the spine rarely occurs

Immunohistochemical localization of angiotensin-converting enzyme, angiotensin II and AT1 receptor in human ocular tissues

We investigated the immunohistochemical distribution of 3 components of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE), angiotensin II (AngII) and AT1 receptor (AT1), in the human eye. ACE and AngII were localized to nonpigmented epithelial cells of the ciliary body, to endothelial and epithelial cells of the cornea, to epithelial cells of the conjunctiva and to trabecular meshwork cells in the anterior part of the eye. In the posterior part of the eye, ACE and AngII were localized to ganglion cells, some cells in the inner nuclear layer, photoreceptor cells and to endothelial cells of the retinal and choroidal vessels. The overall intensity of AT1 immunoreactivity was weak in all ocular tissues, but the main localization was in ganglion cells. As a preliminary investigation, we were able to include 2 Alzheimer's disease (AD) cases. In AD, no differences from controls were found in the cellular distribution and staining intensity of all 3 antigens. The manifold localization sites of the observed antigens point to rather generalized functions of the RAS in human ocular tissues, such as regulatory effects on neuronal cells, vessels and vitreous humor homeostasis

Point of care coagulometry in prehospital emergency care: an observational study

Background: Haemostatic impairment can have a crucial impact on the outcome of emergency patients, especially in cases of concomitant antithrombotic drug treatment. In this prospective observational study we used a point of care (POC) coagulometer in a prehospital physician-based emergency medical system in order to test its validity and potential value in the treatment of emergency patients. Methods: During a study period of 12 months, patients could be included if venous access was mandatory for further treatment. The POC device CoaguChek® was used to assess international normalized ratio (INR) after ambulance arrival at the scene. Results were compared with in-hospital central laboratory assessment of INR. The gain of time was analysed as well as the potential value of POC testing through a questionnaire completed by the responsible prehospital emergency physician. Results: A total of 103 patients were included in this study. POC INR results were highly correlated with results of conventional assessment of INR (Bland-Altman-bias: 0.014). Using a cutoff value of INR >1.3, the device’s sensitivity to detect coagulopathy was 100 % with a specificity of 98.7 %. The median gain of time was 69 min. Treating emergency physicians considered the value of prehospital POC INR testing ‘high’ in 9 % and ‘medium’ in 21 % of all patients. In patients with tracer diagnosis ‘neurology’, the value of prehospital INR assessment was considered ‘high’ or ‘medium’ (63 %) significantly more often than in patients with non-neurological tracer diagnoses (24 %). Conclusions: Assessment of INR through a POC coagulometer is feasible in prehospital emergency care and provides valuable information on haemostatic parameters in patients. Questionnaire results suggest that POC INR testing may present a valuable technique in selected patients. Whether this information translates into an improved management of respective patients has to be evaluated in further studies

The architecture of protein synthesis in the developing neocortex at near-atomic resolution reveals Ebp1-mediated neuronal proteostasis at the 60S tunnel exit

Protein synthesis must be finely tuned in the nervous system, as it represents an essential feature of neurodevelopmental gene expression, and dominant pathology in neurological disease. However, the architecture of ribosomal complexes in the developing mammalian brain has not been analyzed at high resolution. This study investigates the architecture of ribosomes ex vivo from the embryonic and perinatal mouse neocortex, revealing Ebp1 as a 60S peptide tunnel exit binding factor at near-atomic resolution by multiparticle cryo-electron microscopy. The impact of Ebp1 on the neuronal proteome was analyzed by pSILAC and BONCAT coupled mass spectrometry, implicating Ebp1 in neurite outgrowth proteostasis, with in vivo embryonic Ebp1 knockdown resulting in dysregulation of neurite outgrowth. Our findings reveal Ebp1 as a central component of neocortical protein synthesis, and the 60S peptide tunnel exit as a focal point of gene expression control in the molecular specification of neuronal morphology

HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation.

The internal ribosome entry site (IRES) of the hepatitis C virus (HCV) drives noncanonical initiation of protein synthesis necessary for viral replication. Functional studies of the HCV IRES have focused on 80S ribosome formation but have not explored its role after the 80S ribosome is poised at the start codon. Here, we report that mutations of an IRES domain that docks in the 40S subunit's decoding groove cause only a local perturbation in IRES structure and result in conformational changes in the IRES-rabbit 40S subunit complex. Functionally, the mutations decrease IRES activity by inhibiting the first ribosomal translocation event, and modeling results suggest that this effect occurs through an interaction with a single ribosomal protein. The ability of the HCV IRES to manipulate the ribosome provides insight into how the ribosome's structure and function can be altered by bound RNAs, including those derived from cellular invaders

Timed global reorganization of protein synthesis during neocortex neurogenesis at codon resolution

Translation modulates the timing and amplification of gene expression after transcription. Development of the brain’s neocortex requires precisely timed and spatially targeted gene expression, but the relationship between mRNA vs. protein synthesis throughout the genome is unknown. We perform a comprehensive analysis of the reactants, synthesis, and products of mRNA translation spanning mouse neocortex neurogenesis. Ribosome number in the cortical plate decreases sharply at mid-neurogenesis during a transition in neuronal subtype specification, shifting the fundamental kinetics of protein synthesis, with mRNA and protein levels frequently divergent. Satb2, which drives an essential neuronal subtype-specific program, is a highly dynamically translated mRNA with surprisingly broad transcription across diverse neuronal lineages. Satb2 protein achieves its neuronal subtype expression through timed regulation by the RNA-binding protein Pumilio2. Thus, the refinement of transcriptional programs by protein synthesis is a widespread feature of neuronal specification. Developmental neocortex translatome data are provided in an open-source resource: https://shiny.mdc-berlin.de/cortexomics/

Inclusive V0V^0 Production Cross Sections from 920 GeV Fixed Target Proton-Nucleus Collisions

Inclusive differential cross sections $d\sigma_{pA}/dx_F$ and $d\sigma_{pA}/dp_t^2$ for the production of \kzeros, \lambdazero, and \antilambda particles are measured at HERA in proton-induced reactions on C, Al, Ti, and W targets. The incident beam energy is 920 GeV, corresponding to $\sqrt {s} = 41.6$ GeV in the proton-nucleon system. The ratios of differential cross sections \rklpa and \rllpa are measured to be $6.2\pm 0.5$ and $0.66\pm 0.07$, respectively, for \xf $\approx-0.06$. No significant dependence upon the target material is observed. Within errors, the slopes of the transverse momentum distributions $d\sigma_{pA}/dp_t^2$ also show no significant dependence upon the target material. The dependence of the extrapolated total cross sections $\sigma_{pA}$ on the atomic mass $A$ of the target material is discussed, and the deduced cross sections per nucleon $\sigma_{pN}$ are compared with results obtained at other energies.Comment: 17 pages, 7 figures, 5 table

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds