Reference interval of free light chains ratio in patients with end-stage renal disease on chronic hemodialysis.

Not available.

Thermodynamics of Li+-Crown Ether Interactions in Aqueous Solvent.

Lithium ion-based batteries are ubiquitous in modern technology due to applications in personal electronics and high-capacity storage for electric vehicles. Concerns about lithium supply and battery waste have prompted interest in lithium recycling methods. The crown ether 12-crown-4 has been studied for its abilities to form stable complexes with lithium ions (Li+). In this paper, molecular dynamics simulations are applied to examine the binding properties of a 12-crown-4-Li+ system in aqueous solution. It was found that 12-crown-4 did not form stable complexes with Li+ in aqueous solution due to the binding geometry which was prone to interference by surrounding water molecules. In addition, the binding properties of sodium ions (Na+) to 12-crown-4 are examined for comparison. Subsequently, calculations were performed with the crown ethers 15-crown-5 and 18-crown-6 to study their complexation with Li+ as well as Na+. It was determined that binding was unfavorable for both types of ions for all three crown ethers tested, though 15-crown-5 and 18-crown-6 showed a marginally greater affinity for Li+ than 12-crown-4. Metastable minima present in the potential of mean force for Na+ render binding marginally more likely there. We discuss these results in the context of membrane-based applications of crown ethers for Li+ separations.

STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes.

Epstein-Barr virus (EBV) causes lymphomas and epithelial cell cancers. Though generally silent in B lymphocytes, this widely prevalent virus can cause endemic Burkitt lymphoma and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. By learning how EBV breaches barriers to cell proliferation, we hope to undermine those strategies to treat EBV lymphomas and potentially other cancers. We had previously found that EBV, through activation of cellular STAT3 prevents phosphorylation of Chk1, and thereby, suppresses activation of the intra-S phase cell-cycle checkpoint, a potent barrier to oncogene-driven proliferation. This observation prompted us to examine the consequences on DNA repair since homologous recombination repair, the most error-free form, requires phosphoChk1. We now report that the defect in Chk1 phosphorylation also curtails RAD51 nucleation, and thereby, homologous recombination repair of DNA double strand breaks. The resulting reliance on error-prone microhomology-mediated end-joining (MMEJ) repair makes EBV-transformed cells susceptible to PARP inhibition and simultaneous accrual of genome-wide deletions and insertions resulting from synthesis-dependent MMEJ. Analysis of transcriptomic and drug susceptibility data from hundreds of cancer lines reveals a STAT3-dependent gene-set predictive of susceptibility of cancers to synthetic lethal PARP inhibition. These findings i) demonstrate how the tumor virus EBV re-shapes cellular DNA repair, ii) provide the first genome-wide evidence for insertions resulting from MMEJ in human cells, and iii) expand the range of cancers (EBV-related and -unrelated) that are likely to respond to synthetic lethal inhibitors given the high prevalence of cancers with constitutively active STAT3.

Alpha-1 antitrypsin deficiency and risk of lung cancer in never-smokers: a multicentre case-control study.

BACKGROUND: Lung cancer (LC) is the most commonly diagnosed cancer and the leading cause of cancer-related death in both sexes worldwide. Although the principal risk factor in the western world is tobacco smoking, genetic factors, including alpha-1 antitrypsin deficiency (AATD), have been associated with increased risk. This study is the continuation of an earlier one published by the same group in 2015, aimed at analysing risk of LC in never-smokers, associated with carriers of the AATD genotype. METHODS: A multicentre case-control study was conducted in Spain across the period January 2011 to August 2019. Cases were non-smokers diagnosed with LC, and controls were composed of never-smoking individuals undergoing major non-cancer-related surgery. Data were collected on epidemiological characteristics, exposure to environmental tobacco smoke (ETS), residential radon levels, and alpha-1 antitrypsin (AAT) genotype. RESULTS: The study included 457 cases (42%) and 631 controls (58%), with a predominance of women (72,8%). The most frequent histological type was adenocarcinoma (77.5%), followed by squamous cell carcinoma (7.7%). No association of risk of LC was found with the status of AATD genotype carrier, both overall and broken down by age, sex, or exposure to ETS. CONCLUSIONS: No risk association was found between being a carrier of an AAT deficiency genotype and LC among never-smokers. In order to establish the existence of an association, we consider it important to expand the studies in never smokers in different geographical areas as well as to include patients with previous chronic lung diseases to assess if it influences the risk.

Chlorine Concentration Modelling and Supervision in Water Distribution Systems.

The quality of the drinking water distributed through the networks has become the main concern of most operators. This work focuses on one of the most important variables of the drinking water distribution networks (WDN) that use disinfection, chlorine. This powerful disinfectant must be dosed carefully in order to reduce disinfection byproducts (DBPs). The literature demonstrates researchers' interest in modelling chlorine decay and using several different approaches. Nevertheless, the full-scale application of these models is far from being a reality in the supervision of water distribution networks. This paper combines the use of validated chlorine prediction models with an intensive study of a large amount of data and its influence on the model's parameters. These parameters are estimated and validated using data coming from the Supervisory Control and Data Acquisition (SCADA) software, a full-scale water distribution system, and using off-line analytics. The result is a powerful methodology for calibrating a chlorine decay model on-line which coherently evolves over time along with the significant variables that influence it.

Human Mesenchymal Stromal Cells Do Not Cause Radioprotection of Head-and-Neck Squamous Cell Carcinoma.

Radiotherapy of head-and-neck squamous cell carcinoma (HNSCC) can cause considerable normal tissue injuries, and mesenchymal stromal cells (MSCs) have been shown to aid regeneration of irradiation-damaged normal tissues. However, utilization of MSC-based treatments for HNSCC patients undergoing radiotherapy is hampered by concerns regarding potential radioprotective effects. We therefore investigated the influence of MSCs on the radiosensitivity of HNSCCs. Several human papillomavirus (HPV)-negative and HPV-positive HNSCCs were co-cultured with human bone marrow-derived MSCs using two-dimensional and three-dimensional assays. Clonogenic survival, proliferation, and viability of HNSCCs after radiotherapy were assessed depending on MSC co-culture. Flow cytometry analyses were conducted to examine the influence of MSCs on irradiation-induced cell cycle distribution and apoptosis induction in HNSCCs. Immunofluorescence stainings of γH2AX were conducted to determine the levels of residual irradiation-induced DNA double-strand breaks. Levels of connective tissue growth factor (CTGF), a multifunctional pro-tumorigenic cytokine, were analyzed using enzyme-linked immunosorbent assays. Neither direct MSC co-culture nor MSC-conditioned medium exerted radioprotective effects on HNSCCs as determined by clonogenic survival, proliferation, and viability assays. Consistently, three-dimensional microwell arrays revealed no radioprotective effects of MSCs. Irradiation resulted in a G2/M arrest of HNSCCs at 96 h independently of MSC co-culture. HNSCCs' apoptosis rates were increased by irradiation irrespective of MSCs. Numbers of residual γH2AX foci after irradiation with 2 or 8 Gy were comparable between mono- and co-cultures. MSC mono-cultures and HNSCC-MSC co-cultures exhibited comparable CTGF levels. We did not detect radioprotective effects of human MSCs on HNSCCs. Our results suggest that the usage of MSC-based therapies for radiotherapy-related toxicities in HNSCC patients may be safe in the context of absent radioprotection.

Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV's ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers.

Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib.

Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.

HMGB1 decreases CCR-2 expression and migration of M2 macrophages under hypoxia.

OBJECTIVE: The hypoxic milieu at tumor microenvironment is able to drive the behavior of infiltrating tumor cells. Considering that hypoxia-mediated HMGB1 release is known to promote tumor growth, as well to enhance the pro-tumoral profile of M2 macrophages by a RAGE-dependent mechanism, it is tempting to evaluate the potential contribution of HMGB1 under hypoxia to restrain M2 macrophages mobility. METHODS: CCR-2 expression was evaluated in M2 polarized macrophages by western blotting and immunocytochemistry. The secreted levels of CCL-2 and the migration capability were evaluated using an ELISA and a chemotaxis assay, respectively. RESULTS: HMGB1, under hypoxic conditions, markedly reduce both the production of CCL-2 and the expression of its receptor CCR-2; and reduced the migration capacity of M2 macrophages. CONCLUSIONS: These results provided new insights into the mechanisms that regulate M2 macrophages mobility at the tumor microenvironment.

Alelos HLA más comunes y asociados con riesgo o protección en enfermedad renal crónica de etiología no determinada.

INTRODUCTION: Chronic kidney disease accounts for part of overall health expenditure; a potential etiology is related to variations, absence or presence of some human leukocyte antigen (HLA) alleles. METHOD: An analysis of HLA reports of 1965 kidney recipients with no determined etiology, and 1361 kidney donors was performed. It was carried out with Luminex based in cell flow fluorometry for the A, B, DRB1 and DQA loci. An analysis was performed with contingency tables in order to determine the odds ratio (OR) and confidence intervals (CI). Quantitative analysis was also carried out. RESULTS: Of the 101 alleles found, 13 showed association, 7 with risk for chronic kidney disease, with the most significant being HLA-DR17 with an OR of 3.91 (95 % CI = 2.96-5.17) and the one with the highest significance for protection being HLA-DR9, with an OR of 0.043 (95 % CI = 0.005-0.3224). CONCLUSIONS: It is necessary to understand that kidney diseases can be associated with yet unknown immune processes, where the association of the absence or presence of any allele should be known.

INTRODUCCIÓN: La enfermedad renal crónica representa parte del gasto en salud en general; una potencial etiología es la relacionada con variaciones, ausencia o presencia de algunos alelos del human leucocyte antigen (HLA). MÉTODO: Se realizó el análisis de 1965 reportes de HLA sin etiología determinada y de 1361 donadores renales. Se llevó a cabo tecnología Luminex con base en fluorimetría de flujo celular para los locus A, B, DRB1 y DQA. Se realizó análisis con tablas de contingencia para determinar razón de momios (RM) e intervalos de confianza (IC). Se efectuó análisis cuantitativo. RESULTADOS: De 101 alelos encontrados, 13 presentaron asociación, siete con riesgo para enfermedad renal crónica, de los cuales el más significativo fue HLA-DR17, con RM = 3.91 (IC 95 % = 2.96-5.17), y el de mayor significación de protección fue HLA-DR9, con RM = 0.043 (IC 95 % = 0.005-0.3224). CONCLUSIONES: Es necesario entender que las enfermedades renales pueden estar ligadas a procesos inmunológicos, en los que se tiene que conocer la asociación de la ausencia o presencia de algún alelo.

The current understanding of mesenchymal stem cells as potential attenuators of chemotherapy-induced toxicity.

Chemotherapeutic agents are part of the standard treatment algorithms for many malignancies; however, their application and dosage are limited by their toxic effects to normal tissues. Chemotherapy-induced toxicities can be long-lasting and may be incompletely reversible; therefore, causative therapies for chemotherapy-dependent side effects are needed, especially considering the increasing survival rates of treated cancer patients. Mesenchymal stem cells (MSCs) have been shown to exhibit regenerative abilities for various forms of tissue damage. Preclinical data suggest that MSCs may also help to alleviate tissue lesions caused by chemotherapeutic agents, mainly by establishing a protective microenvironment for functional cells. Due to the systemic administration of most anticancer agents, the effects of these drugs on the MSCs themselves are of crucial importance to use stem cell-based approaches for the treatment of chemotherapy-induced tissue toxicities. Here, we present a concise review of the published data regarding the influence of various classes of chemotherapeutic agents on the survival, stem cell characteristics and physiological functions of MSCs. Molecular mechanisms underlying the effects are outlined, and resulting challenges of MSC-based treatments for chemotherapy-induced tissue injuries are discussed.

Radiation-induced pulmonary gene expression changes are attenuated by the CTGF antibody Pamrevlumab.

BACKGROUND: Fibrosis is a delayed side effect of radiation therapy (RT). Connective tissue growth factor (CTGF) promotes the development of fibrosis in multiple settings, including pulmonary radiation injury. METHODS: To better understand the cellular interactions involved in RT-induced lung injury and the role of CTGF in these responses, microarray expression profiling was performed on lungs of irradiated and non-irradiated mice, including mice treated with the anti-CTGF antibody pamrevlumab (FG-3019). Between group comparisons (Welch's t-tests) and principal components analyses were performed in Genespring. RESULTS: At the mRNA level, the ability of pamrevlumab to prolong survival and ameliorate RT-induced radiologic, histologic and functional lung deficits was correlated with the reversal of a clear enrichment in mast cell, macrophage, dendritic cell and mesenchymal gene signatures. Cytokine, growth factor and matrix remodeling genes that are likely to contribute to RT pneumonitis and fibrosis were elevated by RT and attenuated by pamrevlumab, and likely contribute to the cross-talk between enriched cell-types in injured lung. CONCLUSIONS: CTGF inhibition had a normalizing effect on select cell-types, including immune cells not typically regarded as being regulated by CTGF. These results suggest that interactions between RT-recruited cell-types are critical to maintaining the injured state; that CTGF plays a key role in this process; and that pamrevlumab can ameliorate RT-induced lung injury in mice and may provide therapeutic benefit in other immune and fibrotic disorders.

Intracellular Ca2+ Increases and Connexin 43 Hemichannel Opening Are Necessary but Not Sufficient for Thy-1-Induced Astrocyte Migration.

Under pro-inflammatory conditions, astrocytes become reactive and acquire a migratory phenotype. Our results show that hemichannels formed by connexin 43 (Cx43) play an important role in Thy-1-induced astrocyte migration. The neuronal protein Thy-1 binds to αvß3 integrin in astrocytes, thereby leading to intricate signaling pathways that include calcium (Ca2+) release from intracellular stores, opening of Cx43 hemichannels, release of ATP, activation of P2X7 receptor, and Ca2+ influx. However, because these Thy-1 effects occur exclusively in reactive astrocytes, we wondered whether by elevating calcium levels and promoting hemichannel opening we could prompt non-reactive astrocytes to respond to Thy-1. Cx43 immunoreactivity increased at juxta-membrane sites, where hemichannels (not gap junctions) participate in astrocyte polarization and migration stimulated by Thy-1. Also, intracellular Ca2+ increase, due to ionomycin treatment, induced hemichannel opening, but activated astrocyte migration only partially, and this limitation was overcome by pre-treatment with tumor necrosis factor (TNF) and Thy-1. Finally, αvß3 integrin formed membrane clusters after TNF stimulation or overexpression of ß3 integrin. We suggest that these microclusters are required for cells to respond to Thy-1 stimulation. Therefore, the large increase in intracellular Ca2+ and hemichannel opening induced by ionomycin are required, but not sufficient, to permit Thy-1-induced astrocyte migration. Thus, we suggest that proinflammatory stimuli prompt astrocytes to respond to migratory signals of neuronal cells.

Superresolution light microscopy shows nanostructure of carbon ion radiation-induced DNA double-strand break repair foci.

Carbon ion radiation is a promising new form of radiotherapy for cancer, but the central question about the biologic effects of charged particle radiation is yet incompletely understood. Key to this question is the understanding of the interaction of ions with DNA in the cell's nucleus. Induction and repair of DNA lesions including double-strand breaks (DSBs) are decisive for the cell. Several DSB repair markers have been used to investigate these processes microscopically, but the limited resolution of conventional microscopy is insufficient to provide structural insights. We have applied superresolution microscopy to overcome these limitations and analyze the fine structure of DSB repair foci. We found that the conventionally detected foci of the widely used DSB marker γH2AX (Ø 700-1000 nm) were composed of elongated subfoci with a size of ∼100 nm consisting of even smaller subfocus elements (Ø 40-60 nm). The structural organization of the subfoci suggests that they could represent the local chromatin structure of elementary DSB repair units at the DSB damage sites. Subfocus clusters may indicate induction of densely spaced DSBs, which are thought to be associated with the high biologic effectiveness of carbon ions. Superresolution microscopy might emerge as a powerful tool to improve our knowledge of interactions of ionizing radiation with cells.-Lopez Perez, R., Best, G., Nicolay, N. H., Greubel, C., Rossberger, S., Reindl, J., Dollinger, G., Weber, K.-J., Cremer, C., Huber, P. E. Superresolution light microscopy shows nanostructure of carbon ion radiation-induced DNA double-strand break repair foci.

Adherence to a Semiannual Surveillance Program for Hepatocellular Carcinoma in Patients With Liver Cirrhosis.

BACKGROUND: Patient adherence to screening for hepatocellular carcinoma (HCC) is not well known. Our aims were to analyze the adherence to a surveillance program in a prospective cohort of cirrhotic patients and to examine its association with HCC stage at diagnosis. MATERIALS AND METHODS: A total of 770 patients with cirrhosis were examined semiannually by ultrasound and alpha-fetoprotein at a tertiary center. We collected data on 17 variables at baseline. Suboptimal adherence was defined as failure to complete 2 consecutive screening rounds. RESULTS: Over a median follow-up period of 42.0 months (interquartile range: 60.0), 125 patients (16.2%) had suboptimal adherence. Active or previous intravenous drug use [hazard ratio (HR), 5.33; 95% confidence interval (CI), 3.07-9.23], active alcohol consumption (HR, 3.03; 95% CI, 2.03-4.51), absence of liver decompensation before the inclusion in the program (HR, 1.65; 95% CI, 1.07-2.55) and aspartate transaminase/alanine transaminase ratio ≥1.6 (HR, 1.82; 95% CI, 1.23-2.70) were independent predictors of suboptimal adherence. Compared with those with optimal adherence, patients with suboptimal adherence had a more advanced HCC stage at diagnosis (P=0.015), they were less frequently treated with curative intention (P=0.078) and survived less (median: 14.2 mo; IQR: 36.0 vs. 22.7 mo; IQR: 47.4; P=0.160), although these differences were not significant. CONCLUSIONS: The adherence to the process of HCC surveillance can be considered as adequate among cirrhotic patients. Active alcohol consumption and a history of intravenous drug use are the strongest predictors of suboptimal adherence. These patients have a more advanced HCC stage at diagnosis and tend to be less frequently treated with curative intention.

Daam1a mediates asymmetric habenular morphogenesis by regulating dendritic and axonal outgrowth.

Although progress has been made in resolving the genetic pathways that specify neuronal asymmetries in the brain, little is known about genes that mediate the development of structural asymmetries between neurons on left and right. In this study, we identify daam1a as an asymmetric component of the signalling pathways leading to asymmetric morphogenesis of the habenulae in zebrafish. Daam1a is a member of the Formin family of actin-binding proteins and the extent of Daam1a expression in habenular neuron dendrites mirrors the asymmetric growth of habenular neuropil between left and right. Local loss and gain of Daam1a function affects neither cell number nor subtype organisation but leads to a decrease or increase of neuropil, respectively. Daam1a therefore plays a key role in the asymmetric growth of habenular neuropil downstream of the pathways that specify asymmetric cellular domains in the habenulae. In addition, Daam1a mediates the development of habenular efferent connectivity as local loss and gain of Daam1a function impairs or enhances, respectively, the growth of habenular neuron terminals in the interpeduncular nucleus. Abrogation of Daam1a disrupts the growth of both dendritic and axonal processes and results in disorganised filamentous actin and α-tubulin. Our results indicate that Daam1a plays a key role in asymmetric habenular morphogenesis mediating the growth of dendritic and axonal processes in dorsal habenular neurons.

Natural variation in monoterpene synthesis in kiwifruit: transcriptional regulation of terpene synthases by NAC and ETHYLENE-INSENSITIVE3-like transcription factors.

Two kiwifruit (Actinidia) species with contrasting terpene profiles were compared to understand the regulation of fruit monoterpene production. High rates of terpinolene production in ripe Actinidia arguta fruit were correlated with increasing gene and protein expression of A. arguta terpene synthase1 (AaTPS1) and correlated with an increase in transcript levels of the 2-C-methyl-D-erythritol 4-phosphate pathway enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXS). Actinidia chinensis terpene synthase1 (AcTPS1) was identified as part of an array of eight tandemly duplicated genes, and AcTPS1 expression and terpene production were observed only at low levels in developing fruit. Transient overexpression of DXS in Nicotiana benthamiana leaves elevated monoterpene synthesis by AaTPS1 more than 100-fold, indicating that DXS is likely to be the key step in regulating 2-C-methyl-D-erythritol 4-phosphate substrate flux in kiwifruit. Comparative promoter analysis identified potential NAC (for no apical meristem [NAM], Arabidopsis transcription activation factor [ATAF], and cup-shaped cotyledon [CUC])-domain transcription factor) and ETHYLENE-INSENSITIVE3-like transcription factor (TF) binding sites in the AaTPS1 promoter, and cloned members of both TF classes were able to activate the AaTPS1 promoter in transient assays. Electrophoretic mobility shift assays showed that AaNAC2, AaNAC3, and AaNAC4 bind a 28-bp fragment of the proximal NAC binding site in the AaTPS1 promoter but not the A. chinensis AcTPS1 promoter, where the NAC binding site was mutated. Activation could be restored by reintroducing multiple repeats of the 12-bp NAC core-binding motif. The absence of NAC transcriptional activation in ripe A. chinensis fruit can account for the low accumulation of AcTPS1 transcript, protein, and monoterpene volatiles in this species. These results indicate the importance of NAC TFs in controlling monoterpene production and other traits in ripening fruits.

Theoretical Design of a Depolarized Interferometric Fiber-Optic Gyroscope (IFOG) on SMF-28 Single-Mode Standard Optical Fiber Based on Closed-Loop Sinusoidal Phase Modulation with Serrodyne Feedback Phase Modulation Using Simulation Tools for Tactical and Industrial Grade Applications.

This article presents, by means of computational simulation tools, a full analysis and design of an Interferometric Fiber-Optic Gyroscope (IFOG) prototype based on a closed-loop configuration with sinusoidal bias phase- modulation. The complete design of the different blocks, optical and electronic, is presented, including some novelties as the sinusoidal bias phase-modulation and the use of an integrator to generate the serrodyne phase-modulation signal. The paper includes detailed calculation of most parameter values, and the plots of the resulting signals obtained from simulation tools. The design is focused in the use of a standard single-mode optical fiber, allowing a cost competitive implementation compared to commercial IFOG, at the expense of reduced sensitivity. The design contains an IFOG model that accomplishes tactical and industrial grade applications (sensitivity ≤ 0.055 °/h). This design presents two important properties: (1) an optical subsystem with advanced conception: depolarization of the optical wave by means of Lyot depolarizers, which allows to use a sensing coil made by standard optical fiber, instead by polarization maintaining fiber, which supposes consequent cost savings and (2) a novel and simple electronic design that incorporates a linear analog integrator with reset in feedback chain, this integrator generating a serrodyne voltage-wave to apply to Phase-Modulator (PM), so that it will be obtained the interferometric phase cancellation. This particular feedback design with sawtooth-wave generated signal for a closed-loop configuration with sinusoidal bias phase modulation has not been reported till now in the scientific literature and supposes a considerable simplification with regard to previous designs based on similar configurations. The sensing coil consists of an 8 cm average diameter spool that contains 300 m of standard single-mode optical-fiber (SMF-28 type) realized by quadrupolar winding. The working wavelength will be 1310 nm. The theoretical calculated values of threshold sensitivity and dynamic range for this prototype are 0.052 °/h and 101.38 dB (from ±1.164 × 10(-5) °/s up to ±78.19 °/s), respectively. The Scale-Factor (SF) non-linearity for this model is 5.404% relative to full scale, this value being obtained from data simulation results.

Initial experience with golimumab in clinical practice for ulcerative colitis.

BACKGROUND: Golimumab is a TNF-blocking agent indicated as a second-line therapy in ulcerative colitis. PURPOSE: To research the effectiveness and safety of golimumab in patients with ulcerative colitis in clinical practice. METHODS: Retrospective study of the effectiveness and safety of golimumab in patients with ulcerative colitis. All patients received golimumab 200 mg subcutaneously at week 0, and golimumab 100 mg subcutaneously at week 2. After the induction treatment, each patient received 50 mg sc. every 4 weeks in patients with body weight less than 80 kg, and 100 mg every 4 weeks in patients with body weight greater than or equal to 80 kg. RESULTS: Study of a group of 23 ulcerative colitis patients, 7 of whom were naive to any anti-TNF therapy, and 16 patients who had previously been treated with an anti-TNF agent other than golimumab (non-naive patients). The average treatment time with golimumab was 14.3 weeks. Globally, withdrawal of corticosteroids was observed in 74% of cases. Clinical response was observed in 85.5% of patients who had not received biological treatment previously, and in patients who had previously received biological treatment the response rate was 75%. CONCLUSIONS: In this short study, golimumab seems to be an alternative treatment in naive and non-naive anti-TNF ulcerative colitis patients. It is also a safe therapy, given that there were no adverse effects in the patients studied.

Barriers to HCV treatment in the era of triple therapy: a prospective multi-centred study in clinical practice.

BACKGROUND & AIMS: (i) To describe the demographic, clinical, virological and histological characteristics of the patients undergoing evaluation for indication of triple therapy against hepatitis C virus genotype 1, and to identify the reasons why candidate patients are excluded; and (ii) to evaluate the characteristics of the healthcare environment related to treatment. METHODS: Observational, prospective and multi-centred study involving 16 hospitals of Spain. Data were collected on 1122 patients receiving attention in the outpatient clinics between June and December 2012. RESULTS: Of the 1122 patients evaluated, 769 were finally included in this study; 27% (211/769) had contraindications to the therapy. Of those without contraindications, 54% (301/558) did not receive the treatment, and so, only about a third of the patients (33%-257/769) underwent therapy. The reasons for not initiating therapy were as follows: patient refusal (30%), mild disease/awaiting new treatments (34%), restrictions by the health service (30%), other reasons (6%). In univariate analyses, the probability of receiving treatment was related to: age <60 years, male gender, high education level, advanced fibrosis, having had previous treatment, being assessed in a centre of excellence. In multivariate analyses, the factors independently related to the probability of receiving treatment were as follows: high education level of the patients (P = 0.004), advanced fibrosis (P < 0.001) and centres of excellence (P = 0.009). CONCLUSION: Despite the high efficacy of triple therapy, only a small proportion of patients receive the treatment. The causes related to non-treatment depend on patient factors, disease stage and characteristics of the health-service provision.