AA amyloidosis treated with tocilizumab: case series and updated literature review.

BACKGROUND: In published case reports, tocilizumab (TCZ) has shown good efficacy for AA amyloidosis in almost all patients. We investigated the efficacy and safety of TCZ in AA amyloidosis in a multicentre study of unselected cases. METHODS: We e-mailed rheumatology and internal medicine departments in France, Switzerland and North Africa by using the Club Rhumatismes Inflammation (CRI) network and the French TCZ registry, Registry RoAcTEmra (REGATE), to gather data on consecutive patients with histologically proven AA amyloidosis who had received at least one TCZ infusion. Efficacy was defined as a sustained decrease in proteinuria level and/or stable or improved glomerular filtration rate (GFR) and by TCZ maintenance. RESULTS: We collected 12 cases of AA amyloidosis treated with TCZ as monotherapy (mean age of patients 63 ± 16.2 years, amyloidosis duration 20.6 ± 31.3 months): eight patients had rheumatoid arthritis (RA), six with previous failure of anti-tumor necrosis factor α (anti-TNF-α) therapy. In total, 11 patients had renal involvement, with two already on hemodialysis (not included in the renal efficacy assessment). For the nine other patients, baseline GFR and proteinuria level were 53.6 ± 32.8 mL/min and 5 ± 3.3 g/24 h, respectively. The mean follow-up was 13.1 ± 11 months. TCZ was effective for six of the eight RA patients (87.5%) according to European League Against Rheumatism response criteria (four good and two moderate responders). As expected, C-reactive protein (CRP) level decreased with treatment for 11 patients. Renal amyloidosis (n = 9) progressed in three patients and was stabilized in three. Overall, three patients showed improvement, with sustained decrease in proteinuria level (42%, 82% and 96%). Baseline CRP level was higher in subsequent responders to TCZ than other patients (p = 0.02). Among the six RA patients with previous anti-TNF-α therapy, amyloidosis was ameliorated in one and stabilized in three. Three serious adverse events occurred (two diverticulitis and one major calciphylaxia due to renal failure). Finally, 7 of 12 (58%) patients continued TCZ. CONCLUSIONS: The efficacy of TCZ for AA amyloidosis varies depending on the inflammatory status at treatment onset. Discrepancies between our study of unselected consecutive patients and reported cases may be due to publication bias. These results support further prospective trials of TCZ for AA amyloidosis.

ESCCAR international congress on Rickettsia and other intracellular bacteria.

The European Society for the study of Chlamydia, Coxiella, Anaplasma and Rickettsia (ESCCAR) held his triennial international meeting in Lausanne. This meeting gathered 165 scientists from 28 countries and all 5 continents, allowing efficient networking and major scientific exchanges. Topics covered include molecular and cellular microbiology, genomics, as well as epidemiology, veterinary and human medicine. Several breakthroughs have been revealed at the meeting, such as (i) the presence of CRISPR (the "prokaryotic immune system") in chlamydiae, (ii) an Anaplasma effector involved in host chromatin remodelling, (iii) the polarity of the type III secretion system of chlamydiae during the entry process revealed by cryo-electron tomography. Moreover, the ESCCAR meeting was a unique opportunity to be exposed to cutting-edge science and to listen to comprehensive talks on current hot topics.

Peatlands and plantations in Sumatra, Indonesia : Complex realities for resource governance, rural development and climate change mitigation

Peatlands play a crucial role in Indonesia's economic development, and in its stated goal of reducing greenhouse gas emissions. Improved peatland management - including a national moratorium on the granting of any new conversion licenses - forms a cornerstone of Indonesia's climate change mitigation commitment. At the same time, rapid expansion of the plantation sector is driving wide-scale drainage and conversion of peat swamp ecosystems. The province of Riau, in central Sumatra, finds itself at the crossroads of these conflicting agendas. This essay presents a case study of three islands on Riau's east coast affected by industrial timber plantation concessions. It examines the divergent experiences, perceptions and responses of communities on the islands. A mix of dramatic protests, localised everyday actions and constructive dialogue has succeeded in delaying or perhaps halting one of the concessions, while negotiations and contestation with the other two continue. With the support of regional and national non-governmental organisations and local government, communities are pursuing alternative development strategies, including the cultivation of sago, which requires no peat drainage. While a powerful political economy of state and corporate actors shapes the contours of socio-environmental change, local social movements can alter trajectories of change, promoting incremental improvements and alternative pathways.

The activation of the atypical PKC zeta in light-induced retinal degeneration and its involvement in L-DNase II control.

Light-induced retinal degeneration is characterized by photoreceptor cell death. Many studies showed that photoreceptor demise is caspase-independent. In our laboratory we showed that leucocyte elastase inhibitor/LEI-derived DNase II (LEI/L-DNase II), a caspase-independent apoptotic pathway, is responsible for photoreceptor death. In this work, we investigated the activation of a pro-survival kinase, the protein kinase C (PKC) zeta. We show that light exposure induced PKC zeta activation. PKC zeta interacts with LEI/L-DNase II and controls its DNase activity by impairing its nuclear translocation. These results highlight the role of PKC zeta in retinal physiology and show that this kinase can control caspase-independent pathways.

An Advocacy for the Use of 3D Stem Cell Culture Systems for the Development of Regenerative Medicine: An Emphasis on Photoreceptor Generation

The availability of stem cells is of great promise to study early developmental stages and to generate adequate cells for cell transfer therapies. Although many researchers using stem cells were successful in dissecting intrinsic and extrinsic mechanisms and in generating specific cell phenotypes, few of the stem cells or the differentiated cells show the capacity to repair a tissue. Advances in cell and stem cell cultivation during the last years made tremendous progress in the generation of bona fide differentiated cells able to integrate into a tissue after transplantation, opening new perspectives for developmental biology studies and for regenerative medicine. In this review, we focus on the main works attempting to create in vitro conditions mimicking the natural environment of CNS structures such as the neural tube and its development in different brain region areas including the optic cup. The use of protocols growing cells in 3D organoids is a key strategy to produce cells resembling endogenous ones. An emphasis on the generation of retina tissue and photoreceptor cells is provided to highlight the promising developments in this field. Other examples are presented and discussed, such as the formation of cortical tissue, the epithelial gut or the kidney organoids. The generation of differentiated tissues and well-defined cell phenotypes from embryonic stem (ES) cells or induced pluripotent cells (iPSCs) opens several new strategies in the field of biology and regenerative medicine. A 3D organ/tissue development in vitro derived from human cells brings a unique tool to study human cell biology and pathophysiology of an organ or a specific cell population. The perspective of tissue repair is discussed as well as the necessity of cell banking to accelerate the progress of this promising field.

Sickness certification in primary care: a survey on views and practices among Swiss physicians.

QUESTIONS UNDER STUDY: Studies from several countries (Scandinavia, United Kingdom) report that general practitioners (GPs) experience problems in sickness certification. Our study explored views of Swiss GPs towards sickness certification, their practice and experience, professional skills and problematic interactions with patients. METHODS: We conducted an online survey among GPs throughout Switzerland, exploring behaviour of physicians, patients and employers with regard to sickness certification; GPs' views about sickness certification; required competences for certifying sickness absence, and approaches to advance their competence. We piloted the questionnaire and disseminated it through the networks of the five Swiss academic institutes for primary care. RESULTS: We received 507 valid responses (response rate 50%). Only 43/507 GPs experienced sickness certification as problematic per se, yet 155/507 experienced problems in sickness certification at least once a week. The 507 GPs identified estimating a long-term prognosis about work capacity (64%), handling conflicts with patients (54%), and determining the reduction of work capacity (42%) as problematic. Over 75% would welcome special training opportunities, e.g., on sickness certifications during residency (93%), in insurance medicine (81%), and conflict management (80%). CONCLUSION: Sickness certification as such does not present a major problem to Swiss GPs, which contrasts with the experience in Scandinavian countries and in the UK. Swiss GPs did identify specific tasks of sickness certification as problematic. Training opportunities on sick-leave certification and insurance medicine in general were welcomed.

Systematic evaluation of matrix effects in hydrophilic interaction chromatography versus reversed phase liquid chromatography coupled to mass spectrometry.

Reversed phase liquid chromatography (RPLC) coupled to mass spectrometry (MS) is the gold standard technique in bioanalysis. However, hydrophilic interaction chromatography (HILIC) could represent a viable alternative to RPLC for the analysis of polar and/or ionizable compounds, as it often provides higher MS sensitivity and alternative selectivity. Nevertheless, this technique can be also prone to matrix effects (ME). ME are one of the major issues in quantitative LC-MS bioanalysis. To ensure acceptable method performance (i.e., trueness and precision), a careful evaluation and minimization of ME is required. In the present study, the incidence of ME in HILIC-MS/MS and RPLC-MS/MS was compared for plasma and urine samples using two representative sets of 38 pharmaceutical compounds and 40 doping agents, respectively. The optimal generic chromatographic conditions in terms of selectivity with respect to interfering compounds were established in both chromatographic modes by testing three different stationary phases in each mode with different mobile phase pH. A second step involved the assessment of ME in RPLC and HILIC under the best generic conditions, using the post-extraction addition method. Biological samples were prepared using two different sample pre-treatments, i.e., a non-selective sample clean-up procedure (protein precipitation and simple dilution for plasma and urine samples, respectively) and a selective sample preparation, i.e., solid phase extraction for both matrices. The non-selective pretreatments led to significantly less ME in RPLC vs. HILIC conditions regardless of the matrix. On the contrary, HILIC appeared as a valuable alternative to RPLC for plasma and urine samples treated by a selective sample preparation. Indeed, in the case of selective sample preparation, the compounds influenced by ME were different in HILIC and RPLC, and lower and similar ME occurrence was generally observed in RPLC vs. HILIC for urine and plasma samples, respectively. The complementary of both chromatographic modes was also demonstrated, as ME was observed only scarcely for urine and plasma samples when selecting the most appropriate chromatographic mode.

Therapeutic and recreational methadone cardiotoxicity.

Several classes of drugs have been associated with an increased risk of cardiovascular disease and occurrence of arrhythmias potentially involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart possibly due to methadone use. 60 cases were included in the study in total and were divided into three groups (therapeutic methadone users: 20 cases, recreational methadone users: 20 cases, and sudden death group in subjects who had never taken methadone: 20 cases). Autopsies, histology, biochemistry and toxicology were performed in all cases. Macroscopic and microscopic investigation results in therapeutic methadone users were similar to those observed in sudden, unexpected deaths in non-methadone users. In recreational methadone consumers, macroscopic and microscopic examination of the heart failed to provide results consistent with acute or chronic myocardial or coronary damage, thereby corroborating the hypothesis of death most likely following respiratory depression.

Semantic domain and grammatical class effects in the picture-word interference paradigm

The role of grammatical class in lexical access and representation is still not well understood. Grammatical effects obtained in picture-word interference experiments have been argued to show the operation of grammatical constraints during lexicalization when syntactic integration is required by the task. Alternative views hold that the ostensibly grammatical effects actually derive from the coincidence of semantic and grammatical differences between lexical candidates. We present three picture-word interference experiments conducted in Spanish. In the first two, the semantic relatedness (related or unrelated) and the grammatical class (nouns or verbs) of the target and the distracter were manipulated in an infinitive form action naming task in order to disentangle their contributions to verb lexical access. In the third experiment, a possible confound between grammatical class and semantic domain (objects or actions) was eliminated by using action-nouns as distracters. A condition in which participants were asked to name the action pictures using an inflected form of the verb was also included to explore whether the need of syntactic integration modulated the appearance of grammatical effects. Whereas action-words (nouns or verbs), but not object-nouns, produced longer reaction times irrespective of their grammatical class in the infinitive condition, only verbs slowed latencies in the inflected form condition. Our results suggest that speech production relies on the exclusion of candidate responses that do not fulfil task-pertinent criteria like membership in the appropriate semantic domain or grammatical class. Taken together, these findings are explained by a response-exclusion account of speech output. This and alternative hypotheses are discussed.

From Regional Landslide Detection to Site-Specific Slope Deformation Monitoring and Modelling Based on Active Remote Sensors

Landslide processes can have direct and indirect consequences affecting human lives and activities. In order to improve landslide risk management procedures, this PhD thesis aims to investigate capabilities of active LiDAR and RaDAR sensors for landslides detection and characterization at regional scales, spatial risk assessment over large areas and slope instabilities monitoring and modelling at site-specific scales. At regional scales, we first demonstrated recent boat-based mobile LiDAR capabilities to model topography of the Normand coastal cliffs. By comparing annual acquisitions, we validated as well our approach to detect surface changes and thus map rock collapses, landslides and toe erosions affecting the shoreline at a county scale. Then, we applied a spaceborne InSAR approach to detect large slope instabilities in Argentina. Based on both phase and amplitude RaDAR signals, we extracted decisive information to detect, characterize and monitor two unknown extremely slow landslides, and to quantify water level variations of an involved close dam reservoir. Finally, advanced investigations on fragmental rockfall risk assessment were conducted along roads of the Val de Bagnes, by improving approaches of the Slope Angle Distribution and the FlowR software. Therefore, both rock-mass-failure susceptibilities and relative frequencies of block propagations were assessed and rockfall hazard and risk maps could be established at the valley scale. At slope-specific scales, in the Swiss Alps, we first integrated ground-based InSAR and terrestrial LiDAR acquisitions to map, monitor and model the Perraire rock slope deformation. By interpreting both methods individually and originally integrated as well, we therefore delimited the rockslide borders, computed volumes and highlighted non-uniform translational displacements along a wedge failure surface. Finally, we studied specific requirements and practical issues experimented on early warning systems of some of the most studied landslides worldwide. As a result, we highlighted valuable key recommendations to design new reliable systems; in addition, we also underlined conceptual issues that must be solved to improve current procedures. To sum up, the diversity of experimented situations brought an extensive experience that revealed the potential and limitations of both methods and highlighted as well the necessity of their complementary and integrated uses.

ASYMMETRIC SULFOXIDATION OF ALBENDAZOLE TO RICOBENDAZOLE BY FUNGI: EFFECT OF pH

Albendazole (ABZ) is an anthelmintic drug used for the treatment of infectious diseases in veterinary and human medicine. This drug is a prochiral drug that after administration, is rapidly oxidized in the pharmacologically active sulfoxide metabolite, which is also known as ricobendazole (ABZSOX). ABZSOX has a stereogenic center and possibly two enantiomers, (+)-ABZSOX and (-)-ABZSOX. In the present work, we investigate the pH effect on the asymmetric stereoselective sulfoxidation of ABZ into ABZSOX by employing the fungi Nigrospora sphaerica, Papulaspora immera Hotson, and Mucor rouxii. The results show a possibility of obtaining the pure enantiomers of the ricobendazole drug using fungi as biocatalytic agents. The three fungi showed a high degree of enantioselectivity expressed by enantiomeric excess. In addition, M. rouxii can be used as an alternative to obtain the (+)-ABZSOX enantiomer (ee 89.8%).

Spectrophotometric study of the chromium(III)/azide system in the ultraviolet region and its analytical application

A sensitive and alternative method for the spectrophotometric determination of chromium(III) based on the formation of chromium(III)/azide complexes was established by investigating a new band in the ultraviolet region. The best experimental conditions for the analytical determination of this metallic ion were: ligand and perchloric acid analytical concentration = 493 and 12.0 mmol L-1, respectively; aqueous medium; T = 25.0 ºC; contact time = 1 hour. The maximum molar absorptivity coefficient occurred at 287 nm (average 1.481 ± 0.008 ´ 10(4) L mol-1 cm-1), leading to the determination of metal ion concentrations one hundred times lower than the ones formerly determined in the visible region. The system obeys Beer's Law and is suitable for chromium determination in the 0.702-2.81 mg L-1 concentration range (15-65% T, 1.00 cm-width quartz cells). Analytical applications of the current method were tested with a nutritional supplement containing chromium. Results were compared with those obtained with atomic absorption spectrometry.

Studies on Neuromuscular Blocking Agents and Their Antagonists During Anaesthesia

Neuromuscular blocking agents (NMBAs) are widely used in clinical anaesthesia and emergency medicine. Main objectives are to facilitate endotracheal intubation and to allow surgery by reducing muscle tone and eliminating sudden movements, which may otherwise lead to trauma and complications. The most commonly used NMBAs are non-depolarizing agents with a medium duration of action, such as rocuronium and cisatracurium. They bind to the acetylcholine receptors in the neuromuscular junction, thus inhibiting the depolarization of the postsynaptic (muscular) membrane, which is a prerequisite for muscle contraction to take place. Previously, it has been assumed that nitrous oxide (N2O), which is commonly used in combination with volatile or intravenous anaesthetics during general anaesthesia, has no effect on NMBAs. Several studies have since claimed that N2O in fact does increase the effect of NMBAs when using bolus administration of the relaxant. The effect of N2O on the infusion requirements of two NMBAs (rocuronium and cisatracurium) with completely different molecular structure and pharmacological properties was assessed. A closed-loop feedback controlled infusion of NMBA with duration of at least 90 minutes at a 90% level of neuromuscular block was used. All patients received total intravenous anaesthesia (TIVA) with propofol and remifentanil. In both studies the study group (n=35) received N2O/Oxygen and the control group (n=35) Air/Oxygen. There were no significant differences in the mean steady state infusion requirements of NMBA (rocuronium in Study I; cisatracurium in Study II) between the groups in either study. In Study III the duration of the unsafe period of recovery after reversal of rocuronium-induced neuromuscular block by using neostigmine or sugammadex as a reversal agent was analyzed. The unsafe period of recovery was defined as the time elapsed from the moment of no clinical (visual) fade in the train-of-four (TOF) sequence until an objectively measured TOF-ratio of 0.90 was achieved. The duration of these periods were 10.3 ± 5.5 and 0.3 ± 0.3 min after neostigmine and sugammadex, respectively (P < 0.001). Study IV investigated the possible effect of reversal of a rocuronium NMB by sugammadex on depth of anaesthesia as indicated by the bispectral index and entropy levels in thirty patients. Sugammadex did not affect the level of anaesthesia as determined by EEG-derived indices of anaesthetic depth such as the bispectral index and entropy.

Morphology and morphometry of feline bone marrow-derived mesenchymal stem cells in culture

Mesenchymal stem cells (MSC) are increasingly being proposed as a therapeutic option for treatment of a variety of different diseases in human and veterinary medicine. Stem cells have been isolated from feline bone marrow, however, very few data exist about the morphology of these cells and no data were found about the morphometry of feline bone marrow-derived MSCs (BM-MSCs). The objectives of this study were the isolation, growth evaluation, differentiation potential and characterization of feline BM-MSCs by their morphological and morphometric characteristics. in vitro differentiation assays were conducted to confirm the multipotency of feline MSC, as assessed by their ability to differentiate into three cell lineages (osteoblasts, chondrocytes, and adipocytes). To evaluate morphological and morphometric characteristics the cells are maintained in culture. Cells were observed with light microscope, with association of dyes, and they were measured at 24, 48, 72 and 120h of culture (P1 and P3). The non-parametric ANOVA test for independent samples was performed and the means were compared by Tukey's test. On average, the number of mononuclear cells obtained was 12.29 (±6.05x10(6)) cells/mL of bone marrow. Morphologically, BM-MSCs were long and fusiforms, and squamous with abundant cytoplasm. In the morphometric study of the cells, it was observed a significant increase in average length of cells during the first passage. The cell lengths were 106.97±38.16µm and 177.91±71.61µm, respectively, at first and third passages (24 h). The cell widths were 30.79±16.75 µm and 40.18±20.46µm, respectively, at first and third passages (24 h).The nucleus length of the feline BM-MSCs at P1 increased from 16.28µm (24h) to 21.29µm (120h). However, at P3, the nucleus length was 26.35µm (24h) and 25.22µm (120h). This information could be important for future application and use of feline BM-MSCs.

Coercion, Perceived Care and Quality of Life Among Patients in Psychiatric Hospitals

The goals of the study were to describe patients’ perceptions of care after experiencing seclusion/restraint and their quality of life. The goal was moreover to identify methodological challenges related to studies from the perspective of coerced patients. The study was conducted in three phases between September 2008 and April 2012. In the first phase, the instrument Secluded/ Restrained Patients’ Perception of their Treatment (SR-PPT) was developed and validated in Japan in cooperation with a Finnish research group (n = 56). Additional data were collected over one year from secluded/restrained patients using the instrument (n = 90). In the second phase, data were collected during the discharge process (n = 264). In the third phase, data were collected from electronic databases. Methodological and ethical issues were reviewed (n = 32) using systematic review method. Patients perceived that co-operation with the staff was poor; patients’ opinions were not taken into account, treatment targets collated and treatment methods were seen in different ways. Patients also felt that their concerns were not well enough understood. However, patients received getting nurses’ time. In particular, seclusion/restraint was considered unnecessary. The patients felt that they benefited from the isolation in treating their problems more than they needed it, even if the benefit was seen to be minor. Patients treated on forensic wards rated their treatment and care significantly lower than in general units. During hospitalization secluded/restrained patients evaluated their quality of life, however, better than did non-secluded/restrained patients. However, no conclusion is drawn to the effect that the better quality of life assessment is attributable to the seclusion/restraint because patients’ treatment period after the isolation was long and because of many other factors, as rehabilitation, medication, diagnostic differences, and adaptation. According to the systematic mixed studies review variation between study designs was found to be a methodological challenge. This makes comparison of the results more difficult. A research ethical weakness is conceded as regards descriptions of the ethical review process (44 %) and informed consent (32 %). It can be concluded that patients in psychiatric hospital care and having a voice as an equal expert require special attention to clinical nursing, decision-making and service planning. Patients and their family members will be consulted in plans of preventive and alternative methods for seclusion and restraint. The study supports the theory that in ethical decision-making situations account should be taken of medical indications, in addition to the patients’ preferences, the effect of treatment on quality of life, and this depends on other factors. The connection between treatment decisions and a patient’s quality of life should be evaluated more structurally in practice. Changing treatment culture towards patients’ involvement will support daily life in nursing and service planning taking into account improvements in patients’ quality of life.