Respiratory effects of an exposure to grain dust among grain workers in the Vaud region (Switzerland)

Introduction: Bioaerosols such as grain dust (GD) elicit direct immunological reactions within the human respiratory system. Workplace-dependent exposure to GD may induce asthma, chronic bronchitis, and hypersensitivity pneumonitis. Aims: To assess the clinical impact of occupational exposure to GD and to determine quantitative biological markers of bioaerosol exposure in grain workers. Methods: This longitudinal study has been conducted from summer 2012 to summer 2013, comprising 6 groups of 30 active workers with different GD exposure patterns (4 groups of grain workers, 2 control groups). Two evaluations at high- and low-exposing seasons take place, during which an occupational and a medical history are questionnaire-assessed, lung function is evaluated by spirometry, airway inflammation is measured by exhaled nitric oxide (eNO) and specific blood IgG and IgE are titrated. Results: The preliminary results are those of 2 of the 4 exposed groups, (harvesters and mill workers), compared to the control groups, at first assessment (n=100). Mean age is 38.4 [years]; 98% are male. Exposed groups differ from controls (p<0.05) in daily contact with animals (57% vs. 40%) and active smoking (39% vs. 11%). Grain workers have more respiratory (50%), nasal (57%), ocular (45%) and dermatologic (36%) occupational symptoms than controls (6.4%, 19%, 16%, 6.4% respectively, p<0.05). Lower mean peak-expiratory-flow (PEF) values (96.1 ± 18.9 vs. 108.2 ± 17.4 [% of predicted], p<0.05) and eNO values (13.9 ± 9.6 vs. 20.5 ± 14.7 [ppm], p<0.05) are observed in the exposed groups. Conclusion: Preliminary results show a higher prevalence of clinical symptoms and a lower mean PEF value in the groups exposed to GD.

Natural variability of in vitro adherence to fibrinogen and fibronectin does not correlate with in vivo infectivity of Staphylococcus aureus.

Adherence to fibrinogen and fibronectin plays a crucial role in Staphylococcus aureus experimental endocarditis. Previous genetic studies have shown that infection and carriage isolates do not systematically differ in their virulence-related genes, including genes conferring adherence, such as clfA and fnbA. We set out to determine the range of adherence phenotypes in carriage isolates of S. aureus, to compare the adherence of these isolates to the adherence of infection isolates, and to determine the relationship between adherence and infectivity in a rat model of experimental endocarditis. A total of 133 healthy carriage isolates were screened for in vitro adherence to fibrinogen and fibronectin, and 30 isolates were randomly chosen for further investigation. These 30 isolates were compared to 30 infective endocarditis isolates and 30 blood culture isolates. The infectivities of the carriage isolates, which displayed either extremely low or high adherence to fibrinogen and fibronectin, were tested using a rat model of experimental endocarditis. The levels of adherence to both fibrinogen and fibronectin were very similar for isolates from healthy carriers and members of the two groups of infection isolates. All three groups of isolates showed a wide range of adherence to fibrinogen and fibronectin. Moreover, the carriage isolates that showed minimal adherence and the carriage isolates that showed strong adherence had the same infectivity in experimental endocarditis. Adherence was proven to be important for pathogenesis in experimental endocarditis, but even the least adherent carriage strains had the ability to induce infection. We discuss the roles of differential gene expression, human host factors, and gene redundancy in resolving this apparent paradox.

The presence of a CD4+ CD25high CD45RO+ CD127high T-cell population correlates with the clinical status of kidney transplant recipients

Background: Recent data have suggested that a population of CD4+ CD25high T cells, phenotypically characterized by the expression of CD45RO and CD127, is significantly expanded in stable liver and kidney transplant recipients and represents alloreactive T cells. We analyzed this putative new alloreactive cellular marker in various groups of kidney transplant recipients. Patients and methods: Flow cytometry was used to analyze the expression of CD25, CD45RO and CD127 on peripheral CD4+ T cells. Of 73 kidney recipients, 59 had a stable graft function under standard immunosuppressive therapy (IS), 5 had biopsy-proven chronic humoral rejection (CHR), 8 were stable under minimal IS and one was an operationally "tolerant" patient who had discontinued IS for more than 3 years. Sixty-six healthy subjects (HS) were studied as controls. Results: Overall, the alloreactive T cell population was found to be significantly increased in the 73 kidney recipients (mean ± SE: 15.03 ± 1.04% of CD4+ CD25high T cells) compared to HS (5.93 ± 0.39%) (p <0.001). In the 5 patients with CHR, this population was highly expanded (31.33 ± 4.16%), whereas it was comparable to HS in the 8 stable recipients receiving minimal IS (6.12 ± 0.86%), in 4 patients who had been switched to sirolimus (4.21 ± 0.53%) as well as in the unique "tolerant" recipient (4.69%). Intermediate levels (15.84 ± 0.93%) were found in the 55 recipients with stable graft function on standard CNI-based IS. Regulatory T cells, defined as CD4+ CD25high FoxP3+ CD127low, were found to be significantly reduced in all recipients except in those with minimal or no IS, and this reduction was particularly striking in recipients with CHR. Conclusion: After kidney transplantation, an alloreactive T cell population was found to be significantly expanded and it correlates with the clinical status of the recipients. Interestingly, in stable patients with minimal (or no) IS as well as in patients on sirolimus, alloreactive T cells were comparable the healthy controls. Measuring circulating CD4+ CD25high CD45RO+ CD127high T cells may become a useful monitoring tool after transplantation.

The renal hemodynamic effects of ibuprofen in the newborn rabbit.

In early childhood, nonsteroidal anti-inflammatory drugs are mainly used to either prevent or treat premature labor of the mother and patent ductus arteriosus of the newborn infant. The most frequently used prostaglandin-synthesis inhibitor is indomethacin. Fetuses exposed to indomethacin in utero have been born with renal developmental defects, and in both the unborn child and the term and premature newborn this drug may compromise renal glomerular function. The latter has in the past also been observed when i.v. indomethacin or i.v. acetylsalicylic acid (aspirin) were administered to newborn rabbits. The present experiments were designed to evaluate whether ibuprofen has less renal side effects than indomethacin, as claimed. Three groups of anesthetized, ventilated, normoxemic neonatal rabbits were infused with increasing doses of ibuprofen (0.02, 0.2, 2.0 mg/kg body weight) and the following renal parameters were measured: urine volume, urinary sodium excretion, GFR, and renal plasma flow. Renal blood flow, filtration fraction, and the renal vascular resistance were calculated according to standard formulae. Intravenous ibuprofen caused a dose-dependent, significant reduction in urine volume, GFR, and renal blood flow with a fall in filtration fraction in the animals receiving the highest dose of ibuprofen (2 mg/kg body weight). There was a very steep rise in renal vascular resistance. Urinary sodium excretion decreased. These experiments in neonatal rabbits clearly show that acute i.v. doses of ibuprofen also have significant renal hemodynamic and functional side effects, not less than seen previously with indomethacin.

Relationship Between the Development of the Spinal Canal and the Etiopathogenesis of Lumbar Spinal Stenosis

INTRODUCTION: The presence of a pre-existing narrow spinal canal may have an important place in the ethiopathogenesis of lumbar spinal stenosis. By consequence the study of the development of the spinal canal is crucial. The first goal of this work is to do a comprehensive literature search and to give an essential view on the development of spinal canal and its depending factors studied until now. The second goal is to give some considerations and hypothesize new leads for clinically useful researches. MATERIALS AND METHODS: A bibliographical research was executed using different search engines: PubMed, Google Schoolar ©, Ovid ® and Web Of Science ©. Free sources and avaible from the University of Lausanne (UNIL) and Centre Hospitalier Universitaire Vaudois (CHUV) were used. At the end of the bibliographic researches 114 references were found, 85 were free access and just 41 were cited in this work. Most of the found references are in English or in French. RESULTS AND DISCUSSION: The spinal canal is principally limited by the vertebrae which have a mesodermal origin. The nervous (ectodermal) tissue significantly influences the growth of the canal. The most important structure participating in the spinal canal growth is the neurocentral synchondrosis in almost the entire vertebral column. The fusion of the half posterior arches seems to have less importance for the canal size. The growth is not homogeneous but, depends on the vertebral level. Timing, rate and growth potentials differ by regions. Especially in the case of the lumbar segment, there is a craniocaudal tendency which entails a greater post-natal catch-up growth for distal vertebrae. Trefoil-shape of the L5 canal is the consequence of a sagittal growth deficiency. The spinal canal shares some developmental characteristics with different structures and systems, especially with the central nervous system. It may be the consequence of the embryological origin. It is supposed that not all the related structures would be affected by a growth impairment because of the different catch-up potentials. Studies found that narrower spinal canals might be related with cardiovascular and gastrointestinal symptoms, lower thymic function, bone mineral content, dental hypoplasia and Harris' lines. Anthropometric correlations found at birth disappear during the pediatric age. All factors which can affect bone and nervous growth might be relevant. Genetic predispositions are the only factors that can never be changed but the real impact is to ascertain. During the antenatal period, all the elements determining a good supply of blood and oxygen may influence the vertebral canal development, for example smoking during pregnancy. Diet is a crucial factor having an impact on both antenatal and postnatal growth. Proteins intake is the only proved dietetic relationship found in the bibliographic research of this work. The mechanical effects due to locomotion changes are unknown. Socioeconomic situation has an impact on several influencing factors and it is difficult to study it owing to numerous bias. CONCLUSIONS: A correct growth of spinal canal is evidently relevant to prevent not-degenerative stenotic conditions. But a "congenital" narrower canal may aggravate degenerative stenosis. This concerns specific groups of patient. If the size of the canal is highly involved in the pathogenesis of common back pains, a hypothetical measure to prevent developmental impairments could have a not- negligible impact on the society. It would be interesting to study more about dietetic necessities for a good spinal canal development. Understanding the relationship between nervous tissues and vertebra it might be useful in identifying what is needed for the ideal development. Genetic importance and the post-natal influences of upright standing on the canal growth remain unsolved questions. All these tracks may have a double purpose: knowing if it is possible to decrease the incidence of narrower spinal canal and consequently finding possible preventive measures. The development of vertebral canal is a complex subject which ranges over a wide variety of fields. The knowledge of this subject is an indispensable tool to understand and hypothesize the influencing factors that might lead to stenotic conditions. Unfortunately, a lack of information makes difficult to have a complete and satisfactory interdisciplinary vision.

Convergences and divergences of diabetic patients' and healthcare professionals' opinions of care : a qualitative study

OBJECTIVES: To investigate opinions' convergences and divergences of diabetic patients and health-care professionals on diabetes care and the development of a regional diabetes programme. BACKGROUND: Development and implementation of a regional diabetes programme. RESEARCH DESIGN: Qualitative study using focus groups to elicit diabetic patients' and health-care professionals' opinions, followed by content analysis. SETTING AND PARTICIPANTS: Eight focus groups: four focus groups with diabetic patients (n = 39) and four focus groups with various health-care professionals (n = 34) residing or practicing in the canton of Vaud, Switzerland, respectively. RESULTS: Perceived quality of diabetes care varied between individuals and types of participants. To improve quality, patients favoured a comprehensive follow-up while professionals suggested considering existing structures and trained professionals. All participants mentioned communication difficulties between professionals and were favouring teamwork. In addition, they described the role that patients should have in care and self-management. Financial difficulties were also mentioned by both groups of participants. Finally, they were in favour of the development of a regional diabetes programme adapted to actors' needs. For patients indeed, such a programme would represent an opportunity to improve information and to have access to comprehensive care. For professionals, it would help the development of local networks and the reinforcement of existing tools and structures. DISCUSSION AND CONCLUSIONS: Acknowledging convergences and divergences of opinions of both diabetic patients and health-care professionals should help the further development of a programme adapted to users' needs, taking all stakeholders interests and priorities into consideration.

The effect of treatment with calcitonin on vertebral fracture rate in osteoporosis.

The efficacy of treatments for osteoporosis does not become evident when evaluated by fracture incidence (FI). Vertebral FI decreased in all controlled studies on calcitonin, but not significantly. Small sample sizes and short periods of treatment may have masked a possible therapeutic benefit, but longer, controlled studies with sodium fluoride or etidronate in larger groups of patients also failed to show a decrease in FI. The present analysis of nine published, therapeutic studies which indicate the FI per year and the initial prevalence of vertebral fractures, examines the question of whether the initial prevalence of fractures has an effect on the subsequent incidence of new fractures and whether the therapeutic effects have to be evaluated as a function of the initial prevalence of fractures. Bearing in mind the differences in roentgenological evaluation and in the size and quality of the various studies, the analysis revealed (1) that in the control groups there was a higher FI in patients with more than three vertebral fractures at baseline (estimated odds ratio (OR) = 49, p = 0.011); (2) that a similar trend, although not statistically significant, was observed in treated patients; (3) that the groups of control patients treated for more than 1 year showed in general an increase in FI beyond the first year and that the reverse was true in treated patients. In conclusion, failure to allow for the initial prevalence of vertebral fractures at the individual level in therapeutic trials of calcitonin to treat osteoporosis and prevent new fractures might have contributed to the absence of a demonstrable benefit of the treatment in those studies.

Psychological profile of adolescents with a kidney transplant.

To describe the psychological profile of renal transplant adolescents compared to healthy peers and to adolescents with CKD, three groups of adolescents aged 12-18 yr were selected: TX, CX, and adolescents with CKD. Psychiatric symptoms and disorders were evaluated through direct interviews (K-SADS-PL) and self-report questionnaires (YSR and CBCL). Forty TX (14 LRD and 26 DD transplant recipients), 40 CX and 20 CKD were included. Twelve of 40 (30%) TX, three of 20 (15%) CKD, and three of 40 (7.5%) CX had a history of learning difficulties (p = 0.03). Compared to CX, TX had lower total YSR competencies score (p = 0.028) and lower total CBCL competencies score (p = 0.003). Twenty-six of 40 (65%) TX, 12 of 20 (60%) CKD and 15 of 40 (37.5%) CX (p = 0.038) met DSM-IV diagnostic criteria for lifetime psychiatric disorder, with rates of depressive disorder of 35% among TX and CKD compared to 15.2% among CX (p = 0.043). Eight of 40 (20%) TX had a history of simple phobia. Nine of 40 (22.5%) TX met diagnostic criteria for ADHD as compared to one of 20 (5%) CKD and three of 40 (7.5%) CX. In the TX group, we found no significant differences in educational and psychiatric variables between LRD and DD. In conclusion, we found a high prevalence of psychiatric morbidity (depression, phobia, ADHD), educational impairment and social competence problems in the TX group. CKD scored in between TX and CX on most measures.

Analysis of acute brain slices by electron microscopy: A correlative light-electron microscopy workflow based on Tokuyasu cryo-sectioning.

Acute brain slices are slices of brain tissue that are kept vital in vitro for further recordings and analyses. This tool is of major importance in neurobiology and allows the study of brain cells such as microglia, astrocytes, neurons and their inter/intracellular communications via ion channels or transporters. In combination with light/fluorescence microscopies, acute brain slices enable the ex vivo analysis of specific cells or groups of cells inside the slice, e.g. astrocytes. To bridge ex vivo knowledge of a cell with its ultrastructure, we developed a correlative microscopy approach for acute brain slices. The workflow begins with sampling of the tissue and precise trimming of a region of interest, which contains GFP-tagged astrocytes that can be visualised by fluorescence microscopy of ultrathin sections. The astrocytes and their surroundings are then analysed by high resolution scanning transmission electron microscopy (STEM). An important aspect of this workflow is the modification of a commercial cryo-ultramicrotome to observe the fluorescent GFP signal during the trimming process. It ensured that sections contained at least one GFP astrocyte. After cryo-sectioning, a map of the GFP-expressing astrocytes is established and transferred to correlation software installed on a focused ion beam scanning electron microscope equipped with a STEM detector. Next, the areas displaying fluorescence are selected for high resolution STEM imaging. An overview area (e.g. a whole mesh of the grid) is imaged with an automated tiling and stitching process. In the final stitched image, the local organisation of the brain tissue can be surveyed or areas of interest can be magnified to observe fine details, e.g. vesicles or gold labels on specific proteins. The robustness of this workflow is contingent on the quality of sample preparation, based on Tokuyasu's protocol. This method results in a reasonable compromise between preservation of morphology and maintenance of antigenicity. Finally, an important feature of this approach is that the fluorescence of the GFP signal is preserved throughout the entire preparation process until the last step before electron microscopy.

Improved statistical evaluation of group differences in connectomes by screening-filtering strategy with application to study maturation of brain connections between childhood and adolescence.

Detecting local differences between groups of connectomes is a great challenge in neuroimaging, because the large number of tests that have to be performed and the impact on multiplicity correction. Any available information should be exploited to increase the power of detecting true between-group effects. We present an adaptive strategy that exploits the data structure and the prior information concerning positive dependence between nodes and connections, without relying on strong assumptions. As a first step, we decompose the brain network, i.e., the connectome, into subnetworks and we apply a screening at the subnetwork level. The subnetworks are defined either according to prior knowledge or by applying a data driven algorithm. Given the results of the screening step, a filtering is performed to seek real differences at the node/connection level. The proposed strategy could be used to strongly control either the family-wise error rate or the false discovery rate. We show by means of different simulations the benefit of the proposed strategy, and we present a real application of comparing connectomes of preschool children and adolescents.

Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers.

Hemodynamic and biochemical effects of the new renin inhibitor CGP 38560A (molecular weight 826) were tested in 15 healthy volunteers after a single-blind, randomized, placebo-controlled protocol. At a 2-week interval, groups of five subjects received a 30-minute infusion of either 5% dextrose or CGP 38560A 50, 125, or 250 micrograms/kg. Blood pressure, heart rate, plasma renin activity, active and total renin, angiotensin-(1-8)octapeptide (angiotensin II), and aldosterone were sequentially measured up to 3 hours from the onset of the infusion. There was no consistent change in blood pressure or heart rate. Plasma renin activity and angiotensin II decreased dose dependently, and peak suppression was observed at the end of the infusion of CGP 38560A and after the 250-micrograms/kg dose. Plasma renin activity fell from 1.0 +/- 0.19 (mean +/- SEM) to less than 0.05 ng/ml/hr in all five subjects (p less than 0.001), and angiotensin II fell from 7.7 +/- 1.2 to 2.6 +/- 0.9 femtomole/ml (p less than 0.01). Active renin rose fourfold from 24 +/- 1.9 to 98 +/- 14 pg/ml (p less than 0.001) at the end of the infusion of the high dose. Plasma angiotensin II returned toward its initial values much faster than plasma renin activity and active renin. In conclusion, CGP 38560A was well tolerated. It induced a dose-dependent decrease in angiotensin II and plasma renin activity and a long-lasting and dose-dependent rise in active renin. The doses used did not reduce plasma angiotensin II maximally despite reduction of plasma renin activity to unmeasurable levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Registries in rheumatological and musculoskeletal conditions. Paediatric Behçet's disease: an international cohort study of 110 patients. One-year follow-up data.

OBJECTIVE: To set-up an international cohort of patients suspected with Behçet's disease (BD). The cohort is aimed at defining an algorithm for definition of the disease in children. METHODS: International experts have defined the inclusion criteria as follows: recurrent oral aphthosis (ROA) plus one of following-genital ulceration, erythema nodosum, folliculitis, pustulous/acneiform lesions, positive pathergy test, uveitis, venous/arterial thrombosis and family history of BD. Onset of disease is <16 years, disease duration is ≤3 years, future follow-up duration is ≥4 years and informed consent is obtained. The expert committee has classified the included patients into: definite paediatric BD (PED-BD), probable PED-BD and no PED-BD. Statistical analysis is performed to compare the three groups of patients. Centres document their patients into a single database. RESULTS: At January 2010, 110 patients (56 males/54 females) have been included. Mean age at first symptom: 8.1 years (median 8.2 years). At inclusion, 38% had only one symptom associated with ROA, 31% had two and 31% had three or more symptoms. A total of 106 first evaluations have been done. Seventeen patients underwent the first-year evaluation, and 36 had no new symptoms, 12 had one and 9 had two. Experts have examined 48 files and classified 30 as definite and 18 as probable. Twenty-six patients classified as definite fulfilled the International Study Group criteria. Seventeen patients classified as probable did not meet the international criteria. CONCLUSION: The expert committee has classified the majority of patients in the BD group although they presented with few symptoms independently of BD classification criteria.

Pharmacologic profile of UR-7247, an orally active angiotensin II AT1 receptor antagonist, in healthy volunteers. p6.

This study was conducted to assess the pharmacologic properties of the new orally active angiotensin II subtype I (AT1) antagonist UR-7247, a product with a half-life >100 h in humans. The experiment was designed as an open-label, single-dose administration study with four parallel groups of four healthy men receiving increasing single oral doses (2.5, 5, and 10 mg) of UR-7247 or losartan, 100 mg. Angiotensin II receptor blockade was investigated < or =96 h after drug intake, with three independent methods [i.e., the inhibition of blood pressure (BP) response to exogenous Ang II, an in vitro Ang II-receptor assay (RRA), and the reactive increase in plasma angiotensin II. Plasma drug levels also were measured. The degree of blockade observed in vivo was statistically significant < or = 96 h with all UR-7247 doses for diastolic BP (p < 0.05) and < or =48 h for systolic BP. The maximal inhibition achieved with 10 mg UR-7247 was measured 6-24 h after drug intake and reached 54 +/- 17% and 48 +/- 20% for diastolic and systolic responses, respectively. Losartan, 100 mg, induced a greater short-term AT1-receptor blockade than 2.5- and 5.0-mg doses of UR-7247 (p < 0.001 for diastolic BP), but the UR-7247 effect was longer lasting. In vivo, no significant difference was observed between 10 mg UR-7247 and 100 mg losartan 4 h after drug intake, but in vitro, the blockade achieved with 100 mg losartan was higher than that seen with UR-7247. Finally, the results confirm that UR-7247 has a very long plasma elimination half-life, which may be due to a high but also tight binding to protein binding sites. In conclusion, UR-7247 is a long-lasting, well-tolerated AT1 receptor in healthy subjects.

Role of lipase in the regulation of upper gastrointestinal function in humans.

The role of lipase in the regulation of upper gastrointestinal function is poorly understood. We studied the effect of orlistat, a new, potent, and highly specific lipase inhibitor, on gastric emptying, cholecystokinin (CCK) release, and pancreaticobiliary secretion. Three groups of studies were performed in nine healthy volunteers, using the double-indicator technique with a triple-lumen duodenal tube, polyethylene glycol 4000 as a duodenal perfusion marker, and 99mTc-diethylenetriamine pentaacetic acid as a meal marker. Gastric emptying, pancreaticobiliary output, and postprandial plasma CCK levels were measured after ingestion of the following isocaloric 500-ml liquid meals with or without 200 mg orlistat: 1) a pure fat meal (10% Intralipid), 2) a meal containing free fatty acids, or 3) an albumin-glucose meal. All experiments were performed in a randomized, placebo-controlled, crossover design. Orlistat markedly inhibited lipase activity in all three experiments. Orlistat given with the fat meal reduced CCK release and output of lipase, trypsin, and bilirubin and accelerated the rate of gastric emptying (P < 0.05). After ingestion of the free fatty acid or albumin-glucose meal, orlistat had no significant effect on any of these parameters. We conclude that lipase plays an important, nutrient-specific role in the regulation of gastric emptying and pancreaticobiliary secretion after ingestion of fatty meals in humans.

Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial.

In the 2005-01 trial, we have demonstrated that bortezomib-dexamethasone as induction therapy before autologous stem cell transplantation was superior to vincristine-adriamycin-dexamethasone. We conducted a post-hoc analysis to assess the prognostic impact of initial characteristics as well as response to therapy in patients enrolled in this study. Multivariate analysis showed that ISS stages 2 and 3 and achievement of response less than very good partial response (VGPR) both after induction therapy and after autologous stem cell transplantation were adverse prognostic factors for progression-free survival, the most important one being achievement of response less than VGPR after induction. Progression-free survival was significantly improved with bortezomib-dexamethasone induction therapy in patients with poor-risk cytogenetics and ISS stages 2 and 3 compared with vincristine-adriamycin-dexamethasone. In these 2 groups of patients, achievement of at least VGPR after induction was of major importance. This study is registered with EudraCT (https://eudract.ema.europa.eu; EUDRACT 2005-000537-38) and http://clinicaltrials.gov (NCT00200681).