Characteristics of the 100 largest modern zoonotic disease outbreaks.

Zoonotic disease outbreaks are an important threat to human health and numerous drivers have been recognized as contributing to their increasing frequency. Identifying and quantifying relationships between drivers of zoonotic disease outbreaks and outbreak severity is critical to developing targeted zoonotic disease surveillance and outbreak prevention strategies. However, quantitative studies of outbreak drivers on a global scale are lacking. Attributes of countries such as press freedom, surveillance capabilities and latitude also bias global outbreak data. To illustrate these issues, we review the characteristics of the 100 largest outbreaks in a global dataset (n = 4463 bacterial and viral zoonotic outbreaks), and compare them with 200 randomly chosen background controls. Large outbreaks tended to have more drivers than background outbreaks and were related to large-scale environmental and demographic factors such as changes in vector abundance, human population density, unusual weather conditions and water contamination. Pathogens of large outbreaks were more likely to be viral and vector-borne than background outbreaks. Overall, our case study shows that the characteristics of large zoonotic outbreaks with thousands to millions of cases differ consistently from those of more typical outbreaks. We also discuss the limitations of our work, hoping to pave the way for more comprehensive future studies. This article is part of the theme issue 'Infectious disease macroecology: parasite diversity and dynamics across the globe'.

[Medical devices used in digestive system surgical procedures: What's the cost?] / Dépenses en dispositifs médicaux stériles dans certains actes de chirurgie hépatobiliaire et digestive : que resterait-il du Groupe Homogène de Séjour ?

OBJECTIVE: Medical devices innovations and associated procedures represent a large part of health facilities budget. The aim of this work was to evaluate the cost of medical devices used during different surgical procedures. This cost was compare with the revenue collected from hospital stay pricing. METHOD: A prospective analysis of the medical devices used in operating room was carried out for different types of programmed surgeries. For five weeks, references of sterile single-use medical devices used during the interventions were collected. RESULTS: Expenditure on medical devices used during surgical procedures represented 5.7 % of the hospitalization value for an inguinal hernia repair, 12 % for a cholecystectomy, 9.35 % for a colectomy, 14.5 % for a hepatectomy and 7 % for pancreatectomy, any severity index combined. The most important correlations existed between act duration and patient's level of severity and between operating times and consumables expenditure. CONCLUSION: Cost optimization opportunities are equivalence of some medical devices ranges, purchases with national groupings and potential decreases in operating times related to the use of innovative medical devices.

[Transcorneal electrical stimulation in primary open angle glaucoma]. / Transkorneale Elektrostimulation bei primärem Offenwinkelglaukom.

Recently, reports have been published on the effectiveness of electrical stimulation in patients and experimental animal models with neurodegenerative ocular diseases. Our study included 14 patients with primary open angle glaucoma (POAG), who were randomized into one of three groups with 0% (sham, n = 5), 66% (n = 5) or 150% (n = 4) of their individual electrical phosphene thresholds. Patients were treated with transcorneal electrical stimulation (TES) for 30 min once a week for 6 consecutive weeks. Outcome measures of our study were the detection of possible adverse events and efficacy of TES using DTL electrodes in subjective and objective parameters of visual function under treatment. TES was tolerated well and no serious adverse events were registered relating to the treatment. One single adverse event was registered as appearance of an optic disc hemorrhage of a sham-stimulated eye. In summary, one significant increase of intra-ocular pressure in the 66% group was observed in comparison to the sham group (p = 0.04), without significant differences compared to the 150% group (both sham vs. 150% group and 66% vs. 150% group). This difference (mean difference compared to baseline of -2.33 mm Hg for the sham group and +0.97 mm Hg for the 66% group; REML) was not clinical meaningful. All other findings, including results of the visual field, were not statistically significant different between groups. It was shown that TES using DTL electrodes did not trigger adverse or serious adverse events in the stimulated groups in patients with POAG. Patients with POAG should currently receive TES only under study conditions.

Transfer characteristics of subretinal visual implants: corneally recorded implant responses.

PURPOSE: The subretinal Alpha IMS visual implant is a CE-approved medical device for restoration of visual functions in blind patients with end-stage outer retina degeneration. We present a method to test the function of the implant objectively in vivo using standard electroretinographic equipment and to assess the devices' parameter range for an optimal perception. METHODS: Subretinal implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) consists of 1500 photodiode-amplifier-electrode units and is implanted surgically into the subretinal space in blind retinitis pigmentosa patients. The voltages that regulate the amplifiers' sensitivity (V gl) and gain (V bias), related to the perception of contrast and brightness, respectively, are adjusted manually on a handheld power supply device. Corneally recorded implant responses (CRIR) to full-field illumination with long duration flashes in various implant settings for brightness gain (V bias) and amplifiers' sensitivity (V gl) are measured using electroretinographic setup with a Ganzfeld bowl in a protocol of increasing stimulus luminances up to 1000 cd/m2. RESULTS: CRIRs are a meaningful tool for assessing the transfer characteristic curves of the electronic implant in vivo monitoring the implants' voltage output as a function of log luminance in a sigmoidal shape. Changing the amplifiers' sensitivity (V gl) shifts the curve left or right along the log luminance axis. Adjustment of the gain (V bias) changes the maximal output. Contrast perception is only possible within the luminance range of the increasing slope of the function. CONCLUSIONS: The technical function of subretinal visual implants can be measured objectively using a standard electroretinographic setup. CRIRs help the patient to optimise the perception by adjusting the gain and luminance range of the device and are a useful tool for clinicians to objectively assess the function of subretinal visual implants in vivo.

In vivo biocompatibility of a new cyanine dye for ILM peeling.

PURPOSE: To investigate the biocompatibility of the new cyanine dye: 3,3'-Di-(4-sulfobutyl)-1,1,1',1'-tetramethyl-di-1H-benz[e]indocarbocyanine (DSS) as a vital dye for intraocular application in an in vivo rat model and to evaluate the effects of this dye on retinal structure and function. METHODS: DSS at a concentration of 0.5% was applied via intravitreal injections to adult Brown Norway rats with BSS serving as a control. Retinal toxicity was assessed 7 days later by means of retinal ganglion cell (RGC) counts, light microscopy, optical coherence tomography (OCT), and electroretinography (ERG). RESULTS: No significant decrease in RGC numbers was observed. No structural changes of the central retina were observed either in vivo (OCT) or under light microscopy. ERGs detected a temporary reduction of retinal function 7 days after injection; this was no longer evident 14 days after injection. CONCLUSIONS: DSS showed good biocompatibility in a well-established experimental in vivo setting and may be usable for intraocular surgery as an alternative to other cyanine dyes. In contrast to indocyanine green, it additionally offers fluorescence in the visual spectrum. Further studies with other animal models are needed before translation into clinical application.

[Effects of transcorneal electrical stimulation in patients with Stargardt's disease]. / Transkorneale Elektrostimulation bei Patienten mit Morbus Stargardt.

Stargardt's disease is an autosomal recessive inherited juvenile macular degeneration and at present no acknowledged science-based therapy is available for these patients. Recently, reports have been published on the effectiveness of electrical stimulation in experimental animal models and in patients with neurodegenerative ocular disease, particularly retinitis pigmentosa. This study included 12 patients with Stargardt's disease who were randomized into one of three groups (n = 4) with 0% (sham), 66% or 150% of the individual electrically stimulated phosphene threshold. Outcome measures of the study were safety and efficacy of transcorneal electrical stimulation (TES) with DTL electrodes in subjective and objective parameters of visual function under therapy. In general TES was well tolerated and no adverse or serious events were noted. Neither Ganzfeld, multifocal ERG, OCT nor visual field testing showed statistically significant changes in any group.

Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme®) therapy.

Characteristic cardiac valve abnormalities and left ventricular hypertrophy are present in untreated patients with mucopolysaccharidosis type VI (MPS VI). Cardiac ultrasound was performed to investigate these findings in subjects during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB, rhN-acetylgalactosamine 4-sulfatase, galsulfase, Naglazyme®). Studies were conducted in 54 subjects before ERT was begun and at specific intervals for up to 96 weeks of weekly infusions of rhASB at 1 mg/kg during phase 1/2, phase 2, and phase 3 trials of rhASB. At baseline, mitral and aortic valve obstruction was present and was significantly greater in those ≥12 years of age. Mild mitral and trace aortic regurgitation were present, the former being significantly greater in those <12 years. Left ventricular hypertrophy, with averaged z-scores ranging from 1.6-1.9 SD greater than normal, was present for ages both <12 and ≥12 years. After 96 weeks of ERT, ventricular septal hypertrophy regressed in those <12 years. For those ≥12 years, septal hypertrophy was unchanged, and aortic regurgitation increased statistically but not physiologically. Obstructive gradients across mitral and aortic valves remained unchanged. The results suggest that long-term ERT is effective in reducing intraventricular septal hypertrophy and preventing progression of cardiac valve abnormalities when administered to those <12 years of age.

A new DTL-electrode holder for recording of electroretinograms in animals.

PURPOSE: Contact lens electrodes (CLEs) are frequently used to register electroretinograms (ERGs) in small animals such as mice or rats. CLEs are expensive to buy or difficult to be produced individually. In addition, CLE's have been noticed to elicit inconstant results and they carry potential to injure the cornea. Therefore, a new electrode holder was constructed based on the clinically used DTL-electrode and compared to CLEs. MATERIAL AND METHODS: ERGs were recorded with both electrode types in nine healthy Brown-Norway rats under scotopic conditions. For low intensity responses a Naka-Rushton function was fitted and the parameters V(max), k and n were analyzed. The a-wave, b-wave and oscillatory potentials were analyzed for brighter flash intensities (1-60 scot cds/m²). Repeatability was assessed for both electrode types in consecutive measurements. RESULTS: The new electrode holder was faster in setting up than the CLE and showed lower standard deviations. No corneal alterations were observed. Slightly higher amplitudes were recorded in most of the measurements with the new electrode holder (except amplitudes induced by 60 cds/m²). A Bland-Altman test showed good agreement between the DTL holder and the CLE (mean difference 35.2 µV (Holder-CLE)). Pearson's correlation coefficient for test-retest-reliability was r=0.783. CONCLUSIONS: The DTL holder was superior in handling and caused far less corneal problems than the CLE and produced comparable or better electrophysiological results. The minimal production costs and the possibility of adapting the DTL holder to bigger eyes, such as for dogs or rabbits, offers with broader application prospects.

"Motor" impairment in Asperger syndrome: evidence for a deficit in proprioception.

Motor impairment has frequently been described in Asperger syndrome (AS), a pervasive developmental disorder included in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Previous research focusing on this motor dysfunction has yielded inconsistent results, and the "clumsiness" observed clinically remains poorly defined. To clarify further the issue of motor impairment, we compared a group of 10 children and young adults who met DSM-IV criteria for AS with a control group with no neurological impairment. Subjects were matched on age, sex, socioeconomic status, and Verbal IQ. A broad battery of motoric tests was administered. Subjects with AS were found to perform more poorly than controls on tests of apraxia, one-leg balance with eyes closed, tandem gait, and repetitive finger-thumb apposition. No significant differences were found on tests of finger tapping, grooved pegboard, trail making, or visual-motor integration. The pattern of impairments suggests that a proprioceptive deficit may underlie the incoordination observed in AS and that these individuals may be overreliant on visual input to maintain balance and position in space.

Sensitivity and specificity of a computerized test of attention in the diagnosis of Attention-Deficit/Hyperactivity Disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is difficult to diagnose due to the subjectivity of its symptoms and lack of specific assessment measures. Computerized tests of attention have recently been used as objective measures that may assist in the diagnosis of the disorder. The present study evaluated consistency between the Conners Parent Rating Scale and the Test of Variables of Attention (TOVA), which is a computerized test of attention designed to identify symptoms associated with ADHD, in children clinically diagnosed with ADHD (n = 28) and controls (n = 20). Our results showed that both the Conners and the TOVA indicated significant problem areas suggestive of an attention deficit in approximately 85% of children who were clinically diagnosed with ADHD. However, the TOVA also found attentional problems in approximately 30% of control children, whereas none of the controls scored abnormally on the Conners. As computerized measures are administered more frequently, there may be a risk of overdiagnosis and treatment of "ADHD" in normal children. A combined approach using questionnaires, clinical evaluation, and computerized tests of attention in the assessment of possible ADHD may provide the most accurate means of diagnosis.

A hierarchical analysis of block design errors in children with early focal brain damage.

This study investigated the differential effects of very early damage to the left hemisphere (LH) or right hemisphere (RH) on visuospatial processing. Twenty-two children who had suffered either LH or RH strokes in the pre- or perinatal period were included in the study. The Block Design subtest of the Wechsler Intelligence Scale for Children-Revised (Wechsler, 1974) was used. Each missed item was coded as either a global error (e.g., broken configuration), local error (e.g., incorrect details), or time fail error (i.e., not completed within the allotted time). Results showed that the LH lesion and RH lesion groups had similar full scale IQs, verbal IQs, and performance IQs and were within the average to low average range. Block Design scaled scores were also within the average to low average range and did not significantly differ between the 2 lesion groups. Error analysis revealed, however, that the RH focal lesion group produced a significantly higher percentage of global errors than did the LH lesion group, whereas the LH lesion group produced a significantly higher percentage of local errors than did the RH lesion group. The groups did not differ on their percentage of time fail errors. These results are consistent with previous findings that suggest that the RH is involved in more global aspects of visual processing, whereas the LH mediates the more detailed, local aspects of visual information. The fact that these differences in processing are present after such early focal damage implies that hemispheric specialization for visuospatial processing occurs very early in brain development.

Remodeling of the bifurcation asymmetry of right coronary ventricular branches in hypertrophy.

To document the remodeling of the asymmetric branching pattern of the coronary right ventricular branches (RVBs) in right ventricular hypertrophy (RVH), we computed an asymmetry ratio, S, for the diameters and lengths of all vessels, defined as the ratio of the daughter diameters and lengths, respectively. We have previously induced RVH in pigs by pulmonary stenosis for five weeks. At autopsy, silicone elastomer casts of the right coronary arteries were made and the morphometric data on the branching pattern and vascular geometry of the RVB were collected. Data on smaller vessels were obtained from histological specimens while data on larger vessels were obtained from vascular casts. The results show that the diameter asymmetry ratio was significantly decreased in RVH hearts. The asymmetry ratios of diameters and lengths were used to compute the asymmetry ratios for vascular resistance and flow of the various daughter vessels. It was found that the degree of asymmetry of the resistance and flow were decreased, which implies that the flow heterogeneity at a bifurcation is decreased in the RVH hearts.

Functional weightlessness during clinorotation of cell suspensions.

A clinostat is a device often used in gravitational biology studies. Selecting an appropriate speed of rotation, however, is a frequently debated topic, particularly for suspended cells. In an attempt to define the necessary criteria for determining an acceptable revolution speed, the primary forces governing particle behavior during clinorotation--gravity, diffusion and centrifugation--were mathematically assessed. In support of the theoretical exercise, bacterial growth experiments indicated that results obtained using a clinostat followed trends resembling previous space flight results. It is suspected that this is due, in part at least, to similarly altered external transport processes in each environment.

Effects of gravity on early development.

The development of embryonic and larval stages of the South African Toad Xenopus laevis D, was investigated in hyper-g up to 5 g (centrifuge), in simulated 0 g (fast-rotating clinostat), in alternating low g, hyper-g (parabolic flights) and in microgravity (Spacelab missions D1, D-2). The selected developmental stages are assumed to be very sensitive to environmental stimuli. The results showed that the developmental reaction processes run normal also in environments different to 1 g and that aberrations in behavior and morphology normalize after return to 1 g. Development, differentiation, and morphology of the gravity perceiving parts of the vestibular system (macula-organs) had not been affected by exposure to different g-levels.

Evaluation of bleomycin-induced chromosome aberrations under simulated microgravity conditions in human lymphocytes using "FISH" techniques.

In the present investigation we report the effects of simulated microgravity conditions (clinostat) on the induction of chromosomal aberrations in human lymphocytes in vitro by (R) Bleomycin. Chromosomal aberrations have been analysed by means of fluorescent in situ hybridisation (FISH) and chromosome-specific composite DNA probes (chromosome painting). The results obtained show that, under simulated microgravity conditions, the levels of both symmetrical and asymmetrical (dicentrics, rings), the number of cells bearing "complex" aberrations and hence the total numbers of aberrations were significantly elevated at any of the dose-levels assayed, compared to the parallel treatments performed as 1g control ("ground"). Furthermore, the ratio symmetrical:asymmetrical translocations was markedly elevated under simulated microgravity conditions, compared to the findings usually observed under "normal" 1g conditions. On these bases, we are much inclined to believe that simulated microgravity, rather than limiting the resealing of DNA double strand breaks (DSB's) induced by genotoxic agents is influencing in terms of enhancement the misrejoining of DSB's which is actually responsible for the fixation of the original lesions to DNA into chromosomal aberrations. In addition, the possible different misrepair processes leading to the formation of symmetrical and asymmetrical translocations might be differentially influenced by microgravity being the symmetrical translocations significantly more represented.

Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system.

Cannabinoid receptor (CB) expression was characterized in immunological cell and tissue preparations. Northern analysis revealed approximately 6-kb transcripts for CB1 (brain-type) in mouse spleen and brain and in rat cerebellum. CB1 was not detected in mouse thymus or rat spleen RNA by Northern analysis. CB2 (peripheral) was detected as a approximately 4-kb transcript in mouse spleen and thymus and as approximately 2.4-kb transcripts in rat spleen. Quantitation of CB2 transcripts in mouse spleen and thymus revealed approximately 4 x 10(3) and approximately 4 x 10(2) molecules/100 ng RNA, respectively, with no quantifiable CB2 in mouse brain. Conversely, CB1 was expressed in mouse brain (approximately 2 x 10(5) molecules/100 ng RNA) with lower expression in mouse spleen (approximately 2 x 10(2) molecules/100 ng RNA) and was not quantifiable in mouse thymus. Competition binding in intact mouse splenocytes demonstrated that nonradiolabeled cannabinoids CP-55940, Win-55212-2, CP-56667, delta 9-THC, and cannabinol all competed for receptor binding with 3H-CP-55940, a high-affinity nondiscriminating CB1 and CB2 receptor ligand. Based on previous findings which demonstrated a marked inhibition of T-cell-dependent immune responses by cannabinoids, primary T cells and several T-cell lines were characterized. Radioligand binding analysis identified 100-300 cannabinoid receptor binding sites/cell with an approximate Kd of 200-700 pM in purified splenic T cells which also exhibited cannabinoid-induced inhibition of adenylate cyclase. Northern analysis of human T-cell lines revealed approximately 2.4-kb CB2 mRNA transcripts but no CB1 in HPB-ALL cells, a cell line which also exhibited inhibition of adenylate cyclase by delta 9-THC. Conversely, Jurkat E6-1 cells expressed an unusual mRNA banding pattern for CB2 expressing three distinct transcript sizes, none of which were 2.4 kb, the size for human CB2. Jurkat also did not express CB1 mRNA and did not exhibit inhibition of adenylate cyclase when treated with delta 9-THC. Collectively, these results provide further evidence that CB2 is the predominant cannabinoid receptor within the immune system and that this form of the receptor is expressed on T cells.

Longitudinal position matrix of the pig coronary vasculature and its hemodynamic implications.

Hemodynamic analysis of coronary blood flow must be based on a statistically valid geometric model of the coronary vasculature. We have previously developed a diameter-defined Strahler model for the arterial and venous trees and a network model for the capillaries. A full set of data describing the geometric properties of the porcine coronary vasculature was given. The order number, diameter, length, connectivity matrix [m,n] (CM), and parallel-series features were measured for all orders of vessels of the right coronary artery (RCA), left anterior descending artery (LAD), left circumflex artery (LCX), and coronary venous system. The purpose of the present study is to present another feature of the branching pattern of the coronary vasculature: the longitudinal position matrix [m,n] (LPM), whose component in row m and column n is the fractional longitudinal position of the branch point on vessels of order n at which vessels of order m branch off (m < or = n). The LPM of the pig RCA, LAD and LCX arterial trees, as well as the coronary sinusal and thebesian venous trees, are presented. The hemodynamic implications of the LPM are illustrated by comparing two kinds of circuits: one, the CM + LPM model, simulates the mean data on the morphology (diameters, lengths, and numbers), CM, and LPM of vessels, whereas the other, the CM model, simulates the mean data on the morphology and CM without considering the LPM. We found that the LPM affects the hemodynamics of coronary blood flow especially with regard to the nonuniformity or dispersion of flow distribution.

Gravity dependency of the gramicidin A channel conductivity. A model for gravity perception on the cellular level.

Theoretical investigations involving the membrane-solution interface have revealed that the density of the solution varies appreciably within interfacial layers adjacent to charged membrane surfaces. The hypothesis that gravity interacts with this configuration and modifies transport rates across horizontal and vertical membranes differently was supported by initial experiments with gramicidin A channels in phosphatidylserine (PS) membranes in 0.1 M KCl. Channel conductivity was found to be about 1.6 times higher in horizontal membranes than in vertical membranes. Here we present the results of further experiments with gramicidin A channels (incorporated into charged PS- and uncharged phosphatidylcholine (PC) membranes in KCl- and CsCl-solutions) to demonstrate that the hypothesis is more generally applicable. Again, channel conductivity was found to be higher in horizontal PS membranes by a factor of between 1.20 and 1.75 in 0.1 M CsCl. No difference in channel conductivity was found for uncharged PC membranes in 0.1 M KCl and in 0.1 M CsCl. However, for PC membranes in 0.05 M KCl the channel conductivity was significantly higher in horizontal membranes by a factor of between 1.07 and 1.14. These results are consistent with the results of our model calculations of layer density and extension, which showed that the layer formation is enhanced by increasing membrane surface charge and decreasing electrolyte ion concentration. The mechanism of gravity interaction with membrane transport processes via interface reactions might be utilized by biological systems for orientational behaviour in the gravity field, which has been observed even for cellular systems.

Early development in aquatic vertebrates in near weightlessness during the D-2 Mission STATEX project.

Aboard the German-Spacelab-Mission D-2 the project "Gravity Perception and Neuronal Plasticity (STATEX II)" was performed. STATEX is for STATolith EXperiment. Objects were growing tadpoles of the South African Toad (Xenopus laevis D.) and a juvenile cichlid fish (Oreochromis mossambicus). The results give a broader base for the understanding of how environmental stimuli (e.g. linear accelerations) affect the development and function of the gravity perceiving systems in these two vertebrates. These systems are accepted as models for the human vestibulum. Results of experiments in hyper-g (up to 5 g), simulated weightlessness (Fast-rotating-clinostat) and parabolic flights are compared and discussed.

Molecular mechanisms of toxicant-induced immunosuppression: role of second messengers.

Changes in immunocompetence following chemical exposure have been established for a wide variety of unrelated agents. For the vast majority of immunotoxic compounds thus far identified, disruption of normal immune function is clearly mediated through direct interactions between the agent, or its metabolite, and immunocompetent cells. Regardless of whether this interaction occurs at the level of the cell membrane or at intracellular sites, basic regulatory processes mediated by second messengers are often altered. These alterations can ultimately result in immunologic dysfunction, which is most often manifested as immunosuppression. The specific disruptions in intracellular signaling produced by a number of immunotoxic compounds have now been identified, leading to a basic understanding of their molecular mechanism of action. Equally important, through the application of these agents as biological probes, new insights have been gained pertaining to which intracellular processes control which cellular functions within various populations of immunocompetent cells.