Individualized Therapy with Ranibizumab in Wet Age-Related Macular Degeneration.

Individualized treatment regimens may reduce patient burden with satisfactory patient outcomes in neovascular age-related macular degeneration. Intravitreal anti-VEGF drugs are the current gold standard. Fixed monthly injections offer the best visual outcome but this regimen is not commonly followed outside clinical trials. A PRN regimen requires monthly visits where the patient is treated in the presence of signs of lesion activity. Therefore, an early detection of reactivation of the disease with immediate retreatment is crucial to prevent visual acuity loss. Several trials suggest that "treat and extend" and other proactive regimens provide a reasonable approach. The rationale of the proactive regimens is to perform treatment anticipating relapses or recurrences and therefore avoid drops in vision while individualizing patient followup. Treat and extend study results in significant direct medical cost savings from fewer treatments and office visits compared to monthly treatment. Current data suggest that, for one year, PRN is less expensive, but treat and extend regimen would likely be less expensive for subsequent years. Once a patient is not a candidate to continue with treatment, he/she should be sent to an outpatient unit with adequate resources to follow nAMD patients in order to reduce the burden of specialized ophthalmologist services.

Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review.

BACKGROUND: Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. OBJECTIVE: To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. MATERIAL AND METHODS: The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. RESULTS: Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. CONCLUSION: Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.

Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles.

OBJECTIVES We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. METHODS HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. RESULTS A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (p M-H = 3 × 10(-7); odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40-23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (p M-H = 6 × 10(-4); ORM-H = 0.2, 95% CI = 0.08-0.50), with a PPV of 81%. CONCLUSIONS HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration.

Disentangling the attention network test: behavioral, event related potentials, and neural source analyses.

BACKGROUND The study of the attentional system remains a challenge for current neuroscience. The "Attention Network Test" (ANT) was designed to study simultaneously three different attentional networks (alerting, orienting, and executive) based in subtraction of different experimental conditions. However, some studies recommend caution with these calculations due to the interactions between the attentional networks. In particular, it is highly relevant that several interpretations about attentional impairment have arisen from these calculations in diverse pathologies. Event related potentials (ERPs) and neural source analysis can be applied to disentangle the relationships between these attentional networks not specifically shown by behavioral measures. RESULTS This study shows that there is a basic level of alerting (tonic alerting) in the no cue (NC) condition, represented by a slow negative trend in the ERP trace prior to the onset of the target stimuli. A progressive increase in the CNV amplitude related to the amount of information provided by the cue conditions is also shown. Neural source analysis reveals specific modulations of the CNV related to a task-related expectancy presented in the NC condition; a late modulation triggered by the central cue (CC) condition and probably representing a generic motor preparation; and an early and late modulation for spatial cue (SC) condition suggesting specific motor and sensory preactivation. Finally, the first component in the information processing of the target stimuli modulated by the interaction between orienting network and the executive system can be represented by N1. CONCLUSIONS The ANT is useful as a paradigm to study specific attentional mechanisms and their interactions. However, calculation of network effects is based in subtractions with non-comparable experimental conditions, as evidenced by the present data, which can induce misinterpretations in the study of the attentional capacity in human subjects.

Sharing competences in strategic alliances: a case study of the Cosan and Shell biofuel venture

In a competitive world, the way a firm establishes its organizational arrangements may determine the enhancement of its core competences and the possibility of reaching new markets. Firms that find their skills to be applicable in just one type of market encounter constraints in expanding their markets, and through alliances may find a competitive form of value capture. Hybrid forms of organization appear primarily as an alternative to capturing value and managing joint assets when the market and hierarchy modes do not present any yields for the firm's competitiveness. As a result, this form may present other challenging issues, such as the allocation of rights and principal-agent problems. The biofuel market has presented a strong pattern of changes over the last 10 years. New intra-firm arrangements have appeared as a path to participate or survive among global competition. Given the need for capital to achieve better results, there has been a consistent movement of mergers and acquisitions in the Biofuel sector, especially since the 2008 financial crisis. In 2011 there were five major groups in Brazil with a grinding capacity of more than 15 million tons per year: Raízen (joint venture formed by Cosan and Shell), Louis Dreyfus, Tereos Petrobras, ETH, and Bunge. Major oil companies have implemented the strategy of diversification as a hedge against the rising cost of oil. Using the alliance of Cosan and Shell in the Brazilian biofuel market as a case study, this paper analyses the governance mode and challenging issues raised by strategic alliances when firms aim to reach new markets through the sharing of core competences with local firms. The article is based on documentary research and interviews with Cosan's Investor Relations staff, and examines the main questions involving hybrid forms through the lens of the Transaction Cost Economics (TCE), Agency Theory, Resource Based View (RBV), and dynamic capabilities theoretical approaches. One focal point is knowledge "appropriability" and the specific assets originated by the joint venture. Once the alliance is formed, it is expected that competences will be shared and new capabilities will expand the limits of the firm. In the case studied, Cosan and Shell shared a number of strategic assets related to their competences. Raízen was formed with economizing incentives, as well to continue marshalling internal resources to enhance the company's presence in the world energy sector. Therefore, some challenges might be related to the control and monitoring agents' behavior, considering the two-part organism formed by distinctive organizational culture, tacit knowledge, and long-term incentives. The case study analyzed illustrates the hybrid arrangement as a middle form for organizing the transaction: neither in the market nor in the hierarchy mode, but rather a more flexible commitment agreement with a strategic central authority. The corporate governance devices are also a challenge, since the alignment between the parent companies in the joint ventures is far more complex. These characteristics have led to an organism with bilateral dependence, offering favorable conditions for developing dynamic capabilities. However, these conditions might rely on the partners' long-term interest in the joint venture.

Acute Effects of Cannabis Smoking on Skills Related to Driving : an fMRI Study

Introduction : Driving is a complex everyday task requiring mechanisms of perception, attention, learning, memory, decision making and action control, thus indicating that involves numerous and varied brain networks. If many data have been accumulated over time about the effects of alcohol consumption on driving capability, much less is known about the role of other psychoactive substances, such as cannabis (Chang et al.2007, Ramaekers et al, 2006). Indeed, the solicited brain areas during safe driving which could be affected by cannabis exposure have not yet been clearly identified. Our aim is to study these brain regions during a tracking task related to driving skills and to evaluate the modulation due to the tolerance of cannabis effects. Methods : Eight non-smoker control subjects participated to an fMRI experiment based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. Half of the active tracking conditions included randomly presented traffic lights as distractors. Subjects were asked to track with a joystick with their right hand and to press a button with their left index at each appearance of a distractor. Four smoking subjects participated to the same fMRI sessions once before and once after smoking cannabis and a placebo in two independent cross-over experiments. We quantified the performance of the subjects by measuring the precision of the behavioural responses (i.e. percentage of time of correct tracking and reaction times to distractors). Functional MRI data were acquired using on a 3.0T Siemens Trio system equipped with a 32-channel head coil. BOLD signals will be obtained with a gradient-echo EPI sequence (TR=2s, TE=30ms, FoV=216mm, FA=90°, matrix size 72×72, 32 slices, thickness 3mm). Preprocessing, single subject analysis and group statistics were conducted on SPM8b. Results were thresholded at p<0.05 (FWE corrected) and at k>30 for spatial extent. Results : Behavioural results showed a significant impairment in task and cognitive test performance of the subjects after cannabis inhalation when comparing their tracking accuracy either to the controls subjects or to their performances before the inhalation or after the placebo inhalation (p<0.001 corrected). In controls, fMRI BOLD analysis of the active tracking condition compared to the passive one revealed networks of polymodal areas in superior frontal and parietal cortex dealing with attention and visuo-spatial coordination. In accordance to what is known of the visual and sensory motor networks we found activations in V4, frontal eye-field, right middle frontal gyrus, intra-parietal sulcus, temporo-parietal junction, premotor and sensory-motor cortex. The presence of distractors added a significant activation in the precuneus. Preliminary results on cannabis smokers in the acute phase, compared either to themselves before the cannabis inhalation or to control subjects, showed a decreased activation in large portions of the frontal and parietal attention network during the simple tracking task, but greater involvement of precuneus, of the superior part of intraparietal sulcus and middle frontal gyrus bilaterally when distractors were present in the task. Conclusions : Our preliminary results suggest that acute cannabis smoking alters performances and brain activity during active tracking tasks, partly reorganizing the recruitment of brain areas of the attention network.

On concentrators and related approximation constants

Pippenger [Pi77] showed the existence of (6m,4m,3m,6)-concentrator for each positive integer m using a probabilistic method. We generalize his approach and prove existence of (6m,4m,3m,5.05)-concentrator (which is no longer regular, but has fewer edges). We apply this result to improve the constant of approximation of almost additive set functions by additive set functions from 44.5 (established by Kalton and Roberts in [KaRo83] to 39. We show a more direct connection of the latter problem to the Whitney type estimate for approximation of continuous functions on a cube in &b&R&/b&&sup&d&/sup& by linear functions, and improve the estimate of this Whitney constant from 802 (proved by Brudnyi and Kalton in [BrKa00] to 73.

A Lower Olfactory Capacity Is Related to Higher Circulating Concentrations of Endocannabinoid 2-Arachidonoylglycerol and Higher Body Mass Index in Women.

The endocannabinoid (eCB) system can promote food intake by increasing odor detection in mice. The eCB system is over-active in human obesity. Our aim is to measure circulating eCB concentrations and olfactory capacity in a human sample that includes people with obesity and explore the possible interaction between olfaction, obesity and the eCB system. The study sample was made up of 161 females with five groups of body mass index sub-categories ranging from under-weight to morbidly obese. We assessed olfactory capacity with the "Sniffin´Sticks" test, which measures olfactory threshold-discrimination-identification (TDI) capacity. We measured plasma concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine or anandamide (AEA), and several eCB-related compounds, 2-acylglycerols and N-acylethanolamines. 2-AG and other 2-acylglycerols fasting plasma circulating plasma concentrations were higher in obese and morbidly obese subjects. AEA and other N-acylethanolamine circulating concentrations were lower in under-weight subjects. Olfactory TDI scores were lower in obese and morbidly obese subjects. Lower TDI scores were independently associated with higher 2-AG fasting plasma circulating concentrations, higher %body fat, and higher body mass index, after controlling for age, smoking, menstruation, and use of contraceptives. Our results show that obese subjects have a lower olfactory capacity than non-obese ones and that elevated fasting plasma circulating 2-AG concentrations in obesity are linked to a lower olfactory capacity. In agreement with previous studies we show that eCBs AEA and 2-AG, and their respective congeners have a distinct profile in relation to body mass index. The present report is the first study in humans in which olfactory capacity and circulating eCB concentrations have been measured in the same subjects.

Health-related quality of life assessment in people with multiple sclerosis and their family caregivers. A multicenter study in Catalonia (Southern Europe)

Objectives: To measure the health-related quality of life (HRQoL) of multiple sclerosis (MS) patients and their caregivers, and to assess which factors can best describe HRQoL. Methods: A cross-sectional multicenter study of nine hospitals enrolled MS patients and their caregivers who attended outpatient clinics consecutively. The instruments used were the SF-36 for patients and the SF-12 and GHQ-12 for caregivers. Classification and regression tree analysis was used to analyze the explanatory factors of HRQoL. Results: A total of 705 patients (mean age 40.4 years, median Expanded Disability Status Scale 2.5, 77.8% with relapsing-remitting MS) and 551 caregivers (mean age 45.4 years) participated in the study. MS patients had significantly lower HRQoL than in the general population (physical SF-36: 39.9; 95% confidence interval [CI]: 39.1–40.6; mental SF-36: 44.4; 95% CI: 43.5–45.3). Caregivers also presented lower HRQoL than general population, especially in its mental domain (mental SF-12: 46.4; 95% CI: 45.5–47.3). Moreover, according to GHQ-12, 27% of caregivers presented probable psychological distress. Disability and co-morbidity in patients, and co-morbidity and employment status in caregivers, were the most important explanatory factors of their HRQoL. Conclusions: Not only the HRQoL of patients with MS, but also that of their caregivers, is indeed notably affected. Caregivers’ HRQoL is close to population of chronic illness even that the patients sample has a mild clinical severity and that caregiving role is a usual task in the study context

Small vascular and Alzheimer disease-related pathologic determinants of dementia in the oldest-old.

The relative contributions of Alzheimer disease (AD) and vascular lesion burden to the occurrence of cognitive decline are more difficult to define in the oldest-old than they are in younger cohorts. To address this issue, we examined 93 prospectively documented autopsy cases from 90 to 103 years with various degrees of AD lesions, lacunes, and microvascular pathology. Cognitive assessment was performed prospectively using the Clinical Dementia Rating scale. Neuropathologic evaluation included the Braak neurofibrillary tangle (NFT) and β-amyloid (Aβ) protein deposition staging and bilateral semiquantitative assessment of vascular lesions. Statistics included regression models and receiver operating characteristic analyses. Braak NFTs, Aβ deposition, and cortical microinfarcts (CMIs) predicted 30% of Clinical Dementia Rating variability and 49% of the presence of dementia. Braak NFT and CMI thresholds yielded 0.82 sensitivity, 0.91 specificity, and 0.84 correct classification rates for dementia. Using these threshold values, we could distinguish 3 groups of demented cases and propose criteria for neuropathologic definition of mixed dementia, pure vascular dementia, and AD in very old age. Braak NFT staging and severity of CMI allow for defining most of demented cases in the oldest-old. Most importantly, single cutoff scores for these variables that could be used in the future to formulate neuropathologic criteria for mixed dementia in this age group were identified.

Splenic hypereosinophilia in anaphylaxis-related death: different assessments depending on different types of allergens?

The aim of this study was to evaluate splenic eosinophil and mast cell accumulation using pagoda red stain in a series of anaphylaxis-related deaths that underwent medico-legal investigations. Our goal was to assess whether fatal reactions to insect stings, intramuscularly administered antibiotics and intravenously injected contrast media are responsible for specific patterns of eosinophil and mast cell accumulation. Two study groups were prospectively formed, an anaphylaxis-related death group and a control group. Autopsy, histology (haematoxylin-eosin stain, pagoda red stain and immunohistochemistry using anti-tryptase antibodies), toxicology and postmortem biochemistry (beta-tryptase, total IgE and specific IgE) were performed in all cases. All tested parameters (spleen weight, beta-tryptase and total IgE levels as well as eosinophil, mast cell and degranulated mast cell numbers in the spleen) were significantly higher in the anaphylaxis-related death group. No statistically significant differences were observed among the various groups (intramuscular antibiotic injection, intravenous contrast medium administration and stinging insects) in any combination, suggesting that mast cell and eosinophil accumulation in the spleen during anaphylaxis does not have any specific pattern related to the triggering allergen. Despite a lower sensitivity than immunohistochemical staining in discriminating eosinophil and mast cells, pagoda red stain allowed these cells to be identified and could therefore be proposed as a low-cost, first-line diagnostic procedure in those situations where immunohistochemistry is not systematically performed or cannot be carried out.

Comparison of early cortical networks in efficient and inefficient visual search: an event-related potential study.

Functional magnetic resonance imaging studies have indicated that efficient feature search (FS) and inefficient conjunction search (CS) activate partially distinct frontoparietal cortical networks. However, it remains a matter of debate whether the differences in these networks reflect differences in the early processing during FS and CS. In addition, the relationship between the differences in the networks and spatial shifts of attention also remains unknown. We examined these issues by applying a spatio-temporal analysis method to high-resolution visual event-related potentials (ERPs) and investigated how spatio-temporal activation patterns differ for FS and CS tasks. Within the first 450 msec after stimulus onset, scalp potential distributions (ERP maps) revealed 7 different electric field configurations for each search task. Configuration changes occurred simultaneously in the two tasks, suggesting that contributing processes were not significantly delayed in one task compared to the other. Despite this high spatial and temporal correlation, two ERP maps (120-190 and 250-300 msec) differed between the FS and CS. Lateralized distributions were observed only in the ERP map at 250-300 msec for the FS. This distribution corresponds to that previously described as the N2pc component (a negativity in the time range of the N2 complex over posterior electrodes of the hemisphere contralateral to the target hemifield), which has been associated with the focusing of attention onto potential target items in the search display. Thus, our results indicate that the cortical networks involved in feature and conjunction searching partially differ as early as 120 msec after stimulus onset and that the differences between the networks employed during the early stages of FS and CS are not necessarily caused by spatial attention shifts.