A prevalent mutation with founder effect in Spanish Recessive Dystrophic Epidermolysis Bullosa families

<p>Abstract</p> <p>Background</p> <p>Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis caused by more than 500 different mutations in the <it>COL7A1 </it>gene and characterized by blistering of the skin following a minimal friction or mechanical trauma.</p> <p>The identification of a cluster of RDEB pedigrees carrying the c.6527insC mutation in a specific area raises the question of the origin of this mutation from a common ancestor or as a result of a hotspot mutation. The aim of this study was to investigate the origin of the c.6527insC mutation.</p> <p>Methods</p> <p>Haplotypes were constructed by genotyping nine single nucleotides polymorphisms (SNPs) throughout the <it>COL7A1 </it>gene. Haplotypes were determined in RDEB patients and control samples, both of Spanish origin.</p> <p>Results</p> <p>Sixteen different haplotypes were identified in our study. A single haplotype cosegregated with the c.6527insC mutation.</p> <p>Conclusion</p> <p>Haplotype analysis showed that all alleles carrying the c.6527insC mutation shared the same haplotype cosegregating with this mutation (<b><it>CCGCTCAAA_6527insC</it></b>), thus suggesting the presence of a common ancestor.</p

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

A Simulation Study of an Inverse Controller for Closed and Semiclosed-Loop Control in Type 1 Diabetes

Background: Closed-loop control algorithms in diabetes aim to calculate the optimum insulin delivery to maintain the patient in a normoglycemic state, taking the blood glucose level as the algorithm's main input. The major difficulties facing these algorithms when applied subcutaneously are insulin absorption time and delays in measurement of subcutaneous glucose with respect to the blood concentration. Methods: This article presents an inverse controller (IC) obtained by inversion of an existing mathematical model and validated with synthetic patients simulated with a different model and is compared with a proportional-integral-derivative controller. Results: Simulated results are presented for a mean patient and for a population of six simulated patients. The IC performance is analyzed for both full closed-loop and semiclosed-loop control. The IC is tested when initialized with the heuristic optimal gain, and it is compared with the performance when the initial gain is deviated from the optimal one (±10%). Conclusions: The simulation results show the viability of using an IC for closed-loop diabetes control. The IC is able to achieve normoglycemia over long periods of time when the optimal gain is used (63% for the full closed-loop control, and it is increased to 96% for the semiclosed-loop control

The functional response of a generalist predator

Peer reviewedPublisher PD

Biotrickling filtration of isopropanol under intermittent loading conditions

This paper investigates the removal of isopropanol by gas phase biotrickling filtration. Two plastic packing materials, one structured and one random, have been evaluated in terms of oxygen mass transfer and isopropanol removal efficiency (RE). Oxygen mass transfer experiments were performed at gas velocities of 104 and 312 m h-1 and liquid velocities between 3 and 33 m h-1. Both materials showed similar mass transfer coefficients up to liquid velocities of 15 m h-1. At greater liquid velocities, the structured packing exhibited greater oxygen mass transfer coefficients. Biotrickling filtration experiments were carried out at inlet loads (IL) from 20 to 65 g C m-3 h -1 and empty bed residence times (EBRT) from 15 14 to 160 s. To simulate typical industrial emissions, intermittent isopropanol loading (16 h/day, 5 16 day/week) and intermittent spraying frequency (15 min/1.5 hours) were applied. Maximum elimination capacity (EC) of 51 g C m-3 h -1 has been obtained for the random packing (IL of 65 g C m-3 h -1 17 , EBRT of 18 50 s). The decrease in irrigation frequency to 15 min every 3 hours caused a decrease in the outlet emissions from 86 to 59 mg C Nm-3 (inlet of 500 mg C Nm-3). The expansion of spraying to night and weekend periods promoted the degradation of the isopropanol accumulated in the water tank during the day, reaching effluent concentrations as low as 44 mg C Nm-3. After a 7 week starvation period, theperformance was recovered in less than 10 days, proving the robustness of the proces

A Fuzzy Inference System for Closed-Loop Deep Brain Stimulation in Parkinson’s Disease

Parkinsons disease is a complex neurodegenerative disorder for which patients present many symptoms, tremor being the main one. In advanced stages of the disease, Deep Brain Stimulation is a generalized therapy which can significantly improve the motor symptoms. However despite its beneficial effects on treating the symptomatology, the technique can be improved. One of its main limitations is that the parameters are fixed, and the stimulation is provided uninterruptedly, not taking into account any fluctuation in the patients state. A closed-loop system which provides stimulation by demand would adjust the stimulation to the variations in the state of the patient, stimulating only when it is necessary. It would not only perform a more intelligent stimulation, capable of adapting to the changes in real time, but also extending the devices battery life, thereby avoiding surgical interventions. In this work we design a tool that learns to recognize the principal symptom of Parkinsons disease and particularly the tremor. The goal of the designed system is to detect the moments the patient is suffering from a tremor episode and consequently to decide whether stimulation is needed or not. For that, local field potentials were recorded in the subthalamic nucleus of ten Parkinsonian patients, who were diagnosed with tremor-dominant Parkinsons disease and who underwent surgery for the implantation of a neurostimulator. Electromyographic activity in the forearm was simultaneously recorded, and the relation between both signals was evaluated using two different synchronization measures. The results of evaluating the synchronization indexes on each moment represent the inputs to the designed system. Finally, a fuzzy inference system was applied with the goal of identifying tremor episodes. Results are favourable, reaching accuracies of higher 98.7 % in 70 % of the patients.Centro de Investigación Biomédica en RedDepto. de Psicología Experimental, Procesos Cognitivos y LogopediaDepto. de Radiología, Rehabilitación y FisioterapiaFac. de PsicologíaFac. de MedicinaTRUEpu

The uptake and effect of a mailed multi-modal colon cancer screening intervention: A pilot controlled trial

Abstract Background We sought to determine whether a multi-modal intervention, which included mailing a patient reminder with a colon cancer decision aid to patients and system changes allowing direct access to scheduling screening tests through standing orders, would be an effective and efficient means of promoting colon cancer screening in primary care practice. Methods We conducted a controlled trial comparing the proportion of intervention patients who received colon cancer screening with wait list controls at one practice site. The intervention was a mailed package that included a letter from their primary care physician, a colon cancer screening decision aid, and instructions for obtaining each screening test without an office visit so that patients could access screening tests directly. Major outcomes were screening test completion and cost per additional patient screened. Results In the intervention group, 15% (20/137) were screened versus 4% (4/100) in the control group (difference 11%; (95%; CI 3%;18% p = 0.01). The cost per additional patient screened was estimated to be $94. Conclusion A multi-modal intervention, which included mailing a patient reminder with a colon cancer decision aid to patients and system changes allowing patients direct access to schedule screening tests, increased colon cancer screening test completion in a subset of patients within a single academic practice. Although the uptake of the decision aid was low, the cost was also modest, suggesting that this method could be a viable approach to colon cancer screening

Validity of the Walter Reed Visual Assessment Scale to measure subjective perception of spine deformity in patients with idiopathic scoliosis

BACKGROUND: The Walter Reed Visual Assessment Scale (WRVAS) was designed to allow idiopathic scoliosis patients to describe their perception of their deformity. In a previous stduy, the scale has shown good correlation with magnitude of the curve METHODS: The study included 70 patients (60 women and 10 men), mean age 19.4 years (range 12–40), with idiopathic scoliosis. Each patient filled out the WRVAS and the SRS-22 questionnaire. Thoracic and lumbar curve angles were determined in standing X-rays and the largest was named Cobbmax. WRVAS internal consistency was assessed with Cronbach's alpha. Correlation coefficients were calculated between Cobbmax and the various WRVAS questions, and Cobbmax and the SRS-22 scales. The correlation between the WRVAS and SRS-22 was also determined RESULTS: Mean magnitudes were thoracic curve, 36.6° and lumbar curve, 33.2°; average Cobbmax was 37.9°. The mean total WRVAS score was 15.6. Mean scores for the various SRS-22 scales were function 4.6, pain 4.3, self-image 3.7, mental health 4.2, and total score 84.1. Internal consistency for the WRVAS was excellent (Cronbach's alpha, 0.9), and there were no signs of collinearity among the seven questions (tolerance range 0.2–0.5). All the items on the WRVAS correlated significantly with Cobbmax (correlation coefficients, 0.4 to 0.7). The correlation between the total WRVAS and total SRS-22 score was -0.54 (P = .0001) and between WRVAS total score and SRS-22 image domain score was -0.57 (p = 0.0001) CONCLUSION: The WRVAS showed excellent internal consistency and absence of collinearity. There was a highly significant correlation between the results of the test and the magnitude of the deformity. The WRVAS correlated significantly with the SRS-22 image scale. The WRVAS is a valid instrument to assess scoliosis patients perception of their deformit

Vitamin D nutritional status and vitamin D regulated antimicrobial peptides in serum and pleural fluid of patients with infectious and noninfectious pleural effusions

Background: Vitamin D and vitamin D dependent antimicrobial peptides such as Cathelicidin (LL-37) and ?-defensin 2 have an important role in innate and adaptative immunity, but their role in pleural effusions has not been studied before. Methods: Serum and pleural fluid samples from 152 patients with pleural effusion were collected, corresponding to 45 transudates and 107 exudates, 51 infectious effusions (14 complicated and 37 non-complicated), 44 congestive heart failure effusions and 38 malignant effusions. The levels of 25 OH-vitamin D, 1,25-(OH)2-vitamin D, Vitamin D Binding Protein (VDBP), LL-37 and ?-defensin 2, both in serum and pleural fluid were evaluated in this prospective study. Differences between groups were analysed using unpaired t tests or Mann?Whitney tests. Correlations between data sets were examined using Pearson correlation coefficient or Spearman rank correlation coefficient. Diagnostic accuracy was estimated using ROC curve analysis. Results: Low serum 25 OH vitamin D levels were found in all groups. Infectious effusions (IE) had higher serum and pleural fluid LL-37 levels compared to congestive heart failure or malignant effusions. Among IE, complicated had higher serum and pleural fluid LL-37 levels, and lower serum ?-defensin-2 levels. Positive correlations were found between serum 25 OH-vitamin D levels and serum or pleural 1,25-(OH)2-vitamin D levels, and between 1,25-(OH) 2-vitamin D and LL-37 serum. Diagnostic accuracy of the different molecules was moderate at best. Conclusions: Hypovitaminosis D is highly prevalent in pleural effusions. LL-37 is produced intrapleurally in IE. This production is higher in complicated IE. No evidence of pleural production of ?-defensin 2 was found in any of the groups. Diagnostic accuracy of the different molecules is at the best moderate for discriminating different types of effusions