Rescue of infant progressive familial intrahepatic cholestasis type 3 mice by repeated dosing of AAV gene therapy.

Background & Aims: Gene therapy using recombinant adeno-associated virus (rAAV) vector carrying multidrug resistance protein 3 (MDR3) coding sequence (AAV8-MDR3) represents a potential curative treatment for progressive familial intrahepatic cholestasis type 3 (PFIC3), which presents in early childhood. However, patients with the severest form of PFIC3 should receive treatment early after detection to prevent irreversible hepatic fibrosis leading ultimately to liver transplantation or death. This represents a challenge for rAAV-based gene therapy because therapeutic efficacy is expected to wane as rAAV genomes are lost owing to hepatocyte division, and the formation of AAV-specific neutralising antibodies precludes re-administration. Here, we tested a strategy of vector re-administration in infant PFIC3 mice with careful evaluation of its oncogenicity - a particular concern surrounding rAAV treatment. Methods: AAV8-MDR3 was re-administered to infant Abcb4 -/- mice 2 weeks after a first dose co-administered with tolerogenic nanoparticles carrying rapamycin (ImmTOR) given at 2 weeks of age. Eight months later, long-term therapeutic efficacy and safety were assessed with special attention paid to the potential oncogenicity of rAAV treatment. Results: Co-administration with ImmTOR mitigated the formation of rAAV-specific neutralising antibodies and enabled an efficacious second administration of AAV8-MDR3, resulting in stable correction of the disease phenotype, including a restoration of bile phospholipid content and healthy liver function, as well as the prevention of liver fibrosis, hepatosplenomegaly, and gallstones. Furthermore, efficacious repeat rAAV administration prevented the appearance of liver malignancies in an animal model highly prone to developing hepatocellular carcinoma. Conclusions: These outcomes provide strong evidence for rAAV redosing through co-administration with ImmTOR, as it resulted in a long-term therapeutic effect in a paediatric liver metabolic disorder, including the prevention of oncogenesis. Impact and implications: Redosing of gene therapy for inborn hepatobiliary disorders may be essential as effect wanes during hepatocyte division and renewal, particularly in paediatric patients, but the approach may carry long-term risks of liver cancer. Viral vectors carrying a therapeutic gene exerted a durable cure of progressive familial intrahepatic cholestasis type 3 in infant mice and reduced the risk of liver cancer only following a second administration.

Optimising the IgG-degrading enzyme treatment regimen for enhanced adeno-associated virus transduction in the presence of neutralising antibodies.

OBJECTIVE: Pre-existing neutralising antibodies (NAbs) to adeno-associated viruses (AAVs) remain an impediment for systemically administered AAV-mediated gene therapy treatment in many patients, and various strategies are under investigation to overcome this limitation. Here, IgG-degrading enzymes (Ides) derived from bacteria of the genus Streptococcus were tested for their ability to cleave human IgG and allow AAV-mediated transduction in individuals with pre-existing NAbs. METHODS: Cleavage activity of three different Ides was evaluated in vitro in serum from different species. Passively immunised mice or non-human primates (NHP) with naturally occurring anti-AAV NAbs were used to define the optimal IdeS dose and administration window for AAVAnc80 and AAV8 vectors in mice and AAV3B in NHPs. RESULTS: The selected candidate, IdeS, was found to be highly efficient at cleaving human IgG, less efficient against NHP IgG and inefficient against mouse IgG. In vivo, we observed differences in how IdeS affected liver transduction in the presence of NAbs depending on the AAV serotype. For AAVAnc80 and AAV3B, the best transduction levels were achieved when the vector was administered after IgG digestion products were cleared from circulation. However, for AAV8 we only observed a modest and transient inhibition of transduction by IdeS cleavage products. CONCLUSION: Preconditioning with IdeS represents a unique treatment opportunity for patients primarily excluded from participation in gene therapy clinical trials because of elevated circulating anti-AAV NAb levels. However, careful determination of the optimal IdeS dose and timing for the administration of each AAV serotype is essential for optimal transduction.

Catatonia Related to Cannabis and Synthetic Cannabinoids: A Review.

OBJECTIVE: Cannabis and synthetic cannabinoids (SC) are related to several neuropsychiatric symptoms and disorders, especially psychotic symptoms and disorders. Interestingly, catatonia-like symptoms associated with cannabis and SC have been generally neglected in research and scarcely described despite the clinical repercussions. Hence, this review aims to analyze current clinical publications on catatonia induced by cannabis or SC in a systematized way. Methods: A search using PRISMA guidelines was performed on three databases based on a specific inclusion and exclusion criteria. Results: 11 publications describing 14 patients (10 males; mean age 22.50 ± 6.67 years old) with catatonia apparently precipitated by the use of cannabis (n = 6) or SC (n = 8) were found. Clinical features and treatment are described and discussed. Conclusion: From a clinical perspective, cannabis and SC use may be related to catatonia-like symptoms and catatonia syndrome in the same way these substances (cannabis and SC) are related to induced-psychotic episodes. However, further research will be required to understand the exact nature of that relationship. Additionally, investigations focused on the clinical significance (i.e., prognosis, evolution, and outcomes) of catatonia-like symptoms induced by cannabis and SC use in patients are also needed.

Impacto de la cirugía metabólica en pacientes obesos con hipertensión arterial / Impact of metabolic surgery in obese patients with arterial hypertension

INTRODUCCIÓN. La obesidad, problema de Salud Pública a nivel mundial, asociada a patologías metabólicas, como Hipertensión Arterial, Diabetes Mellitus, dislipidemia. Se ha observado que la cirugía bariátrica previene complicaciones relacionadas con Presión Arterial elevada; la gastrectomía vertical en manga y el bypass gástrico, son efectivos para la reducción del peso y el riesgo cardiovascular según la evidencia. OBJETIVO. Identificar los beneficios de la cirugía bariátrica en pacientes que presentan obesidad e hipertensión arterial. MATERIALES Y MÉTODOS. Estudio descriptivo transversal, con datos de Histo-rias Clínicas de 155 pacientes obesos sometidos a cirugía bariátrica con hipertensión ar-terial, con una muestra de 67 que cumplían con los criterios de inclusión, en el Hospital de Especialidades Carlos Andrade Marín de Quito, en el período comprendido entre febrero 2018 y junio 2019; se realizó operacionalización de las variables y análisis de datos en el programa SPSS, versión 25. RESULTADOS. La mayoría de pacientes con obesidad tipo II, controlaban su presión arterial con un promedio de dos medicamentos, los cuales tras el procedimiento de cirugía bariátrica lograron una reducción aproximada del 28% de su peso inicial a los 12 meses y una reducción en el número de fármacos antihipertensivos, alcanzando la descontinuación de los mismos en un 21,05% (8; 38) en gastrectomía en manga y 31% (9; 29) en bypass gástrico. CONCLUSIÓN. La cirugía bariátrica es un trata-miento efectivo en pacientes con obesidad e hipertensión arterial ya que permite disminuir peso y además el número y la dosis de los medicamentos a largo plazo.

INTRODUCTION. Obesity, a world health public problem, with an increase in the younger people, is associated with some metabolic diseases, as arterial hypertension, diabetes mellitus, dyslipidemia. It is proved that metabolic-bariatric surgery prevents any compli-cations related with high levels of arterial pressure. The sleeve gastrectomy and Roux-Y bypass gastrectomy are effective in weight reduction and cardiovascular risk reduction in order to evidence. OBJECTIVE. Identify the benefits of bariatric surgery in patients with obesity and arterial hypertension. MATERIALS AND METHODS. Transversal descriptive study, with data of clinical history of 155 obese patients that were under metabolic surgery with arterial hypertension, among all patients, 67 cases accomplished the appropriate pro-file for the investigation. The study was developed at the Carlos Andrade Marin Specialties Hospital, Quito; between February 2018 and June 2019. All the data was collected for va-riable operationalization and the data analysis was done on SPSS 25 software. RESULTS. Most patients with type II obesity were taking two different antihypertensive medicines. After a year of surgery, they reduce the weight about 28% from initial weight ant a reduc-tion in the number of antihypertensive medicines with the discontinuation of them about 21,05% (8; 38) with sleeve gastrectomy and 31% (9; 29) with gastric bypass, respectively. CONCLUSION. Metabolic/Bariatric surgery is an effective treatment in obese patients with arterial hypertension, this allows weight loss and also the number and doses of medicines in the future.

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates.

Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure. The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate.

Genetic-Based Approaches to Inherited Metabolic Liver Diseases.

In vertebrates, the liver is the central metabolic organ of the body, which carries out an estimated 500 functions that range from general detoxification to protein synthesis, bile production, metabolism of fats, carbohydrates, proteins, bilirubin, vitamin and mineral storage and it even has an immune function. Hepatocytes are considered the professional liver cells, which carry out all of these functions. With such a variety of tasks to perform, it is not surprising that more than 400 rare monogenic disorders of hepatic origin have been described. For many of these, liver transplantation remains the only curative strategy, however, this is limited by organ availability and requires lifelong immune suppression. The fact that liver transplantation is curative led to the assumption that the restoration of the expression of the defective gene would result in the resolution of the disease. Indeed, liver-directed gene therapy trials for hemophilia A and B have demonstrated the potential of gene therapy to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Thus, liver-directed gene therapy and gene editing strategies have emerged as promising alternatives to transplantation in inherited monogenic liver disorders. Herein, we review the advances and limitations of gene therapy for such disorders, covering therapeutic strategies based on gene addition and gene editing and the exciting clinical results obtained with the use of ribonucleic acid as therapeutic molecules.

Chronic softening spinal cord stimulation arrays.

OBJECTIVE: We sought to develop a cervical spinal cord stimulator for the rat that is durable, stable, and does not perturb the underlying spinal cord. APPROACH: We created a softening spinal cord stimulation (SCS) array made from shape memory polymer (SMP)-based flexible electronics. We developed a new photolithographic process to pattern high surface area titanium nitride (TiN) electrodes onto gold (Au) interconnects. The thiol-ene acrylate polymers are stiff at room temperature and soften following implantation into the body. Durability was measured by the duration the devices produced effective stimulation and by accelerated aging in vitro. Stability was measured by the threshold to provoke an electromyogram (EMG) muscle response and by measuring impedance using electrochemical impedance spectroscopy (EIS). In addition, spinal cord modulation of motor cortex potentials was measured. The spinal column and implanted arrays were imaged with MRI ex vivo, and histology for astrogliosis and immune reaction was performed. MAIN RESULTS: For durability, the design of the arrays was modified over three generations to create an array that demonstrated activity up to 29 weeks. SCS arrays showed no significant degradation over a simulated 29 week period of accelerated aging. For stability, the threshold for provoking an EMG rose in the first few weeks and then remained stable out to 16 weeks; the impedance showed a similar rise early with stability thereafter. Spinal cord stimulation strongly enhanced motor cortex potentials throughout. Upon explantation, device performance returned to pre-implant levels, indicating that biotic rather than abiotic processes were the cause of changing metrics. MRI and histology showed that softening SCS produced less tissue deformation than Parylene-C arrays. There was no significant astrogliosis or immune reaction to either type of array. SIGNIFICANCE: Softening SCS arrays meet the needs for research-grade devices in rats and could be developed into human devices in the future.

The neural correlates of visual imagery vividness - An fMRI study and literature review.

Using the Vividness of Visual Imagery Questionnaire we selected 14 high-scoring and 15 low-scoring healthy participants from an initial sample of 111 undergraduates. The two groups were matched on measures of age, IQ, memory and mood but differed significantly in imagery vividness. We used fMRI to examine brain activation while participants looked at, or later imagined, famous faces and famous buildings. Group comparison revealed that the low-vividness group activated a more widespread set of brain regions while visualising than the high-vividness group. Parametric analysis of brain activation in relation to imagery vividness across the entire group of participants revealed distinct patterns of positive and negative correlation. In particular, several posterior cortical regions show a positive correlation with imagery vividness: regions of the fusiform gyrus, posterior cingulate and parahippocampal gyri (BAs 19, 29, 31 and 36) displayed exclusively positive correlations. By contrast several frontal regions including parts of anterior cingulate cortex (BA 24) and inferior frontal gyrus (BAs 44 and 47), as well as the insula (BA 13), auditory cortex (BA 41) and early visual cortices (BAs 17 and 18) displayed exclusively negative correlations. We discuss these results in relation to a previous, functional imaging study of a clinical case of 'blind imagination', and to the existing literature on the functional imaging correlates of imagery vividness and related phenomena in visual and other domains.

Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5ch and AAV1.

In the gene therapy field, re-administration of adeno-associated virus (AAV) is an important topic because a decrease in therapeutic protein expression might occur over time. However, an efficient re-administration with the same AAV serotype is impossible due to serotype-specific, anti-AAV neutralizing antibodies (NABs) that are produced after initial AAV treatment. To address this issue, we explored the feasibility of using chimeric AAV serotype 5 (AAV5ch) and AAV1 for repeated liver-targeted gene delivery. To develop a relevant model, we immunized animals with a high dose of AAV5ch-human secreted embryonic alkaline phosphatase (hSEAP) that generates high levels of anti-AAV5ch NAB. Secondary liver transduction with the same dose of AAV1-human factor IX (hFIX) in the presence of high levels of anti-AAV5ch NAB proved to be successful because expression/activity of both reporter transgenes was observed. This is the first time that two different transgenes are shown to be produced by non-human primate (NHP) liver after sequential administration of clinically relevant doses of both AAV5ch and AAV1. The levels of transgene proteins achieved after delivery with AAV5ch and AAV1 illustrate the possibility of both serotypes for liver targeting. Furthermore, transgene DNA and RNA biodistribution patterns provided insight into the potential cause of decrease or loss of transgene protein expression over time in NHPs.

Improvement of Adeno-Associated Virus-Mediated Liver Transduction Efficacy by Regional Administration in Macaca fascicularis.

The liver is a central organ in metabolism and can be affected by numerous inherited metabolic disorders. Recombinant adeno-associated virus (AAV)-based gene therapy represents a promising therapeutic approach for such diseases. AAVs have been demonstrated to be safe, and resulted in high and long-term expression in preclinical and clinical studies. However, there are still some concerns regarding the expression levels that can be achieved and the percentage of hepatocytes that can be transduced. Because of the cell-autonomous nature of most metabolic liver disorders, a high percentage of hepatocytes needs to be corrected in order to achieve a therapeutic effect. The goal of our work was to improve transduction efficacy of the liver by conveying the vector directly to hepatic tissue. Interventional radiology procedures were used to administer an AAV5 vector expressing a secreted form of human embryonic alkaline phosphatase (hSEAP) under the control of a liver-specific promoter to a clinically relevant animal model, Macaca fascicularis. Balloon occlusion of the regional hepatic venous flow was performed while injecting the vector either into the hepatic artery (HA) or, against flow, via the suprahepatic vein (SHV). In both cases the vector was injected into the right hepatic lobules, and the two routes were compared with conventional intravenous administration. Higher hSEAP levels were obtained when the vector was administered via SHV or HA than after intravenous injection. Furthermore, higher expression levels correlated with a higher number of vector genomes in the injected lobules. In conclusion, direct administration of AAV vectors via the hepatic blood flow with simultaneous balloon occlusion of the hepatic outflow increases liver transduction efficacy in comparison with systemic delivery and can be further improved in bigger animals or humans, where it would be technically feasible to inject the vector into the hepatic vasculature in the generality of lobules.

Design and demonstration of an intracortical probe technology with tunable modulus.

Intracortical probe technology, consisting of arrays of microelectrodes, offers a means of recording the bioelectrical activity from neural tissue. A major limitation of existing intracortical probe technology pertains to limited lifetime of 6 months to a year of recording after implantation. A major contributor to device failure is widely believed to be the interfacial mechanical mismatch of conventional stiff intracortical devices and the surrounding brain tissue. We describe the design, development, and demonstration of a novel functional intracortical probe technology that has a tunable Young's modulus from ∼2 GPa to ∼50 MPa. This technology leverages advances in dynamically softening materials, specifically thiol-ene/acrylate thermoset polymers, which exhibit minimal swelling of < 3% weight upon softening in vitro. We demonstrate that a shape memory polymer-based multichannel intracortical probe can be fabricated, that the mechanical properties are stable for at least 2 months and that the device is capable of single unit recordings for durations up to 77 days in vivo. This novel technology, which is amenable to processes suitable for manufacturing via standard semiconductor fabrication techniques, offers the capability of softening in vivo to reduce the tissue-device modulus mismatch to ultimately improve long term viability of neural recordings. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 159-168, 2017.

The Learning Objective Catalogue for Patient Safety in Undergraduate Medical Education--A Position Statement of the Committee for Patient Safety and Error Management of the German Association for Medical Education.

BACKGROUND: Since the report "To err is human" was published by the Institute of Medicine in the year 2000, topics regarding patient safety and error management are in the focal point of interest of science and politics. Despite international attention, a structured and comprehensive medical education regarding these topics remains to be missing. GOALS: The Learning Objective Catalogue for Patient Safety described below the Committee for Patient Safety and Error Management of the German Association for Medical Education (GMA) has aimed to establish a common foundation for the structured implementation of patient safety curricula at the medical faculties in German-speaking countries. METHODS: The development the Learning Objective Catalogue resulted via the participation of 13 faculties in two committee meetings, two multi-day workshops, and additional judgments of external specialists. RESULTS: The Committee of Patient Safety and Error Management of GMA developed the present Learning Objective Catalogue for Patient Safety in Undergraduate Medical Education, structured in three chapters: Basics, Recognize Causes as Foundation for Proactive Behavior, and Approaches for Solutions. The learning objectives within the chapters are organized on three levels with a hierarchical organization of the topics. Overall, the Learning Objective Catalogue consists of 38 learning objectives. All learning objectives are referenced with the National Competency-based Catalogue of Learning Objectives for Undergraduate Medical Education. DISCUSSION: The Learning Objective Catalogue for Patient Safety in Undergraduate Medical Education is a product that was developed through collaboration of members from 13 medical faculties. In the German-speaking countries, the Learning Objective Catalogue should advance discussion regarding the topics of patient safety and error management and help develop subsequent educational structures. The Learning Objective Catalogue for Patient Safety can serve as a common ground for an intensified, constructive, subject-specific discussion about these topics at the medical faculties, and guide the implementation of hopefully multiple patient safety curricula in undergraduate medical education.

Integration of High-Charge-Injection-Capacity Electrodes onto Polymer Softening Neural Interfaces.

Softening neural interfaces are implanted stiff to enable precise insertion, and they soften in physiological conditions to minimize modulus mismatch with tissue. In this work, a high-charge-injection-capacity iridium electrode fabrication process is detailed. For the first time, this process enables integration of iridium electrodes onto softening substrates using photolithography to define all features in the device. Importantly, no electroplated layers are utilized, leading to a highly scalable method for consistent device fabrication. The iridium electrode is metallically bonded to the gold conductor layer, which is covalently bonded to the softening substrate via sulfur-based click chemistry. The resulting shape-memory polymer neural interfaces can deliver more than 2 billion symmetric biphasic pulses (100 µs/phase), with a charge of 200 µC/cm(2) and geometric surface area (GSA) of 300 µm(2). A transfer-by-polymerization method is used in combination with standard semiconductor processing techniques to fabricate functional neural probes onto a thiol-ene-based, thin film substrate. Electrical stability is tested under simulated physiological conditions in an accelerated electrical aging paradigm with periodic measurement of electrochemical impedance spectra (EIS) and charge storage capacity (CSC) at various intervals. Electrochemical characterization and both optical and scanning electron microscopy suggest significant breakdown of the 600 nm-thick parylene-C insulation, although no delamination of the conductors or of the final electrode interface was observed. Minor cracking at the edges of the thin film iridium electrodes was occasionally observed. The resulting devices will provide electrical recording and stimulation of the nervous system to better understand neural wiring and timing, to target treatments for debilitating diseases, and to give neuroscientists spatially selective and specific tools to interact with the body. This approach has uses for cochlear implants, nerve cuff electrodes, penetrating cortical probes, spinal stimulators, blanket electrodes for the gut, stomach, and visceral organs and a host of other custom nerve-interfacing devices.

Trayectorias de jóvenes de Zaragoza (España) en configuraciones familiares obreras / Trajectories of young people from Zaragoza (Spain) in configurations of working-class families

Nuestro objetivo general en este artículo es analizar las trayectorias biográficas de jóvenes que viven en la ciudad de Zaragoza (España). Para ello seguimos un enfoque metodológico a través de historias de vida, reconstruyendo 4 biografías de jóvenes pertenecientes a familias obreras. Los principales resultados del estudio son que los jóvenes y las jóvenes desarrollan trayectorias sociales heterogéneas, según sea su configuración familiar concreta (producto de la interacción de las acciones de sus miembros). Mostramos la concordancia o disonancia entre capital educativo familiar institucionalizado e interiorizado, un elemento explicativo en la trayectoria seguida por los sujetos jóvenes. Así, las configuraciones familiares con mayor capital educativo interiorizado -prácticas de cultura oral y escrita más amplias- siguen trayectorias educativas más largas...

Can prognostic scoring systems for chronic myeloid leukemia as established in adults be applied to pediatric patients?

In contrast to adult medicine, specific scoring systems predicting the treatment response for an individual pediatric patient (pt) with chronic myeloid leukemia (CML) have not yet been defined. We evaluated to what extend prognostic scores as described for adults (e.g., Sokal, Hasford, EUTOS score) resulted in comparable risk group categorizations in a pediatric cohort. Parameters for score calculation were extracted from a data set of 90 patients enrolled into trial CML-PAED-II and treated by a standard dose of imatinib. At month 3 and at month 6, treatment response was analyzed based on the transcript ratio BCR-ABL1/ABL1. By the EUTOS, Hasford, and Sokal scores 81, 59, and 62 % of the patients were categorized as low risk, respectively; 19, 14, and 16 % of the patients as high risk, respectively; and by Hasford and Sokal scores 27 and 22 % of the patients, respectively, as intermediate risk. Twenty-seven out of 72 patients analyzable (38 %) exhibited a transcript ratio >10 % at month 3. We show that only the EUTOS score, but not the Sokal and Hasford score, correlates with this early outcome (p = 0.008). Analyzing the EUTOS score separately, we can demonstrate that lowering the cutoff from 87 to 48 points for categorization in low- and high-risk individuals increases the odds ratio from 2.4 (95 % CI 0.6 to 10.4) to 3.6 (95 % CI 1.3 to 10.9). Data are provided on the distribution of risk categories and resulting discrepancies when adult scores are applied on children and adolescents with CML at diagnosis. A larger number of patients and longer follow-up are still needed to develop a prognostic score specifically adapted to the pediatric and adolescent age cohorts.

Mechanically adaptive organic transistors for implantable electronics.

A unique form of adaptive electronics is demonstrated, which change their mechanical properties from rigid and planar to soft and compliant, in order to enable soft and conformal wrapping around 3D objects, including biological tissue. These devices feature excellent mechanical robustness and maintain initial electrical properties even after changing shape and stiffness.

Mechanical cycling stability of organic thin film transistors on shape memory polymers.

Organic thin film transistors on shape memory polymers are fabricated by full photolithography. Devices show high mobility (0.2 cm(2) V(-1) s(-1)) and close to zero threshold voltage (-4.5 V) when characterized as fabricated. After 1, 10, and 100 deformation cycles and in a deformed, metastable shape memory transition state, changes in mobility and V(th) are measured and indicate sustained device functionality.

Hydrophobic gentamicin-loaded nanoparticles are effective against Brucella melitensis infection in mice.

The clinical management of human brucellosis is still challenging and demands in vitro active antibiotics capable of targeting the pathogen-harboring intracellular compartments. A sustained release of the antibiotic at the site of infection would make it possible to reduce the number of required doses and thus the treatment-associated toxicity. In this study, a hydrophobically modified gentamicin, gentamicin-AOT [AOT is bis(2-ethylhexyl) sulfosuccinate sodium salt], was either microstructured or encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The efficacy of the formulations developed was studied both in vitro and in vivo. Gentamicin formulations reduced Brucella infection in experimentally infected THP-1 monocytes (>2-log10 unit reduction) when using clinically relevant concentrations (18 mg/liter). Moreover, in vivo studies demonstrated that gentamicin-AOT-loaded nanoparticles efficiently targeted the drug both to the liver and the spleen and maintained an antibiotic therapeutic concentration for up to 4 days in both organs. This resulted in an improved efficacy of the antibiotic in experimentally infected mice. Thus, while 14 doses of free gentamicin did not alter the course of the infection, only 4 doses of gentamicin-AOT-loaded nanoparticles reduced the splenic infection by 3.23 logs and eliminated it from 50% of the infected mice with no evidence of adverse toxic effects. These results strongly suggest that PLGA nanoparticles containing chemically modified hydrophobic gentamicin may be a promising alternative for the treatment of human brucellosis.

Terson's syndrome presenting as an ophthalmic emergency.

PURPOSE: To report an unusual case of Terson's syndrome caused by a ruptured intracranial aneurysm presenting as an ophthalmic emergency with visual loss, without any neurological features at the time of presentation. METHODS: Case report. A 38-year-old man was referred to the eye emergency department with sudden loss of vision in both eyes. Vitreous haemorrhage was noted in both eyes. There was no history of loss of consciousness or headaches and no signs of meningeal irritation at presentation. The patient subsequently developed progressive neck stiffness and headache. RESULTS: Neuro-imaging studies revealed a subarachnoid haemorrhage resulting from a ruptured carotid-ophthalmic artery aneurysm. CONCLUSIONS: It is important to consider Terson's syndrome, a potentially life-threatening condition, in any patient presenting with bilateral vitreous haemorrhage. Some patients may not show any headache, neurological deficits or signs of meningeal irritation at presentation but may develop them later on.

Sindrome de Brachmann-de Lange: diagnóstico objetivo / Brachmann-de lange syndrome: objective diagnosis

Se aplica el índice diagnóstico de Preus y Rex a pacientes peruanos diagnosticados clínicamente con retardo mental de etiología diversa y con controles normales y con rasgos fenotípicos similares, para demostrar que el índice es aplicable como método diagnóstico en nuestro medio. Se recomienda su uso para permitir el diagnóstico objetivo y comparable del síndrome.