Pharmacological Potential of Lathyrane-Type Diterpenoids from Phytochemical Sources.

Lathyrane diterpenoids are one of the primary types of secondary metabolites present in the genus Euphorbia and one of the largest groups of diterpenes. They are characterized by having a highly oxygenated tricyclic system of 5, 11 and 3 members. These natural products and some synthetic derivatives have shown numerous interesting biological activities with clinical potential against various diseases, such as cytotoxic activity against cancer cell lines, multi-drug resistance reversal, antiviral properties, anti-inflammatory activity and their capability to induce proliferation or differentiation into neurons of neural progenitor cells. The structure of the lathyrane skeleton could be considered privileged because its framework is able to direct functional groups in a well-defined space. The favorable arrangement of these makes interaction possible with more than one target. This review aims to highlight the evidence of lathyranes as privileged structures in medicinal chemistry. Chemical structures of bioactive compounds, the evaluation of biological properties of natural and semisynthetic derivatives, and the exploration of the mechanisms of action as well as target identification and some aspects of their targeted delivery are discussed.

Embedded bleeding detector into a PMMA applicator for electron intraoperative radiotherapy.

PURPOSE: The aim of this work is to present a ready to industrialize low-cost and easy-to-install bleeding detector for use in intraoperative electron radiation therapy (IOERT). The detector works in stand-alone mode and is embedded into a translucent polymethylmethacrylate (PMMA) applicator avoiding any contact with the patient, which represent a novelty compared to previous designs. The use of this detector will prevent dose misadministration during irradiation in the event of accumulation of fluids in the applicator. METHODS: The detector is based on capacitive sensor and wireless power-supply electronics. Both sensor and electronics have been embedded in the applicator, so that any contact with the patient would be avoided. Since access to the tumor can be done through different trajectories, the detector has been calibrated for different tilting angles. RESULTS: The result of the calibration provides us with a fit curve that allows the interpolation of the results at any angle. Comparison of estimated fluid height vs real height gives an error of 1 mm for tilting angles less than 10° and 2 mm for tilting angles greater than 15°. This accuracy is better than the one required by clinic. CONCLUSIONS: The performance of the bleeding detector was evaluated in situ. No interference was observed between the detector and the beam. In addition, a user-friendly mobile application has been developed to help the surgical team making decisions before and during irradiation. The measurement provided by the mobile application was stable during the irradiation process.

Pie neurológico: neuroartropatía de Charcot y su tratamiento quirúrgico / Neurological foot: Charcot’s neuroarthropathy and surgical treatment

La artropatía neuropática o también llamada artropatía de Charcot es un proceso de degeneración y destrucción progresiva de las articulaciones del pie ocasionada por la alteración de sensibilidad propioceptiva y nociceptiva. Se podría definir como una artropatía crónica, progresiva y destructiva. La causa más frecuente de la pérdida o alteración de sensibilidad en el mundo occidental es la diabetes, aunque, también puede ocurrir en la siringomielia y otros trastornos neurológicos; es decir, cualquier paciente con pérdida de fibras propioceptivas aferentes es susceptible a este proceso degenerativo. La respuesta osteopénica producto del cambio en la vascularización del miembro por aumento del flujo y aparición de fístulas arteriovenosas conduce a la inestabilidad y al colapso articular con la carga de peso. Los huesos involucrados progresan a través de etapas de destrucción hasta la consolidación, un proceso que puede llevar meses o incluso años para resolverse por completo. En la mayoría de las ocasiones aparece de forma unilateral, afectando solo a un pie y tan solo en el 10% de los casos aparece de forma bilateral. En cuanto al tratamiento, debe realizarse un abordaje multidisciplinar debiendo incluir a un cirujano ortopédico, cirujano vascular, reumatólogo, infectólogo, ortopedistas u ortésicos, enfermeros especializados… Patogenia La patogenia de esta condición sigue siendo incierta, probablemente multifactorial. La alteración sensitiva, debida a la falta de propiocepción secundaria a la neuropatía periférica, y la osteopenia, debida a cambios vasomotores producidos por la neuropatía autonómica, provocan que incluso traumatismos menores repetitivos puedan llegar a generar alteraciones estructurales y cambios en la carga del peso que llevan al colapso progresivo de las articulaciones afectas. Los continuos traumas que sufre el pie hacen que se pueda desencadenar una respuesta inflamatoria mediada por citoquinas proinflamatorias (TNF-α e IL-1), que dará lugar a la osteoartropatía. La lesión de las estructuras estabilizadoras del pie (afectación ósea, ligamentosa e incluso debilidad muscular) originarán un fracaso dinámico progresivo que con la consiguiente desestructuración de las articulaciones llevará al fracaso estático y deformidad del miembro. En condiciones en las que las estructuras del pie están debilitadas, las fuerzas que actúan sobre el mismo darán lugar a fallos estructurales que acabarán con deformidades del pie y tobillo. Con la presión continua y la falta de sensibilidad al dolor como resultado de la neuropatía sensorial, los tejidos blandos corren el riesgo de sufrir lesiones como las úlceras e infecciones.(AU)

Predictive Value of Serum Antibodies and Point Mutations of AQP4, AQP1 and MOG in A Cohort of Spanish Patients with Neuromyelitis Optica Spectrum Disorders.

The detection of IgG aquaporin-4 antibodies in the serum of patients with Neuromyelitis optica (NMO) has dramatically improved the diagnosis of this disease and its distinction from multiple sclerosis. Recently, a group of patients have been described who have an NMO spectrum disorder (NMOsd) and who are seronegative for AQP4 antibodies but positive for IgG aquaporin-1 (AQP1) or myelin oligodendrocyte glycoprotein (MOG) antibodies. The purpose of this study was to determine whether AQP1 and MOG could be considered new biomarkers of this disease; and if point mutations in the gDNA of AQP4, AQP1 and MOG genes could be associated with the etiology of NMOsd. We evaluated the diagnostic capability of ELISA and cell-based assays (CBA), and analyzed their reliability, specificity, and sensitivity in detecting antibodies against these three proteins. The results showed that both assays can recognize these antigen proteins under appropriate conditions, but only anti-AQP4 antibodies, and not AQP1 or MOG, appears to be a clear biomarker for NMOsd. CBA is the best method for detecting these antibodies; and serum levels of AQP4 antibodies do not correlate with the progression of this disease. So far, the sequencing analysis has not revealed a genetic basis for the etiology of NMOsd, but a more extensive analysis is required before definitive conclusions can be drawn.

A New Centralized Clustering Algorithm for Wireless Sensor Networks.

Clustering is presently one of the main routing techniques employed in randomly deployed wireless sensor networks. This paper describes a novel centralized unequal clustering method for wireless sensor networks. The goals of the algorithm are to prolong the network lifetime and increase the reliability of the network while not compromising the data transmission. In the proposed method, the Base Station decides on the cluster heads according to the best scores obtained from a Type-2 Fuzzy system. The input parameters of the fuzzy system are estimated by the base station or gathered from the network with a careful design that reduces the control message exchange. The whole network is controlled by the base station in a rounds-based schedule that alternates rounds when the base station elects cluster heads, with other rounds in which the cluster heads previously elected, gather data from their contributing nodes and forward them to the base station. The setting of the number of rounds in which the Base Station keeps the same set of cluster heads is another contribution of the present paper. The results show significant improvements achieved by the proposal when compared to other current clustering methods.

Recurrent pseudotumoral relapses in multiple sclerosis: a case report.

OBJECTIVES: Multiple sclerosis (MS) is the most common chronic disabling disease of the central nervous system (CNS) in young adults. It is characterized by the presence of multiple demyelinating inflammatory lesions disseminated in the CNS. Pseudotumoral lesions (PL) are rarely observed in patients with MS. METHODS: These atypical lesions can pose a diagnostic problem, especially when they are present at disease onset. RESULTS: Most MS patients with PLs only have a single episode throughout their disease course, which reflects its low tendency of recurrence. CONCLUSIONS: We report the rare case of a 34-year-old MS patient who suffered from recurrent pseudotumoral episodes during follow-up.

Comparative Analysis for the Presence of IgG Anti-Aquaporin-1 in Patients with NMO-Spectrum Disorders.

Detection of IgG anti-Aquaporin-4 (AQP4) in serum of patients with Neuromyelitis optica syndrome disorders (NMOSD) has improved diagnosis of these processes and differentiation from Multiple sclerosis (MS). Recent findings also claim that a subgroup of patients with NMOSD, serum negative for IgG-anti-AQP4, present antibodies anti-AQP1 instead. Explore the presence of IgG-anti-AQP1 using a previously developed cell-based assay (CBA) highly sensitive to IgG-anti-AQP4. Serum of 205 patients diagnosed as NMOSD (8), multiple sclerosis (94), optic neuritis (39), idiopathic myelitis (29), other idiopathic demyelinating disorders of the central nervous system (9), other neurological diseases (18) and healthy controls (8), were used in a CBA over fixed HEK cells transfected with hAQP1-EGFP or hM23-AQP4-EGFP, treated with Triton X-100 and untreated. ELISA was also performed. Analysis of serum with our CBA indicated absence of anti-AQP1 antibodies, whereas in cells pretreated with detergent, noisy signal made reliable detection impossible. ELISA showed positive results in few serums. The low number of NMOSD serums included in our study reduces its power to conclude the specificity of AQP1 antibodies as new biomarkers of NMOSD. Our study does not sustain detection of anti-AQP1 in serum of NMOSD patients but further experiments are expected.

Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

An immunoassay that distinguishes real neuromyelitis optica signals from a labeling detected in patients receiving natalizumab.

BACKGROUND: Cell-based assays for neuromyelitis optica (NMO) diagnosis are the most sensitive and specific methods to detect anti-aquaporin 4 (AQP4) antibodies in serum, but some improvements in their quantitative and specificity capacities would be desirable. Thus the aim of the present work was to develop a sensitive quantitative method for detection of anti-AQP4 antibodies that allows clear diagnosis of NMO and distinction of false labeling produced by natalizumab treatment. METHODS: Sera from 167 individuals, patients diagnosed with NMO (16), multiple sclerosis (85), optic neuritis (24), idiopathic myelitis (21), or other neurological disorders (13) and healthy controls (8), were used as the primary antibody in an immunofluorescence assay on HEK cells transfected with the M23 isoform of human AQP4 fused with enhanced green fluorescent protein. Cells used were freshly transfected or stored frozen and then thawed just before adding the serum. RESULTS: Microscopic observation and fluorescence quantification produced similar results in fresh and frozen samples. Serum samples from patients diagnosed with NMO were 100% positive for anti-AQP4 antibodies, while all the other sera were negative. Using serum from patients treated with natalizumab, a small and unspecific fluorescent signal was produced from all HEK cells, regardless of AQP4 expression. CONCLUSIONS: Our cell-based double-label fluorescence immunoassay protocol significantly increases the signal specificity and reduces false diagnosis of NMO patients, especially in those receiving natalizumab treatment. Frozen pretreated cells allow faster detection of anti-AQP4 antibodies.

Pseudotumoral forms of multiple sclerosis: report of 14 cases and review of the literature.

BACKGROUND: The pseudotumoral form of multiple sclerosis (MS) is a rare condition with few descriptions in the literature. It supposes a diagnostic challenge especially when appearing at the onset of disease. METHODS: We retrospectively describe a case series of pseudotumoral MS patients that attended our hospital from 2004, analyzing demographic, clinical and radiological variables. We classified the lesions according to the recently proposed morphologic classification (infiltrative, megacystic, Baló or ring-like) and according to the contrast enhancement pattern (nodular, complete ring, incomplete ring and diffuse). RESULTS: Fourteen patients (11 female, 3 male), with a mean age of 35 years, were identified. All of them suffered from a relapsing-remitting form of MS. Eleven patients (78.57%) had symptomatic pseudotumoral lesions (PL), being the form of clinical presentation in the majority of those patients that were symptomatic (81.81%). Several patients presented atypical clinical manifestations such as cognitive impairment (21.42%) and epileptic seizures (14.28%). Full recovery was found in 53.84% of all symptomatic episodes. After a mean follow-up of 43 months, recurrent PL episodes were seldom observed (21.42%), the annualized relapse rate was 0.95 and the mean final Expanded Disability Status Scale score was 1.5. The majority of PLs were supratentorial, coexisted with typical demyelinating plaques and showed the ring-like morphology and the ring pattern of contrast enhancement. Three patients had more than one PL on the same scan, all of the lesions with similar morphology. CONCLUSIONS: Our findings contribute to a better characterization of pseudotumoral forms of MS. However, larger studies are required to define this atypical entity more exactly.

Biotransformation of clovane derivatives. Whole cell fungi mediated domino synthesis of rumphellclovane A.

Here we describe the biotransformation of clovane derivatives by filamentary fungi Pestalotiopsis palustris and Penicillium minioluteum, and the application of the latter to the synthesis and determination of the absolute configuration of rumphellclovane A (2). Methoxyclovanol (1), a growth inhibitor of the phytopathogen Botrytis cinerea, is metabolised by P. palustris to yield rumphellclovane A (2), a natural compound recently isolated from the gorgonian coral Rumphella antipathies, two new compounds, (1R,2S,5S,8R,9S,10R)-2-methoxyclovane-9,10-diol (5) and (1S,2S,5S,7R,8R,9R)-2-methoxyclovane-7,9-diol (6), hydroxylated in positions not easily accessed by classic synthetic chemistry, and clovanodiols 3 and 4. P. minioluteum is able to selectively transform methoxyclovanol (1) into clovanodiols 3 and 4 and, in turn, lactone 8, the putative intermediate in the above mentioned synthesis of rumphellclovane A (2), into compound 2 via a domino process. The ability of P. minioluteum to carry out the cleavage of ethers on clovane derivatives is also evaluated.

Ultra-fast gradient LC method for omeprazole analysis using a monolithic column: assay development, validation, and application to the quality control of omeprazole enteric-coated pellets.

A method was optimized for the analysis of omeprazole (OMZ) by ultra-high speed LC with diode array detection using a monolithic Chromolith Fast Gradient RP 18 endcapped column (50 x 2.0 mm id). The analyses were performed at 30 degrees C using a mobile phase consisting of 0.15% (v/v) trifluoroacetic acid (TFA) in water (solvent A) and 0.15% (v/v) TFA in acetonitrile (solvent B) under a linear gradient of 5 to 90% B in 1 min at a flow rate of 1.0 mL/min and detection at 220 nm. Under these conditions, OMZ retention time was approximately 0.74 min. Validation parameters, such as selectivity, linearity, precision, accuracy, and robustness, showed results within the acceptable criteria. The method developed was successfully applied to OMZ enteric-coated pellets, showing that this assay can be used in the pharmaceutical industry for routine QC analysis. Moreover, the analytical conditions established allow for the simultaneous analysis of OMZ metabolites, 5-hydroxyomeprazole and omeprazole sulfone, in the same run, showing that this method can be extended to other matrixes with adequate procedures for sample preparation.

Fungal terpene metabolites: biosynthetic relationships and the control of the phytopathogenic fungus Botrytis cinerea.

The structures and biosynthesis of the sesquiterpenoid metabolites of Botrytis cinerea and their relationship to the presilphiperfolanes are reviewed. The development of a novel strategy for the control of this phytopathogenic fungus based on analogues of these metabolites is described. There are 75 references.