Human amylin aggregates release within exosomes as a protective mechanism in pancreatic ß cells: Pancreatic ß-hippocampal cell communication.

Pancreatic ß cells are essential in the maintenance of glucose homeostasis during the progression to type 2 Diabetes Mellitus (T2DM), generating compensatory hyperinsulinemia to counteract insulin resistance. It is well known, that throughout the process there is an increased mTORC1 signaling pathway, with an impairment in different quality control systems including ubiquitin-proteasome system and autophagy. In addition, under this situation, pancreatic ß cells start to accumulate amylin protein (IAPP) in aggregates, and this accumulation contributes to the failure of autophagy, damaging different organelles such as plasma membrane, endoplasmic reticulum, mitochondria, and others. Here, we report that IAPP can be incorporated to multivesicular bodies (MVB) and secreted into exosomes, a mechanism responsible for the exportation of these toxic aggregates as vehicles of cell to cell communication. On this regard, we have demonstrated that the exosomes bearing toxic hIAPP released from pancreatic ß cells are capable to induce hyperactivation of mTORC1 signaling, a failure in the autophagic cellular quality control, and favor pro-fission status of the mitochondrial dynamics in hippocampal cells. In summary, our results show that harmful accumulation of hIAPP in pancreatic ß cells may be detoxified by the release of exosomes, which may be captured by endocytosis mechanism damaging neuronal hippocampal cells, which suggest an underlying molecular mechanism to the link between type 2 diabetes and neurodegenerative diseases.

Recommendations of the Spanish Brachytherapy Group of SEOR for HDR endoluminal treatments. Part 1: Oesophagus.

The endoesophageal brachytherapy technique provides good results in the treatment of oesophageal cancer, when indicated. In a consensus meeting, the Spanish Brachytherapy Group of SEOR and the Spanish Society of Medical Physics (SEFM) agreed on the indications, dose, fractionation schedule, prescription and reporting to be performed in endoesophageal brachytherapy. The results of this consensus are presented here as recommendations for medical practice.

Asociación entre el polimorfismo genético de la interleucina-1Beta (3953 T/C) y la hernia discal lumbar sintomática / Association between the genetic polymorphism of interleukin-1Beta (3953 T/C) and symptomatic lumbar herniated disc

Objetivo. Evaluar la asociación entre la presencia en el genotipo de determinados polimorfismos genéticos (PG) de las citocinas y del óxido nítrico sintasa (NOS) y el desarrollo de la hernia discal lumbar (HDL) sintomática.Material y método. Se revisaron 179 pacientes en un estudio retrospectivo de casos y controles. El grupo de casos estaba formado por 50 pacientes con HDL confirmada mediante resonancia magnética. El grupo control lo componían pacientes ingresados para cirugía protésica de la cadera o de la rodilla que no presentaban ni habían presentado nunca clínica compatible con HDL. Se realizó una extracción de sangre a todos los participantes del estudio. Se genotiparon los PG de las citocinas que pretendíamos estudiar: interleucina (IL)-1 (IL-1alfa [−889 C/T] e IL-1Beta [+3953 T/C]) y factor de necrosis tumoral-alfa (TNF-alfa´ [−308 G/A] y TNF-alfa´ [−238 G/A]). Resultados. El genotipo CC y la frecuencia del alelo C del PG IL-1Beta (+3953 T/C) fueron significativamente mayores en el grupo de pacientes con HDL respecto a la población control. Por el contrario, los pacientes del grupo control portaban los PG de NOS endotelial (−768 T/C) y de NOS inducible 22 G/A con mayor frecuencia que el grupo de pacientes con HDL, esta diferencia es estadísticamente significativa para ambos polimorfismos. Conclusiones. Encontramos que ser portador del alelo C del PG IL-1Beta (+3953 T/C) puede ser un factor de predisposición para desarrollar una HDL. Por otro lado, ser portador del PG NOS endotelial (−768 T/C) y del NOS inducible 22 G/A parece comportarse como un factor protector frente al desarrollo de esta enfermedad (AU)

Objective. To evaluate the association between the presence of the genotype of certain genetic polymorphisms (GP) of the cytokine and oxide nitric synthase (NOS) and the development of lumbar herniated disc (LHD). Materials and methods. We reviewed 179 patients in a retrospective case-control study. The case group was made up of 50 patients with confirmed lumbar herniated disc diagnosed by Magnetic Resonance Imaging (MRI). The control group was made up of patients admitted for hip and knee prosthetic surgery who did not have or had not had any symptoms consistent with LHD. Blood was drawn from all of the study participants. The genotypes of the GP were obtained of the cytokines to be studied: Interleukin-1 [IL-1alpha(−889 C/T), IL-1Beta(+3953 T/C)], Tumor Necrosis Factor-alpha [TNF-alpha (−308 G/A) and (−238G/A)]. Results. The CC genotype and C allele frequency of the IL-1Betaβ PG (+3953T/C) polymorphism were significantly more frequent in patients with LDH compared to the controls. On the contrary, the control group patients carried eNos GPs (−768 T/C) and iNOS22 G/A polymorphisms more frequently than the LHD group, this difference being statistically different for both polymorphisms. Conclusions. We found that individuals who were carriers of the CC genotype of the IL-1b(+3953T/C) polymorphism showed higher susceptibility to suffer lumbar disc herniation. Furthermore, being a carrier of ENOS (−786 T/C) and iNOS (22 G/A) polymorphisms suggests that this could behave as a protection factor against disc herniation (AU)

Effects of hydroxypropyl-beta-cyclodextrin on the chemical stability and the aqueous solubility of thalidomide enantiomers.

The aim of this work was to study the effect of hydroxypropyl-beta-cyclodextrin on the solubility and stability of thalidomide enantiomers in aqueous solutions for clinical oral administration to be used in HIV-infected children. For this reason racemic thalidomide was added to solutions containing different concentrations of hydroxypropyl-beta-cyclodextrin. True complexes were obtained by using hydroxypropyl-beta-cyclodextrin and the solubility of both thalidomide enantiomers was increased directly depending on the amount of hydroxylpropyl-beta-cyclodextrin in the medium although no enantioselective differences were observed at 37 degrees C. The chemical stability of thalidomide enantiomers is clearly improved by hydroxypropyl-beta-cyclodextrin. No enantioselective degradation of thalidomide was observed in sodium chloride solution (0.9%) samples stored at 6 degrees C for nine days when hydroxypropyl-beta-cyclodextrin was employed as excipient. Therefore a thalidomide solution suitable for oral administration can be prepared by adding hydroxypropyl-beta-cyclodextrin at 10% (w/v).

Peptidomimetics in cancer chemotherapy.

A summary of the current status of the application of peptidomimetics in cancer therapeutics as an alternative to peptide drugs is provided. Only compounds that are used in therapy or at least under clinical trials are discussed, using inhibitors of farnesyltransferase, proteasome and matrix metalloproteinases as examples.

Peptidomimetics in cancer chemotherapy

A summary of the current status of the application of peptidomimetics in cancer therapeutics as an alternative to peptide drugs is provided. Only compounds that are used in therapy or at least under clinical trials are discussed, using inhibitors of farnesyltransferase, proteasome and matrix metalloproteinases as examples (AU)

Inestabilidad atloaxoidea en la infancia / Atloaxoid joint instability in children

Introducción. El os odontoideum es un huesecillo redondo separado del axis por un defecto transversal, que deja al segmento apical sin soporte. Puede asociarse a determinadas displasias óseas como la polisacaridosis de Morquio y la displasia espondiloepifisaria. Su forma de presentación es variable, de tal manera que los síntomas de presentación pueden ser dolor de cuello, tortícolis o cefalea provocada por la irritación local de la articulación atloaxoidea. Los estudios radiológicos deben incluir siempre proyecciones laterales en flexión y extensión. Caso clínico. Se presenta el caso de un niño de diez años de edad, diagnosticado de una inestabilidad cervical C1-C2, tras realizarse unos estudios radiológicos rutinarios. Como antecedentes destacables presenta síndrome de Down e hipotiroidismo. Los estudios de tomografía axial computarizada (TAC) confirmaron el diagnóstico de inestabilidad atloaxoidea secundaria, asociada a os odontoideum. El paciente es intervenido quirúrgicamente realizándose una artrodesis posterior C1-C2

Introduction. The os odontoideum is a small round ossicle separated from the axis by a transverse defect that leaves the apical segment with no support. It may be associated with bone dysplasias such as Morquio's disease or mucopolysaccharidosis (MPS), and spondyloepiphyseal dysplasia. The mode of presentation of this condition is variable and symptoms on presentation may be neck pain, torticollis and headache caused by local irritation of the atloaxoid joint. X-ray studies must include lateral projections in flexion and extension. Case report. In this study we present a clinical case of a 10 year old boy diagnosed with cervical C1-C2 instability after a routine X-ray. Medical history included Down syndrome and hypothyroidism. Computed axial tomography (CAT) scans confirmed the diagnosis of secondary atloaxoid joint instability associated with os odontoideum. The patient underwent surgery and a subsequent C1-C2 arthrodesis was carried out

Static headspace versus head space solid-phase microextraction (HS-SPME) for the determination of volatile organochlorine compounds in landfill leachates by gas chromatography.

The determination of five volatile organochlorine compounds, VOX (chloroform, 1,1,1-trichloroethane, carbon tetrachloride, trichloroethene and tetrachloroethene) in raw landfill leachates and biologically cleansed leachates by GC-MS is investigated. Two extraction and preconcentration procedures were evaluated for recovery of such analies from the samples, including static headspace (HS) and solid phase microextraction by sampling the headspace above the sample (HS-SPME). Optimisation of operating parameters for the best performance of both, sampling and preconcentration techniques was described. Detection limits, time of analysis, precision and linear ranges of both introduction techniques have been established. Application of proposed methods to the determination of the five VOX under study in the above referred samples revealed the absence of such analytes in both leachates. Then both methods were applied to the determination to the five organochlorine compounds under study on spiked leachates samples. While HS-GC-MS offered better analytical precision than HS-SPME-GC-MS, this last technique gave a faster analytical response because no dilution must be done for a reliable VOX determination in landfill leachates. In any case, both sample introduction techniques tested provides excellent recoveries and good analytical precision (ranged from 1 to 3%).

Detection and characterization of cyclodextrin complexes with beta-carboline derivatives by spectroscopic techniques.

beta-Carboline alkaloids exhibit a great variety of pharmacological activities. The solid inclusion complexes of harmane and harmine with beta-cyclodextrin and also with hydroxypropyl-beta-cyclodextrin, have been prepared following different procedures. IR and NMR spectroscopies were employed to verify the interaction of the guest molecules with the cyclodextrin cavities. The differences observed in the IR and NMR spectra are in agreement with those described in the literature for other guest molecules. The shifts in the 13C- and 1H-NMR spectra confirm the existence of the inclusion complexes. The fluorescence emission spectra of these complexes dissolved in buffered aqueous solution (pH 7.3) exhibit the characteristic peaks of the cationic form for harmane alkaloids. The neutral bands are not present for the free alkaloids in aqueous solutions. Fluorescence quenching emission of the complexes is compared to that of the corresponding free alkaloids.

A new route toward 4-substituted pyrazino[2,1-b]quinazoline-3,6-dione systems. Total synthesis of glyantrypine.

Treatment of sodium N-(o-azidobenzoyl)aminoacylglycinates 8 with acetic anhydride afforded 1-acetyl-4-(o-azidobenzoyl)-2,5-piperazinediones 7, with complete retention of the stereochemistry. The intramolecular aza Wittig reactions of compounds 7 in the presence of tributylphosphine followed by deacetylation gave 1,2-unsubstituted pyrazino[2,1-b]quinazoline-3,6-diones 1. This route was adapted to the synthesis of both enantiomers of the alkaloid glyantrypine.

Quantitative determination of dimethicone in commercial tablets and capsules by Fourier transform infrared spectroscopy and antifoaming activity test.

Fourier transform infrared (FTIR) spectroscopy and antifoaming activity test have been employed for the quantitative analysis of dimethicone. Linearity, accuracy and precision are presented for both methods. These methods have been also used to compare different dimethicone-containing proprietary medicines. FTIR spectroscopy has shown to be adequate for quantitation of dimethicone in commercial tablets and capsules in order to comply with USP requirements. The antifoaming activity test is able to detect incompatibilities between dimethicone and other constituents. The presence of certain enzymes in some medicinal products increases the defoaming properties of these formulations.

Effects of radiation on endothelial function.

PURPOSE: The response of endothelium to ionizing radiation was studied. METHODS AND MATERIALS: The abdominal aorta in different experimental groups of rats was irradiated, and the response of arterial rings from the irradiated segments to norepinephrine, acetylcholine (ACh), and nitroglycerin (NTG) was studied. Nonirradiated thoracic segments in the same experimental animals were used as as a control for comparisons. Two age-matched nonirradiated control groups were also studied. RESULTS: A poor endothelium-dependent vasodilator response was obtained with ACh in the irradiated rings and also in those not directly irradiated; the endothelium-independent vasodilator response to NTG was preserved during the first 3 days after irradiation. By 6 months, both the endothelium-dependent response and endothelium-independent response were impaired. CONCLUSIONS: Alterations in nitric oxide synthesis and/or release by the endothelium were observed during the early phase of radiation in irradiated and nonirradiated segments. In the delayed phase of radiation, endothelium-independent muscular relaxation was also affected.

Analytical applications of retinoid-cyclodextrin inclusion complexes. 1. Characterization of a retinal-beta-cyclodextrin complex.

In studies in these laboratories on the supramolecular chemistry of the retinoids, it has been recently confirmed that inclusion of these substances within the cavity of cyclodextrins protects their excited states, thus improving their photochemical stability. In the present paper, the isolation is described of a crystalline stable complex between retinal and beta-cyclodextrin, which has been characterized by means of several techniques including atomic force microscopy (AFM). The complex shows distinct spectroscopic differences from both retinal and beta-cyclodextrin. Thus, it absorbs at lambda(max) = 380 nm in water whereas retinal is insoluble; it shows room-temperature luminescence, which retinal does not; finally, it give 1H-NMR and 13C-NMR spectra in d6-DMSO with clear differences in chemical shifts with respect to those of beta-cyclodextrin. Besides these studies in solution, the behaviour of the complex in the solid state has been compared with that of physical mixtures of retinal and beta-cyclodextrin. IR spectroscopy shows clear differences, particularly a shift in the retinal carbonyl absorption (1644-1672 cm-1). AFM studies reveal the existence of aggregates; X-ray diffractometry also supports the formation of a cyclodextrin-retinal complex.

Pharmacokinetics of sulfamethoxazole and trimethoprim in Mexicans: bioequivalence of two oral formulations (URO-TS D and Bactrim F).

Two oral pharmaceutical formulations (URO-TS D and Bactrim F) containing 800 mg of sulfamethoxazole (SMZ) and 160 mg of trimethoprim (TMP) were given to 10 Mexican healthy volunteers, following a randomized cross-over design. Blood and urine samples were obtained, concentrations of TMP, SMZ, and its metabolite N4-acetyl SMZ were measured by HPLC and pharmacokinetic analyses were performed. The observed Cmax, tmax, half-life, AUC, and cumulative urinary excretion values for the three compounds studied were within the ranges that have been previously reported for European and North American subjects. Therefore, it appears that pharmacokinetics of SMZ and TMP in Mexicans are similar to those observed in Caucasian populations. When the two studied formulations were compared, no statistically significant differences were detected in any pharmacokinetic parameter. Therefore, it is concluded that both brands tested are bioequivalent. Moreover, these two formulations manufactured in Mexico yield SMZ and TMP plasma and urine levels similar to those obtained with equivalent formulations of European or North American origin.

[Microscopic innervation of the spermatic ducts and testis. I. Vas deferens]. / Inervación microscópica de las vías espermáticas y testículo. I. Vas deferens.

The microscopic innervation of the vas deferens in the rat was studied both in light and electron microscope. The nerve fibres form perivascular, intramuscular and subepithelial plexuses. Inside the connective tissue surrounding the vas deferens both isolated nerve fibres and sensory corpuscles (glomerular and Ruffine-like types) were observed. The varicosities and endings of nerve fibres contain synaptic vesicles of different sizes and electron characteristics. These varicosities were closely related to the smooth muscle cells and some of them lacked of Schwannian sheath. The nervous fibres were not in direct contact with the epithelial cells.