Systemic phenotype of sarcoidosis associated with radiological stages. Analysis of 1230 patients.

BACKGROUND: To analyze the association between Scadding radiological stages of sarcoidosis at diagnosis and the disease phenotype (epidemiology, clinical presentation and extrathoracic involvement) in one of the largest cohorts of patients with sarcoidosis reported from southern Europe. METHODS: The SARCOGEAS-Study Group includes a multicenter database of consecutive patients diagnosed with sarcoidosis according to the WASOG 1999 criteria. Extrathoracic disease at diagnosis was defined according to the 2014 instrument and the clusters proposed by Schupp et al. RESULTS: We analyzed 1230 patients (712 female, mean age 47 yrs.) who showed the following Scadding radiologic stages at diagnosis: stage 0 (n = 98), stage I (n = 395), stage II (n = 500), stage III (n = 195) and stage IV (n = 42). Women were overrepresented in patients presenting with extrathoracic/extrapulmonary disease, while the diagnosis was made at younger ages in patients presenting with BHL, and at older ages in those presenting with pulmonary fibrosis (q values <0.05). Multivariable adjusted analysis showed that patients presenting with pulmonary involvement (especially those with stages II and III) had a lower frequency of concomitant systemic involvement in some specific extrathoracic clusters (cutaneous-adenopathic/musculoskeletal, ENT and neuro-ocular/OCCC) but a higher frequency for others (hepatosplenic), in comparison with patients with extrapulmonary involvement (stages 0 and I). The presence of either BHL or fibrotic lesions did not influence the systemic phenotype of patients with pulmonary involvement. CONCLUSIONS: The key determinant associated with a differentiated systemic phenotype of sarcoidosis at diagnosis was interstitial pulmonary involvement rather than the individual Scadding radiological stage.

Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients.

OBJECTIVE: To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS). PATIENTS AND METHODS: We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models. RESULTS: After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease. CONCLUSIONS: Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death.

How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients.

OBJECTIVE: To describe how systemic disease is treated in a large cohort of Spanish patients with primary Sjögren syndrome (pSS) in daily practice, focusing on the adequacy of therapies for the level of systemic activity measured by ESSDAI score. PATIENTS AND METHODS: By December 2014, our database included 1120 consecutive patients who fulfilled the 2002 classification criteria for SS. Therapeutic schedules were classified into 4 categories: no systemic therapies, hydroxychloroquine (HCQ) and/or low dose glucocorticoids (GCS) (<20mg/day), high dose GCS (>20mg/day) and use of second-line therapies (immunosuppressive agents, intravenous immunoglobulins [IVIG] and/or rituximab [RTX]). RESULTS: There were 1048 (94%) women and 72 (6%) men , with a mean age at diagnosis of 54 years. The main drug-based therapeutic approaches for systemic pSS during follow-up were HCQ in 282 (25%) patients, GCS in 475 (42%, at doses >20mg/day in 255-23%), immunosuppressive agents in 148 (13%), IVIG in 25 (2%) and RTX in 35 (3%) patients. HCQ was associated with a lower risk of death (adjusted HR of 0.57, 95% 0.34-0.95). We classified 16 (7%) of the 255 patients treated with >20mg GCS and 21/148 (14%) treated with immunosuppressive agents as patients inadequately treated, mainly associated with articular involvement of low/moderate activity. CONCLUSION: The management of pSS should be organ-specific, using low dose GCS in patients with moderate systemic activity, limiting the use of high dose GCS and second-line therapies to refractory or potentially severe scenarios. The use of systemic therapies for dryness, chronic pain or fatigue is not warranted.

Apoptosis, shape change and reactive oxygen species generation in human neutrophils exposed to olanzapine, an a typical antipsychotic drug

The effects of olanzapine (OLZ) on the viability and functioning of human polymorphonuclearcells (PMNs) are clearly opposite to those previously reported forclozapine (CLZ). In fact, after 4- or 24-h-treatment with 20-50 μM OLZ, a significant inhibition of the respiratory burst in PMNs activated with opsonized zimosanor phorbol myristate acetate (PMA) was observed, whereas the burst provoked byformyl-methionyl-leucyl-phenylalanine (fMLP) was only inhibited at 50 μM OLZ.Under the same conditions, spontaneous apoptosis was accelerated at 20-50 μMOLZ, while the exogenous addition of H2O2 resulted in the PMN apoptosis beingdose-dependently inhibited by OLZ in the entire range of concentrations. However,when H2O2 was intracellularly generated by treatment with PMA, the induced apoptosis was only decreased at 2 μM OLZ. Absorbance scans revealed that OLZis able to react with equimolar quantities of either H2O2 or HOCl. These results suggest that OLZ inhibits both ROS-induced PMN apoptosis and respiratory burst due to extracellular scavenging of released ROS.

Los efectos de olanzapine (olz) sobre la viabilidad y el funcionamiento de células humanas polimorfonucleares (pmn, por sus siglas en inglés) claramente son opuestosa los señalados para la clozapine (clz). En efecto, después de 4-24 h de tratamiento con 20-50 μM olz, se observó una inhibición significativa del estallido respiratorio en pmn activados con zimosan o con forbol acetato miristato, mientras que la inhibición provocada por el formil-metionil-leucil-fenilalanina fue sólo inhibida a 50μM de olz. En las mismas condiciones, la apoptosis espontánea se aceleró con 20-50μM olz, mientras que la adición exógena de H2O2 dio lugar a la apoptosis de pmn en dosis dependiente inhibida por olz en el rango entero de concentraciones. Sin embargo, cuando se generó H2O2 intracelular por tratamiento con pma, la apoptosis inducida se disminuyó solamente con 2 μM olz. Las exploraciones de los espectros de absorbancia revelaron que olz puede reaccionar con cantidades equimolares de H2O2 o de HOCL. Estos resultados sugieren que olz inhibe ambos tipos de apoptosis de pmn (la inducida por especies reactivas oxigenadas y por estallido respiratorio debido a atrapadores extracelulares de estas especies reactivas oxigenadas).

Estudio biomecánico experimental del sistema musculo-esquelético masticatorio. Aplicaciones para el estudio de la osteosíntesis / Experimental Biomechanical Study of the Musculo-Skeletal Masticatory System. Applications to the Study of Osteosynthesis

El comportamiento biomecánico del sistema músculoesqueléticodista mucho de estar esclarecido. Los modelos matemáticos han mostradoimportantes limitaciones, y los ensayos biomecánicos se han visto frustradospor la dificultad de simular las cargas musculares y la distribución delas tensiones en el espesor mandibular. En el presente trabajo se desarrollaun simulador estático del sistema músculo esquelético masticatorio que reproducefielmente la situación fisiológica, empleándose la foto elasticidad tridimensionalpara el estudio de los cambios tensionales que ocurren en laestructura mandibular en diversas situaciones fisiopatológicas. Los resultadosde los ensayos demuestran que la fotoelasticidad 3D aplicada en el simuladorda resultados muy útiles para el análisis de la aplicación hueso-materialde osteosíntesis utilizado en la práctica clínica(AU)

The biomechanical behavior of the masticatory system isnot well known. The mathematical models that have been developedto date are limited and experimental studies have not yet solvedthe problem of reproducing muscular forces and stress distributionsin the internal mandibular structure. A static simulator of themasticatory system was developed in the present study and threedimensionalphotoelasticity was used to analyze stress distributionin several physiologic and pathologic situations. The results showedthat the simulator and 3D photoelasticity were useful for studyinginteractions and ostheosynthesis materials used in daily clinicalpractice(AU)

Aplasia pura de células rojas secundaria a carbamazepina / No disponible

No disponible

Aplasia pura de células rojas adquirida secundaria a carbamazepina / No disponible

No disponible

Quilotórax espontáneo después de ejercicio mínimo en una mujer de mediana edad: una entidad a reconocer con buen pronóstico / Spontaneous chylothorax after minimum exercise in middle-aged woman. A disease to be recognized with good prognosis

No disponible

Clozapine prevents apoptosis and enhances receptor-dependent respiratory burst in human neutrophils.

The present study was undertaken to determine if the antipsychotic drug clozapine (CLZ) in the concentration range 2-50 microM can rescue polymorphonuclear cells (PMNs) from undergoing apoptosis. Our results indicate that 20 microM CLZ can rescue PMNs both from UVB-accelerated (28.0% vs. 45.9% for control without CLZ; P < 0.05) and from spontaneous (35.8% vs. 57.6%; P < 0.05) apoptosis whereas 50 microM CLZ could rescue PMNs from spontaneous (34.3% vs. 57.6%; P < 0.05) apoptosis only. Furthermore, since apoptosis has been reported to involve the impairment of PMN function, we evaluated the effects of CLZ on respiratory burst in UVB-irradiated and in unirradiated PMNs. When 20 or 50 microM CLZ-pretreated PMNs were aged in a culture during 4 h, the luminol-dependent chemiluminescence (CL) response was 3-fold (P < 0.01) and 2.5-fold (P < 0.05) increased, respectively, by subsequent exposure to serum opsonized zymosan (OZ). When 50 microM-pretreated PMNs were either UVB-irradiated or unirradiated, the CL response was 2.6-fold (P < 0.05) and 3.3-fold (P < 0.05) increased, respectively, after subsequent exposure to formyl-methionyl-leucyl-phenylalanine (fMLP). In contrast, the degree of enhancement was negligible upon subsequent exposure to ionomycin or phorbol myristate acetate (PMA). When incubation times were extended up to 22 h, the CL response induced by OZ in 20 microM CLZ-treated PMNs had a 4.9-fold increase (P < 0.001). This priming effect could be reverted when 20 microM CLZ-treated PMNs (aged 4 h in culture) were coincubated for 5 min with the protein tyrosine kinase inhibitor genistein as well as with the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin. These findings suggest that CLZ primes respiratory burst and prevents PMN apoptosis as a consequence of tyrosine phosphorylation- and PI3-K activation-dependent signal transduction pathways.

Antioxidant properties of dipyridamole as assessed by chemiluminescence.

The ability of dipyridamole (DIP) to scavenge oxygen metabolites generated by either activated human neutrophils (PMNs) or cell-free systems using luminol(s)- and lucigenin-enhanced chemiluminescence was investigated. In the presence of DIP (15-50 microM) a dose-dependent inhibition period was seen in phorbol myristate acetate (PMA)-stimulated PMNs as assayed by isoluminol-enhanced chemiluminescence (ILCL) with horseradish peroxidase (HRP). Although such a lag period was not observed in the absence of HRP, 50 microM DIP inhibited extracellular ILCL by more than 50%. Intracellular luminol-enhanced chemiluminescence (LCL) as assayed in either PMA- or in ionomycin-activated PMNs was not affected by dipyridamole (15-50 microM). In cell-free systems, DIP produced concentration-dependent inhibition in H2O2-(45% at 50 microM), OH- (40%, at 0.1 microM) and HOCl-(20% at 10 microM). Both absorbance and fluorescence scans revealed that DIP is able to react with equimolar quantities of either H202 or HOCl. These results suggest that DIP scavenges reactive oxygen species (ROS) presumably secreted by activated human PMNs in the following decreasing order: *OH > HOCl > H2O2 >> O2-.

Tratamiento ortodóncico-quirúrgico de una fisura labio-palatina bilateral severa / Combined treatment (orthodontic-surgical) of a severe bilateral lip-palatal fissure

Las fisuras labiopalatinas bilaterales son un verdadero reto para los especialistas que las diagnostican y tratan. La aberración anatómica es tan severa que hace necesario aplicar un protocolo terapéutico, ortopédico-ortodóncico y quirúrgico, durante todo el desarrollo de los pacientes. Muchas veces esto no es posible, porque en el momento que llegan a nuestra consulta, los pacientes tienen una edad avanzada y es difícil aplicar el protocolo idóneo. Estos pacientes presentan alteraciones, no solo inherentes a su malformación, sino también fruto de cirugías anteriores y de la ausencia de una ortodoncia precisa y de un seguimiento protocolizado. Presentamos a un paciente con una malformación con repercusión funcional y estética facial y maloclusión severa por una fisura labio palatina bilateral. Aplicamos un protocolo ortodóncico-quirúrgico ajustado a la severidad del caso. Describimos la queiloplastia y rinoplastia secundaria, el tratamiento ortodóncico, la alveoloplastia con injertos óseos con la erupción espontánea de ambos caninos y la reposición quirúrgica del maxilar y la premaxila (AU)

Studies on the photostability and phototoxicity of aloe-emodin, emodin and rhein.

Aloe-emodin (1), emodin (2) and rhein (3) were found to be photolabile by visible (390-500 nm) light under aerobic conditions. The drugs 1, 2 and 3 were phototoxic in vitro when examined by the photohemolysis test under both oxygen and argon atmospheres, although the photohemolysis rate was markedly lower under anaerobic conditions. The experiments were also carried out in the presence of butylated hydroxyanisole (BHA), reduced glutathione (GSH), sodium azide (NaN3) and superoxide dismutase (SOD). Based on the inhibition of this process on addition of BHA, GSH, SOD and NaN3, there would seem to be involvement of free radicals (type I mechanism) and singlet oxygen in the process (type II mechanism). The in vitro phototoxicity of this anthraquinone series was also verified in a lipid-photoperoxidation test with linoleic acid. In summary, this anthraquinone series is phototoxic in vitro. This behavior can be explained through the involvement of singlet oxygen and stable photoproducts.

Photosensitizing activity of thiocolchicoside: photochemical and in vitro phototoxicity studies.

The phototoxic drug thiocolchicoside (2-dimethoxy-2-glucosidoxythiocolchicine, 1), is photolabile under irradiation with UV-A light from TL 100 W-P Philips bulbs (at lambda max 355 nm) light and also with a N2 laser (at 337 nm) in aerobic and anaerobic conditions. Irradiation of a methanol solution of 1 produces two photoproducts without a glucoside group. One of these lost the methylthio-group, while the other is oxidized (only under aerobic conditions) to sulfoxide. The formation of singlet oxygen by photolysis of 1 was evidenced by trapping with 2,5-dimethylfuran (GC-MS), furfuryl alcohol, 1,3-cyclohexadiene-1,4-diethanoate (HPLC) and by the histidine test as 1O2 scavengers. Thiocolchicoside has been shown to photosensitize the reduction of nitro blue tetrazolium by direct electron transfer mechanism, when irradiated under the same conditions as for photolysis. Oxygen may also be involved in this electron transfer reaction to form the superoxide anion radical. Thiocolchicoside was screened in vitro in different concentrations for UV-Vis-induced phototoxic effects in a photohemolysis test, in the presence and absence of different radical scavengers, singlet oxygen and superoxide radical quenchers. In addition, 1 photosensitized the peroxidation of linoleic acid, monitored by the UV-detection of dienic hydroperoxides. Studies on peripheral blood mononuclear cells (lymphocytes) demonstrated phototoxic effects on them. Protection by GSH, DABCO, sodium azide and SOD are indicative of both Type I and II photosensitization pathways mediated by free radicals and singlet molecular oxygen.

In vitro antioxidant and photo-oxidant properties of dipyridamole.

The in vitro antioxidant and photo-oxidant activity of dipyridamole was studied by its effect on superoxide- and singlet oxygen-mediated photohemolysis and viability of neutrophils. Dipyridamole was found to be phototoxic when examined by the photohemolysis on human erythrocytes and on linoleic acid as lipid peroxidation model at concentrations above 3.0 x 10(-5) M. On the contrary, when lower concentrations (1.0 x 10(-5) to 1.0 x 10(-6) M) were used, dipyridamole showed a protector action against singlet oxygen-mediated photohemolysis by other phototoxic compounds like triamterene. This antioxidant property is proposed to result from quenching of triamterene mediated by fluorescence energy transfer. Auto-oxidation and fluorescence-energy transfer is clearly an important mechanism for protection for this drug.

Studies on the in vitro phototoxicity of the antidiabetes drug glipizide.

The phototoxic antidiabetes drug glipizide (1) is photolabile under aerobic conditions and UV-B light. Irradiation of a phosphate-buffered solution of 1 under oxygen atmosphere produces 4 photoproducts as well as singlet oxygen, which was detected by trapping it with 2,5-dimethylfuran and by the histidine test. The photochemistry of 1 involves cleavage of the sulfonamine and the sulfonamine-R bonds. Red blood cell lysis, photosensitized by glipizide and the products of its aerobic photolysis were demonstrated. The photohemolysis rate was lower for 1 than for its photoproducts. Inhibition of this process on addition of 1, 4-diazabicyclo[2.2.2]octane (DABCO), reduced glutathione (GSH), Vitamin C, sodium azide, superoxide dismutase, and a-tocopherol confirmed the possibility of singlet oxygen, superoxide ion and free radicals participation. Furthermore, in a lipid-photoperoxidation test with linoleic acid the in vitro phototoxicity of glipizide was also verified. A low decreasing cell viability of lymphocytes and neutrophils was observed.

Photochemistry and phototoxicity studies of flutamide, a phototoxic anti-cancer drug.

The phototoxic anti-cancer drug flutamide is photolabile under UV-B light in either aerobic or anaerobic conditions. Irradiation of a methanol solution of this drug produces several photoproducts, one by photoreduction of the nitro group, one by rupture of the aromatic-NO2 bond of the parent compound, two as a result of the rupture of the CO-NH bond and one derived from the photoreduction product by scission of the aromatic-NH2 bond. Flutamide shows a photohemolytic effect on human erythrocytes and photoinduces lipid peroxidation. Studies on peripheral blood polymorphonuclear cells (neutrophils) demonstrated the phototoxicity of flutamide as well as inhibition of the cytotoxicity respiratory burst by the photoproduct derived from its photoreduction. The results suggest that the inhibition of the respiratory burst observed in phorbol myristate acetate (PMA)-activated cells is mediated by photosensitization and concomitant singlet oxygen production and/or formation of toxic photoproducts.

Photodegradation and phototoxicity studies of furosemide. Involvement of singlet oxygen in the photoinduced hemolysis and lipid peroxidation.

The phototoxic diuretic drug furosemide (1), a 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)-amino] benzoic acid is photolabile under aerobic and anaerobic conditions. Irradiation of a methanol solution of 1 under oxygen produces photoproducts 2, 3, 4 and singlet oxygen, while under argon the photoproducts 2 and 4 were isolated. A peroxidic unstable photoproduct was detected during the photolysis under oxygen atmosphere. The formation of singlet oxygen by photolysis of 1 was evidenced by trapping with 2,5-dimethylfuran (GC-mass), furfuryl alcohol and 1,3-cyclohexadiene-1,4-diethanoate (HPLC) as 1O2 scavengers and by the histidine test. Furosemide was screened in vitro at different concentrations for UV-Vis-induced phototoxic effects in a photohemolysis test, in the presence and absence of different radical scavengers, singlet oxygen and hydroxyl radical quenchers. However, furosemide photosensitized the peroxidation of linoleic acid, as monitored by the UV-detection of dienic hydroperoxides and it also photosensitized the oxidation of histidine. The photodegradation was catalyzed in the presence of human serum albumin. Studies on peripheral blood mononuclear and polymorphonuclear cells (lymphocytes and neutrophils) demonstrated no phototoxicity on these cell lines.