Validación externa de las ecuaciones europea y americana para el cálculo del riesgo cardiovascular en población laboral española / Validación externa de las ecuaciones europea y americana para el cálculo del riesgo cardiovascular en población laboral española External validation of the European and American equations for calculating cardiovascular risk in a Spanish working population

Objetivo Validar externamente los modelos europeo y norteamericano de cálculo de riesgo cardiovascular en prevención primaria. Métodos Estudio transversal de una cohorte nacional de población laboralmente activa. Se incluyeron trabajadores sin antecedentes de enfermedad cardiovascular que acudieron a una revisión laboral entre los años 2004 y 2007, y se siguieron hasta 2017. Resultados Participaron 244.236 sujetos. El 24,5% eran mujeres, la edad media se situó en 48,10 años (DE 6,26). El riesgo medio según el modelo europeo SCORE fue de 1,70 (DE 1,81) para hombres y de 0,37 (DE 0,53) para mujeres. Según el modelo norteamericano PCE, el riesgo medio fue de 6,98 (DE 5,66) para hombres y de 1,97 (DE 1,96) para mujeres. Se registró un total de 1.177 eventos (0,51%) considerados en la calculadora SCORE, y un total de 2.330 eventos (1%) considerados según las PCE. El estadístico C de Harrell fue de 0,746 (SCORE) y 0,725 (PCE). La sensibilidad y especificidad para el punto de corte del 5% en SCORE fue del 17,59% (IC95% 15,52-19,87%) y 95,68% (IC95% 95,59-95,76%) y para el punto de corte del 20% de las PCE de 9,06% (IC95% 7,96-10,29%) y 97,55% (IC95% 97,48-97,61%), respectivamente. Conclusiones Las tablas europeas del SCORE y americanas de las PCE sobreestiman el riesgo en nuestra población, manteniendo una discriminación aceptable. SCORE mostró mejores índices de validez que las PCE. El perfil de riesgo de las poblaciones va cambiando, por lo que es necesario ir actualizando las ecuaciones que incluyan información de poblaciones más contemporáneas (AU)

Objective This work aims to externally validate the European and American models for calculating cardiovascular risk in the primary prevention. Methods This is a cross-sectional study of a nation-wide cohort of individuals who are active in the work force. Workers without a medical history cardiovascular disease who attended occupational health check-ups between 2004 and 2007 were included. They were followed-up on until 2017. Results A total of 244,236 subjects participated. Of them, 24.5% were women and the mean age was 48.10 years (SD 6.26). According to the European SCORE risk chart, the mean risk was 1.70 (SD 1.81) for men and 0.37 (SD 0.53) for women. According to the North American PCE model, the mean risk was 6.98 (SD 5.66) for men and 1.97 (SD 1.96) for women. A total of 1,177 events (0.51%) were registered according to the SCORE tool and 2,330 events (1.00%) were registered according to the PCE tool. The Harrell's C-statistic was 0.746 for SCORE and 0.725 for PCE. Sensitivity and specificity for the SCORE'S 5% cut-off point were 17.59% (95%CI 15.52%-19.87%) and 95.68% (95%CI 95.59%-95.76%). Sensitivity and specificity for the PCE's 20% cut-off point were 9.06% (95%CI 7.96%-10.29%) and 97.55% (95%CI 97.48%-97.61%), respectively. Conclusions The European SCORE and North American PCE models overestimate the risk in our population but with an acceptable discrimination. SCORE showed better validity indices than the PCE. The population's risk is continuously changing; therefore, it is important continue updating the equations to include information on current populations (AU)

External validation of the European and American equations for calculating cardiovascular risk in a Spanish working population.

INTRODUCTION AND OBJECTIVE: This work aims to externally validate the European and American models for calculating cardiovascular risk in the primary prevention. METHODS: This is a cross-sectional study of a nation-wide cohort of individuals who are active in the work force. Workers without a medical history cardiovascular disease who attended occupational health check-ups between 2004 and 2007 were included. They were followed-up on until December 2017. RESULTS: A total of 244,236 subjects participated. Of them, 24.5% were women and the mean age was 48.10 years (SD 6.26). According to the European SCORE risk chart, the mean risk was 1.70 (SD 1.81) for men and 0.37 (SD 0.53) for women. According to the North American PCE model, the mean risk was 6.98 (SD 5.66) for men and 1.97 (SD 1.96) for women. A total of 1177 events (0.51%) were registered according to the SCORE tool and 2,330 events (1.00%) were registered according to the PCE tool. The Harrell's C-statistic was 0.746 for SCORE and 0.725 for PCE. Sensitivity and specificity for the SCORE'S 5% cut-off point were 17.59% (95%CI 15.52%-19.87%) and 95.68% (95%CI 95.59%-95.76%). Sensitivity and specificity for the PCE's 20% cut-off point were 9.06% (95%CI 7.96%-10.29%) and 97.55% (95%CI 97.48%-97.61%), respectively. CONCLUSIONS: The European SCORE and North American PCE models overestimate the risk in our population but with an acceptable discrimination. SCORE showed better validity indices than the PCE. The population's risk is continuously changing; therefore, it is important continue updating the equations to include information on current populations.

Daylight photodynamic therapy for prevention of new actinic keratosis and keratinocyte carcinomas in organ transplants. A cryotherapy-controlled randomized clinical trial.

BACKGROUND: Organ transplant recipients (OTR) have a higher risk of actinic keratosis (AK) and keratinocyte carcinomas (KC). There are no clinical trials assessing the effectiveness of daylight photodynamic therapy (DPDT) to prevent new AK and KC in OTR. OBJECTIVES: To determine whether repeated treatments of field cancerization with DPDT are effective in preventing new AK and KC in OTR. METHODS: A randomized, intra-subject controlled, evaluator-blind, split-face and/or scalp trial, from April 2016 to October 2018. Participants were OTR older than 18 years, 1-year posttransplant, with at least 5 AK on each hemi-face/hemi-scalp. One side received six field treatments with DPDT: two sessions 15 days apart at baseline, two at 3 months and two at 9 months after baseline. Control side received lesion-directed treatment with cryotherapy (double freeze-thaw) at baseline, 3 and 9 months. Total number of lesions (AK and KC) at 21 months, number of new AK and KC at 3, 9, 15 and 21 months and treatment preferences were analysed. RESULTS: Of 24 men included, 23 were analysed at 3 months; and 21, at 9, 15 and 21 months. Mean (SD) age was 69.8 years (9.2). The total number of lesions at 21 months was 4.7 (4.3) for DPDT and 5.8 (5.0) for control side; P = 0.09. DPDT showed significantly lower means [SD] of new lesions compared to control side at 3 months (4.2 [3.4] vs. 6.8 [4.8]; P < 0.001), 9 months (3.0 [3.3] vs. 4.3 [3.4]; P = 0.04) and 15 months (3.0 [4.6] vs. 4.8 [5.0]; P = 0.02), and non-significant at 21 months (3.7 [3.5] vs. 5.0 [4.5]; P = 0.06). Most participants preferred DPDT. CONCLUSION: DPDT showed potential effectiveness in preventing new AK and KC in OTR by consecutive treatments of field cancerization. The preference for DPDT could facilitate adherence to the long-term treatment necessary in these patients.

Bacterias Multirresistentes. Revisión del Estado Actual / No disponible

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Tratamiento con ondas de choque en un caso de rotura muscular del delgado plantar complicada / Shock wave treatment in a case of complicated plantaris muscle rupture

Las lesiones musculares son frecuentes en el ámbito laboral. Se producen por el mecanismo de traumatismos directos o indirectos bruscos, que ocasiona una rotura de sus fibras, provocando hematomas. Actualmente no existe un modelo único protocolizado de tratamiento. Presentamos el caso de un paciente diagnosticado de rotura muscular completa del delgado plantar por mecanismo traumático indirecto (elongación muscular brusca), con hematoma asociado de gran volumen. Se realizó estudio clínico mediante ecografía, resonancia magnética (RM), escala visual analógica (EVA) para valoración del dolor al inicio y al finalizar el tratamiento (3 semanas), así como la duración de su incapacidad laboral. Recibió terapia con ondas de choque electromagnéticas focales (OCEF) según protocolo. Al finalizar el tratamiento se objetivó una desaparición del hematoma y no hubo complicaciones. Las OCEF pudieran ser una alternativa terapéutica complementaria al tratamiento convencional en esta afección, no obstante, sería necesario proseguir la investigación incluyendo un mayor número de pacientes, y a través de estudios aleatorizados con grupo control

Muscle injuries are frequent in the workplace. They are produced by sudden direct or indirect trauma that involves a rupture of the fibres, causing bruising. Currently, there is no single protocol-based model of treatment. We present the case of a patient diagnosed with complete muscular rupture of the plantaris muscle by an indirect traumatic mechanism (abrupt muscular elongation), with an associated large-volume hematoma. Clinical study consisted of ultrasound, magnetic resonance (MR), pain assessment (VAS) at the beginning and at the end of the treatment (3 weeks), as well as duration of occupational disability. The patient underwent extracorporeal shockwave therapy (ESWT) according to the protocol. At the end of treatment, the hematoma was resolved and there were no complications. ESWT could be a complementary therapeutic alternative to conventional treatment in this entity. However, there is a need for further, randomised controlled studies including a larger number of patients

[Shock wave treatment in a case of complicated plantaris muscle rupture]. / Tratamiento con ondas de choque en un caso de rotura muscular del delgado plantar complicada.

Muscle injuries are frequent in the workplace. They are produced by sudden direct or indirect trauma that involves a rupture of the fibres, causing bruising. Currently, there is no single protocol-based model of treatment. We present the case of a patient diagnosed with complete muscular rupture of the plantaris muscle by an indirect traumatic mechanism (abrupt muscular elongation), with an associated large-volume hematoma. Clinical study consisted of ultrasound, magnetic resonance (MR), pain assessment (VAS) at the beginning and at the end of the treatment (3 weeks), as well as duration of occupational disability. The patient underwent extracorporeal shockwave therapy (ESWT) according to the protocol. At the end of treatment, the hematoma was resolved and there were no complications. ESWT could be a complementary therapeutic alternative to conventional treatment in this entity. However, there is a need for further, randomised controlled studies including a larger number of patients.

Estimating the impact of obesity and metabolic phenotype on sickness absence. Results from the ICARIA study.

BACKGROUND AND AIMS: To assess the impact of obesity and being overweight on sickness absence (SA) as a function of healthy/unhealthy metabolic phenotype. METHODS AND RESULTS: A total of 173 120 healthy workers who underwent a routine check-up, consisting of a structured interview, anthropometric measurements and blood pressure and fasting blood analysis, were included as the study sample (67.1% males; 49.2% manual workers; mean age 40.6 ± 21.9 years). Workers were classified according to their body mass index (BMI) and metabolic phenotype. A metabolically unhealthy phenotype was defined as the presence of three or more of the following criteria: glycaemia ≥110 mg/dL or previously diagnosed type I/II diabetes or treatment for diabetes; triglycerides ≥150 mg/dL or lipid-lowering therapy; HDL <40/50 mg/dL M/F; blood pressure ≥130/85 mmHg or previously diagnosed hypertension or antihypertensive therapy; waist circumference >102/88 cm M/F. A one-year follow-up was conducted to evaluate the incidence of work-related and non-work-related SA (WRSA/NWRSA). The association of BMI with SA was tested using Poisson regression (standard error correction), segmenting on the basis of metabolic phenotype. The overall percentages of workers who were overweight, obese and/or had a metabolically unhealthy phenotype were 37.7%, 16.3% and 8.8%, respectively. BMI was associated with increased incidence of NWRSA in both phenotypes. It was also associated with WRSA in subjects with a BMI in the range of 35-39.99 kg/m2 and in metabolically healthy individuals. WRSA was lower in subjects with a BMI ≥40 kg/m2 and among metabolically unhealthy individuals. CONCLUSION: Obesity is associated with health problems that have a significant impact on SA.

Prevalence of atherogenic dyslipidemia: association with risk factors and cardiovascular risk in Spanish working population. "ICARIA" study.

OBJECTIVE: The aim of this study was to assess the prevalence of atherogenic dyslipidemia (AD) and the lipid triad (LT) in the working population in Spain, their associated variables and how far they are linked to cardiovascular risk (CVR). METHODS: Observational cross-sectional study of 70,609 workers (71.5% male (M), 28.5% female (F), mean age 39.2 ± 10), who attended medical checkups and agreed to participate. Plasma samples were analysed in a central laboratory. AD definition used was: triglycerides ≥150 mg/dl and HDL cholesterol <40 mg/dl (M)/<50 mg/dl (F) and LT when LDL cholesterol > 160 mg/dl is further added. Univariate comparisons in the absence and presence of AD and LT and the probability of AD according to different parameters and their possible association with CVR were assessed. CVR was stratified following the European SCORE model for low risk-population. RESULTS: 5.7% (95% CI 4.7-6.9) of the working population have AD and 1.1% (95% CI 1.0-1.2) LT. In univariate analysis, workers with AD and LT had a higher prevalence of obesity, hypertension, smoking and diabetes than those who had not (p < 0.001). In multivariate analysis, BMI, sex, age 40-49, diabetes, tobacco, uric acid, LDL or blood pressure significantly influenced the risk of AD. AD was significantly associated with CVR after adjusting for alcohol and obesity. However, most of the AD subjects (91.8%) were classified as low risk. CONCLUSIONS: About 6% of the working population in Spain meets AD criteria. Assuming that these subjects have increased CVR, AD allows to identify additional 5% of subjects with increased CVR to that one the SCORE model detects, helping to improve cardiovascular risk stratification.

Dermatomiositis del adulto asociada a lipodistrofia / Adult Dermatomyositis Associated With Lipodystrophy

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Photodynamic therapy for actinic keratosis in organ transplant patients.

BACKGROUND: The incidence of actinic keratoses (AK) and non-melanoma skin cancer (NMSC) in organ transplant recipients (OTRs) is significantly higher than in immunocompetent patients. Rates of progression and recurrence following treatment are higher too, in part due to the effects of the immunosuppressant drugs. Conventional therapies for AK, using curettage, cryotherapy, surgical excision, topical therapies and photodynamic therapy (PDT), are often less effective, and may be inappropriate, for treating the greater numbers and extent of lesions in OTRs. Moreover, there are no specific protocols for treating this patient population that take into account the need for more frequent treatment and the increased pain associated with treating larger areas. OBJECTIVES: Recently, a pan-European group of dermatologists with expertise in this area met to share current best practice in PDT for the treatment of AK in OTRs. METHODS: The group identified areas where PDT currently is not meeting the needs of these patients and discussed how these gaps might be addressed. RESULTS/CONCLUSIONS: This position article summarizes those discussions and makes recommendations concerning a standardized protocol for treating OTRs, for a large randomized controlled trial to provide robust data on safety, efficacy and optimal pain control, and to provide pharmaco-economics data that can be used to support extended reimbursement in this patient group. The authors also recommend a second clinical trial to further investigate induced immunosuppression with PDT in healthy volunteers.

High cardiovascular risk in Spanish workers.

BACKGROUND AND AIMS: To investigate the prevalence of high cardiovascular risk in the Spanish working population, and its distribution among different occupations and gender. METHODS AND RESULTS: Cross-sectional study of 309,955 workers (72.6% males, mean age 36.5 years, range 16-74 years), who underwent a routine medical check-up. Workers were classified as high, intermediate or low cardiovascular risk, according to the SCORE system. Workers with a relative risk greater than 4 were also considered as high-risk. The prevalence of high cardiovascular risk was 7.6% (95% CI 7.5-7.7) in males and 1.7% (95% CI 1.6-1.8) in females. After adjusting for age and gender, the prevalence of high cardiovascular risk was greater in workers from the Agriculture and Construction sectors than in those from Industry and Service sectors. The prevalence of high cardiovascular risk was higher in blue-collar than in white-collar occupations. CONCLUSIONS: A sizeable proportion of workers, especially blue-collar males, are at high cardiovascular risk. Knowledge of this risk for certain workers may serve as a basis for preventive strategies.

Actualización en malformaciones venosas / Current management of venous malformations

Las malformaciones venosas representan 2/3 de todas las malformaciones vasculares y con frecuencia son mucho más complejas de lo que realmente parecen. Los pacientes con grandes malformaciones venosas requieren un estudio analítico y radiológico profundo, así como tratamiento específico para controlar una posible coagulación intravascular localizada. Si las lesiones son extensas, especialmente en el miembro inferior, se debe estudiar la presencia de una osteoporosis subyacente con la idea de prevenir fracturas patológicas. Igualmente debe controlarse la artropatía, y valorar la realización de una sinovectomía profiláctica precoz cuando la extensión radiológica lo aconseje, con la idea de evitar daños articulares irreversibles con el paso de los años. Actualmente la escleroterapia con microespuma se preconiza como el tratamiento de elección para las malformaciones vasculares de bajo flujo. En un futuro no muy lejano la utilización de fármacos antiangiogénicos selectivos, además de las heparinas de bajo peso molecular, servirán para controlar y tratar las malformaciones venosas (AU)

Las malformaciones venosas representan 2/3 de todas las malformaciones vasculares y con frecuencia son mucho más complejas de lo que realmente parecen. Los pacientes con grandes malformaciones venosas requieren un estudio analítico y radiológico profundo, así como tratamiento específico para controlar una posible coagulación intravascular localizada. Si las lesiones son extensas, especialmente en el miembro inferior, se debe estudiar la presencia de una osteoporosis subyacente con la idea de prevenir fracturas patológicas. Igualmente debe controlarse la artropatía, y valorar la realización de una sinovectomía profiláctica precoz cuando la extensión radiológica lo aconseje, con la idea de evitar daños articulares irreversibles con el paso de los años. Actualmente la escleroterapia con microespuma se preconiza como el tratamiento de elección para las malformaciones vasculares de bajo flujo. En un futuro no muy lejano la utilización de fármacos antiangiogénicos selectivos, además de las heparinas de bajo peso molecular, servirán para controlar y tratar las malformaciones venosas (AU)

[Current management of venous malformations]. / Actualización en malformaciones venosas.

Venous malformations represent 2/3rds of all vascular malformations and are frequently much more complex than they appear to be. Patients with large venous malformations require a deep analytical and radiological study, as well as specific treatment to control any possible localised intravascular coagulation. If the lesions are extensive, especially in the lower member, a study should be made to detect the presence of an underlying osteoporosis with the idea of preventing pathological fractures. Equally, a check must be made for arthropathy, and an early prophylactic synovectomy must be considered when the radiological extension makes this advisable, with the idea of avoiding irreversible damage to the joints with the passage of time. Currently, microfoam scleropathy is favoured as the treatment of choice for low-flow vascular malformations. In the not too distant future, the use of selective antiangiogenic medicines, besides low-molecular-weight heparins, will serve to control and treat malformations.

Angiogenic and prothrombotic markers in extensive slow-flow vascular malformations: implications for antiangiogenic/antithrombotic strategies.

BACKGROUND: Venous and combined malformations are slow-flow haemodynamically inactive lesions that are present at birth and worsen slowly with advancing age, showing no tendency towards involution. The pathogenesis of vascular anomalies has not been fully elucidated, but their formation and progression are closely related to angiogenesis. Localized intravascular coagulation associated with venous or combined malformations is characterized by low fibrinogen, high D-dimers, and normal platelet count. OBJECTIVES: To assess the relationship of angiogenic factors with prothrombotic and endothelial damage/dysfunction markers in patients with extensive slow-flow vascular malformations. METHODS: A 2-year study (2005-2007) included 31 consecutive patients with extensive slow-flow vascular malformations from one centre. RESULTS: Serum levels of the endothelial receptor tyrosine kinase TIE-2, matrix metalloproteinase (MMP)-9 and angiopoietin (Ang)-2 and plasma levels of D-dimer, plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator and von Willebrand factor (vWf) were significantly increased in patients compared with healthy controls, whereas serum levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, MMP-2, Ang-1, platelet-derived growth factor (PDGF)-AB and PDGF-BB were significantly decreased in patients compared with controls. A strong positive correlation was present between Ang-1 and PDGF-AB levels (r = 0.63, P < 0.001), between PDGF-AB and PDGF-BB levels (r = 0.67, P < 0.001), and between fibrinogen and PAI-1 levels (r = 0.41, P = 0.031). A strong negative correlation was present between Ang-1 and vWf levels (r = -0.48, P = 0.006), between D-dimer and fibrinogen levels (r = -0.71, P < 0.001), and between PDGF-AB and vWf levels (r = -0.42, P = 0.017). CONCLUSIONS: These findings suggest that angiogenic, coagulation and endothelial damage/dysfunction markers are possibly linked in pathogenesis of extensive slow-flow vascular malformations, and might have therapeutic implications.

Quantitative profiling of in vivo generated cisplatin-DNA adducts using different isotope dilution strategies.

Platinum compounds are the major group of metal-based chemotherapeutic drug used in current practice and still a topic of intense investigation. The relative contribution of structurally defined cisplatin adducts with DNA to induce apoptosis and the cellular processing of these lesions is still poorly understood mostly due to the lack of sensitive and accurate analytical tools for in vivo studies. In this regard, two novel sensitive and selective strategies are proposed here to quantify cisplatin-DNA adducts generated in Drosophila melanogaster larvae and in head and neck squamous cell carcinoma cultures. The methods involve the isolation and enzymatic digestion of the DNA in the samples exposed to cisplatin and further quantification by high-performance liquid chromatography with inductively coupled plasma mass spectrometric detection (HPLC-ICPMS). Two different strategies, based on isotope dilution analysis (IDA), have been attempted and evaluated for quantification: species-unspecific (the postcolumn addition of a 194Pt-enriched solution) and the species-specific (by means of a synthesized isotopically enriched cisplatin (194Pt) adduct). For the second approach, the synthesis and characterization of the cisplatin adduct in a custom oligonucleotide containing the sequence (5'-TCCGGTCC-3') was necessary. The adducted oligo was then added to the DNA samples either before or after enzymatic hydrolysis. The results obtained using these two strategies (mixing before and after enzymatic treatment) permit to address, quantitatively, the column recoveries as well as the efficiency of the enzymatic hydrolysis. Species-specific spiking before enzymatic digestion provided accurate and precise analytical results to clearly differentiate between Drosophila samples and carcinoma cell cultures exposed to different cisplatin concentrations.

[Prolonged complete clinical remission in patients with severe pemphigus vulgaris after cycles of intravenous cyclophosphamide]. / Remisión clínica completa prolongada en pacientes con pénfigo vulgar grave después del tratamiento con ciclos intravenosos de ciclofosfamida.

BACKGROUND: Corticosteroids are the systemic treatment of choice in patients with pemphigus vulgaris, but chronic administration is associated with side effects. Intravenous treatment with cyclophosphamide can improve the clinical signs of pemphigus vulgaris. MATERIAL AND METHODS: We prospectively studied 8 patients diagnosed with pemphigus vulgaris. Six of these had mucocutaneous pemphigus vulgaris and 2 had mucosal pemphigus vulgaris. Treatment consisted of 10 cycles of cyclophosphamide at a dose of 10-15 mg/kg separated by 15 days, while maintaining the initial corticosteroid and immunosuppressant dose. Clinical efficacy was assessed and the anti-epidermal intercellular substance (EIS) and anti-desmoglein (DSG) 3 and 1 antibody titers were monitored (by indirect immunofluorescence and enzyme-linked immunosorbent assay, respectively). RESULTS: All patients with pemphigus vulgaris responded excellently to treatment. Five of the 8 patients achieved complete remission of pemphigus lesions after 10 cycles of cyclophosphamide. In the other 3 patients, the skin lesions disappeared a few weeks after the last cycle of cyclophosphamide. A substantial reduction in immuno suppressant dose was possible in all patients. Furthermore, an improved immunologic response was observed in all cases after cyclophosphamide treatment, with decreased anti-DSG1 and anti-DSG3 antibody titers and well as decreased circulating anti-EIS antibody titers. During the mean 15.1 month follow-up (range, 1-25 months), no new lesions appeared and no side effects of cyclophosphamide therapy were reported. CONCLUSIONS: Fortnightly cycles of intravenous cyclophosphamide may be a useful therapeutic option in patients with severe pemphigus vulgaris. A reduction of corticosteroid dose was possible with this therapeutic approach and the cumulative cyclophosphamide dose was lower than with daily oral administration. Our findings also show that the therapeutic approach induces clinical and immunologic remission in most patients.

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule "crystallization chaperone" 5'-O-tritylinosine (KIN59).

Thymidine phosphorylase (TP) is a catabolic enzyme in thymidine metabolism that is frequently upregulated in many solid tumors. Elevated TP levels are associated with tumor angiogenesis, metastasis and poor prognosis. Therefore, the use of TP inhibitors might offer a promising strategy for cancer treatment. The tritylated inosine derivative 5'-O-tritylinosine (previously designated KIN59) is a non-competitive inhibitor of TP which was previously found to be instrumental for the crystallization of human TP. A combination of computational studies including normal mode analysis, automated ligand docking and molecular dynamics simulations were performed to define a plausible binding site for 5'-O-tritylinosine on human TP. A cavity in which 5'-O-tritylinosine could fit was identified in the vicinity of the Gly405-Val419 loop at a distance of about 11A from the substrate-binding site. In the X-ray crystal structure, this pocket is characterized by an intricate hydrogen-bonding network in which Asp203 was found to play an important role to afford the loop stabilization that is required for efficient enzyme catalysis. Site-directed mutagenesis of this amino acid residue afforded a mutant enzyme with a severely compromised catalytic efficiency (V(max)/K(m) of mutant enzyme approximately 50-fold lower than for wild-type TP) and pronounced resistance to the inhibitory effect of 5'-O-tritylinosine. In contrast, the D203A mutant enzyme kept full sensitivity to the competitive inhibitors 6-aminothymine and 6-amino-5-bromouracil, which is in line with the kinetic properties of these inhibitors. Our findings reveal the existence of a previously unrecognized site in TP that can be targeted by small molecules to inhibit the catalytic activity of TP.

Remisión clínica completa prolongada en pacientes con pénfigo vulgar grave después del tratamiento con ciclos intravenosos de ciclofosfamida / Prolonged Complete Clinical Remission in Patients With Severe Pemphigus Vulgaris After Cycles of Intravenous Cyclophosphamide

Introducción: Los corticosteroides son el tratamiento sistémico de elección en los pacientes con pénfigo vulgar (PV). Su administración crónica produce efectos secundarios. La administración de ciclofosfamida (CF) intravenosa puede mejorar las manifestaciones clínicas del PV. Material y método: Estudiamos prospectivamente 8 pacientes diagnosticados de PV. Seis de los pacientes presentaban PV cutáneo-mucoso (PVCM) y 2 casos PV mucoso (PVM). El tratamiento consistió en 10 ciclos quincenales de CF en dosis de 10-15 mg/kg, manteniendo la dosis inicial de corticosteroides y de inmunosupresor. Se evaluó la eficacia clínica y la evolución del título de anticuerpos anti-sustancia intercelular epidérmica (SIE) (inmunofluorescencia indirecta) y específicamente anti-desmogleína (Dsg) 1 y 3 (ELISA). Resultados: Todos los pacientes con PV presentaron una excelente respuesta al tratamiento. Cinco de los 8 pacientes presentaron una remisión completa de las lesiones de PV después de los 10 ciclos de CF. En los otros 3 pacientes las lesiones cutáneas desparecieron unas semanas después del último ciclo de CF. En todos los pacientes se redujo de forma importante la dosis de inmunosupresores. Además, en todos los casos se observó una mejoría en la respuesta inmunológica después del tratamiento con CF, con disminución en el título de anticuerpos frente a las Dsg 1 y 3, así como del título de anticuerpos circulantes frente a la SIE. Tras un seguimiento medio de 15,1 meses (1-25 meses) ningún paciente ha presentado nuevas lesiones de PV. A su vez, no se han observado efectos secundarios por la CF. Conclusiones: La administración de pulsos quincenales de CF intravenosa puede ser una opción terapéutica útil en pacientes con PV grave. Este esquema terapéutico permite disminuir la dosis de corticosteroides con una menor dosis acumulada de CF que en la administración oral diaria. Además, nuestros resultados muestran que este esquema terapéutico se acompaña de una remisión clínica e inmunológica en la mayoría de los pacientes (AU)

Background: Corticosteroids are the systemic treatment of choice in patients with pemphigus vulgaris, but chronic administration is associated with side effects. Intravenous treatment with cyclophosphamide can improve the clinical signs of pemphigus vulgaris. Material and methods: We prospectively studied 8 patients diagnosed with pemphigus vulgaris. Six of these had mucocutaneous pemphigus vulgaris and 2 had mucosal pemphigus vulgaris. Treatment consisted of 10 cycles of cyclophosphamide at a dose of 10-15 mg/kg separated by 15 days, while maintaining the initial corticosteroid and immunosuppressant dose. Clinical efficacy was assessed and the anti-epidermal intercellular substance (EIS) and anti-desmoglein (DSG) 3 and 1 antibody titers were monitored (by indirect immunofluorescence and enzyme-linked immunosorbent assay, respectively). Results: All patients with pemphigus vulgaris responded excellently to treatment. Five of the 8 patients achieved complete remission of pemphigus lesions after 10 cycles of cyclophosphamide. In the other 3 patients, the skin lesions disappeared a few weeks after the last cycle of cyclophosphamide. A substantial reduction in immunosuppressant dose was possible in all patients. Furthermore, an improved immunologic response was observed in all cases after cyclophosphamide treatment, with decreased anti-DSG1 and anti-DSG3 antibody titers and well as decreased circulating anti-EIS antibody titers. During the mean 15.1 month follow-up (range, 1-25 months), no new lesions appeared and no side effects of cyclophosphamide therapy were reported. Conclusions: Fortnightly cycles of intravenous cyclophosphamide may be a useful therapeutic option in patients with severe pemphigus vulgaris. A reduction of corticosteroid dose was possible with this therapeutic approach and the cumulative cyclophosphamide dose was lower than with daily oral administration. Our findings also show that the therapeutic approach induces clinical and immunologic remission in most patients (AU)

Lesions of pemphigus vulgaris on irradiated skin.

Summary Pemphigus vulgaris (PV) is an autoimmune blistering disease produced by IgG autoantibodies against desmoglein (Dsg)3. Lesions on the skin and mucosa can, in rare cases, be induced by radiotherapy. We report a patient with a history of microprolactinoma and PV, who had only oral lesions from the beginning of her illness but 2 months after treatment with radiotherapy for a breast neoplasia, developed skin lesions limited to the irradiated area. Over the following few months, she also developed autoantibodies against Dsg1.