PICO questions and DELPHI methodology for improving the management of patients with acute hepatic porphyria.

BACKGROUND: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients. MATERIAL AND METHODS: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP. RESULTS: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP. CONCLUSIONS: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP.

The enzymatic properties of Arabidopsis thaliana DNA polymerase λ suggest a role in base excision repair.

Base excision repair (BER) generates gapped DNA intermediates containing a 5'-terminal 2-deoxyribose-5-phosphate (5'-dRP) group. In mammalian cells, gap filling and dRP removal are catalyzed by Pol ß, which belongs to the X family of DNA polymerases. In higher plants, the only member of the X family of DNA polymerases is Pol λ. Although it is generally believed that plant Pol λ participates in BER, there is limited experimental evidence for this hypothesis. Here we have characterized the biochemical properties of Arabidopsis thaliana Pol λ (AtPol λ) in a BER context, using a variety of DNA repair intermediates. We have found that AtPol λ performs gap filling inserting the correct nucleotide, and that the rate of nucleotide incorporation is higher in substrates containing a C in the template strand. Gap filling catalyzed by AtPol λ is most efficient with a phosphate at the 5'-end of the gap and is not inhibited by the presence of a 5'-dRP mimic. We also show that AtPol λ possesses an intrinsic dRP lyase activity that is reduced by mutations at two lysine residues in its 8-kDa domain, one of which is present in Pol λ exclusively and not in any Pol ß homolog. Importantly, we also found that the dRP lyase activity of AtPol λ allows efficient completion of uracil repair in a reconstituted short-patch BER reaction. These results suggest that AtPol λ plays an important role in plant BER.

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.

Multiple identification of most important waterborne protozoa in surface water used for irrigation purposes by 18S rRNA amplicon-based metagenomics.

Understanding waterborne protozoan parasites (WPPs) diversity has important implications in public health. In this study, we evaluated a NGS-based method as a detection approach to identify simultaneously most important WPPs using 18S rRNA high-throughput sequencing. A set of primers to target the V4 18S rRNA region of WPPs such as Cryptosporidium spp., Giardia sp., Blastocystis sp., Entamoeba spp, Toxoplasma sp. and free-living amoebae (FLA) was designed. In order to optimize PCR conditions before sequencing, both a mock community with a defined composition of representative WPPs and a real water sample inoculated with specific WPPs DNA were prepared. Using the method proposed in this study, we have detected the presence of Giardia intestinalis, Acanthamoeba castellanii, Toxoplasma gondii, Entamoeba histolytica and Blastocystis sp. at species level in real irrigation water samples. Our results showed that untreated surface irrigation water in open fields can provide an important source of WPPs. Therefore, the methodology proposed in this study can establish a basis for an accurate and effective diagnostic of WPPs to provide a better understanding of the risk associated to irrigation water.

Síndrome coronario agudo y enfermedad de Erdheim-Chester. Patogénesis e implicaciones terapéutica / Acute Coronary Syndrome in Erdheim-Chester. Etiopathogenesis and therapeutic Implications

Resumen La enfermedad de Erdheim-Chester es una histiocitosis celular diferente a la histiocitosis de Langerhans, de origen incierto. Se caracteriza por una implicación multi-orgánica debida a la infiltración de los histiocitos CD68+/CD1a-, en forma de xantogranulomas, que afectan principal y comúnmente a la metáfisis y diáfisis de huesos largos. El diagnóstico se realiza mediante biopsia, donde se revelan histiocitos CD68+/CD1a-, carencia de proteína S, y presencia de gránulos de Birbeck. Se ha subestimado la implicación cardiovascular. Reportamos un caso de un varón de 67 años con la enfermedad de Erdheim-Chester e infarto de miocardio agudo, debido a implicación coronaria, además de enfermedad ósea, vascular, pituitaria y retroperitoneal. Revisamos la literatura relevante y describimos el tratamiento clínico de estos pacientes.

Abstract Erdheim-Chester disease is a non-Langerhans cell histiocytosis of uncertain origin. It is characterized by multiorgan involvement due to infiltration of CD68+/CD1a- histiocytes, in the form of xantogranulomas, most commonly affecting the metaphysis and diaphysis of long bones. The diagnosis is made by biopsy showing CD68+/CD1ahistiocytes, lack of S protein and Birbeck granules. Cardiovascular involvement is underestimated. We report a case of a 67 year-old man with Erdheim-Chester disease and acute myocardial infarction due to coronary involvement, in addition to bone, vascular, pituitary and retroperitoneal disease. We review relevant literature and describe the clinical management of these patients.

Clinical characteristics of adult patients with inborn errors of metabolism in Spain: A review of 500 cases from university hospitals.

Patients with inborn errors of metabolism (IEMs) have become an emerging and challenging group in the adult healthcare system whose needs should be known in order to implement appropriate policies and to adapt adult clinical departments. We aimed to analyze the clinical characteristics of adult patients with IEMs who attend the most important Spanish hospitals caring for these conditions. A cohort study was conducted in 500 patients, categorized by metabolic subtype according to pathophysiological classification. The most prevalent group of IEMs was amino acid disorders, with 108 (21.6%) patients diagnosed with phenylketonuria. Lysosomal storage disorders were the second group, in which 32 (6.4%) and 25 (5%) patients had Fabry disease and Gaucher disease respectively. The great clinical heterogeneity, the significant delay in diagnosis after symptom onset, the existence of some degree of physical dependence in a great number of patients, the need for a multidisciplinary and coordinated approach, and the lack of specific drug treatment are common features in this group of conditions.

The relationship between insulin resistance and periodontitis is not affected by Mediterranean diet in a Spanish population.

OBJETIVE: To examine the insulin resistance measured by surrogate indices in subjects with and without periodontitis and to find out any correlation among dietary intake with insulin resistance. DESIGN: Fifty-five patients were recruited to participate in this cross-sectional study. Insulin resistance measured by the homoeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index moreover glycaemia, creatinine, uric acid, high density lipoproteins, low density lipoproteins, very low density lipoproteins and triglycerides among others. True periodontal disease was elucidated through the examination of probing pocket depth, clinical attachment level, recession of the gingival margin and gingival bleeding. The statistical analyses used were the student's T-test for independent variables, Kolmogorov-Smirnov if variations were homogeneous; if not, the Mann-Whitney U Test was applied instead. Correlations between variables were assessed using Pearson's correlation coefficients. True periodontal disease was confirmed through the greater values of probing pocket depth, clinical attachment level, gingival margin and gingival bleeding in the periodontitis group in comparison with non-periodontitis group. RESULTS: Insulin resistance was evidenced by the greater values of HOMA-IR as well as by the lower quantitative insulin sensitivity check index values in the periodontitis group. Fasting insulin, glucose, uric acid, creatinine, low density lipoproteins, triglycerides and very low density lipoprotein levels were significant higher in periodontitis group. Pearson's correlations did not show any association among diet data and insulin resistance parameters in periodontitis patients. CONCLUSION: A putative systemic relationship between insulin resistance and periodontitis exists but it does not seem conceivable any effect of diet over such relationship.

Interlinkages between bacterial populations dynamics and the operational parameters in a moving bed membrane bioreactor treating urban sewage.

Bacteria are key players in biological wastewater treatments (WWTs), thus a firm knowledge of the bacterial population dynamics is crucial to understand environmental/operational factors affecting the efficiency and stability of the biological depuration process. Unfortunately, little is known about the microbial ecology of the advanced biological WWTs combining suspended biomass (SB) and attached biofilms (AB). This study explored in depth the bacterial community structure and population dynamics in each biomass fraction from a pilot-scale moving bed membrane bioreactor (MBMBR) treating municipal sewage, by means of temperature-gradient gel electrophoresis (TGGE) and 454-pyrosequencing. Eight experimental phases were conducted, combining different carrier filling ratios, hydraulic retention times and concentrations of mixed liquor total suspended solids. The bacterial community, dominated by Proteobacteria (20.9-53.8%) and Actinobacteria (20.6-57.6%), was very similar in both biomass fractions and able to maintain its functional stability under all the operating conditions, ensuring a successful and steady depuration process. Multivariate statistical analysis demonstrated that solids concentration, carrier filling ratio, temperature and organic matter concentration in the influent were the significant factors explaining population dynamics. Bacterial diversity increased as carrier filling ratio increased (from 20% to 35%, v/v), and solids concentration was the main factor triggering the shifts of the community structure. These findings provide new insights on the influence of operational parameters on the biology of the innovative MBMBRs.

The role of 18FDG, 18FDOPA PET/CT and 99mTc bone scintigraphy imaging in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocitosis, characterized by multisystemic xanthogranulomatous infiltration by foamy histiocytes that stain positively for CD68 marker but not express CD1a and S100 proteins. Etiology and pathogenesis are still unknown and only about 500 cases are related in the literature. Multisystemic involvement leads to a wide variety of clinical manifestations that results in a poor prognosis although recent advances in treatment. We present the clinical, nuclear medicine findings and therapeutic aspects of a serie of 6 patients with histopathological diagnosis of ECD, who have undergone both bone scintigraphy (BS) and 18F-fluorodeoxyglucose (18FDG)-PET/CT scans in our institution. A complementary 18F-fluorodopa (18FDOPA)-PET/CT was performed in one case. Three different presentations of the disease were observed in our casuistic: most indolent form was a cutaneous confined disease, presented in only one patient. Multifocal involvement with central nervous system (CNS) preservation was observed in two patients. Most aggressive form consisted in a systemic involvement with CNS infiltration, presented in three patients. In our experience neurological involvement, among one case with isolate pituitary infiltration, was associated with mortality in all cases. 18FDG-PET/CT and BS were particularly useful in despite systemic involvement; locate the site for biopsy and the treatment response evaluation. By our knowledge, 18FDOPA-PET/CT not seems useful in the initial staging of ECD. A baseline 18FDG-PET/CT and BS may help in monitoring the disease and could be considered when patients were incidentally diagnosed and periodically 18FDG-PET/CT must be performed in the follow up to evaluate treatment response.

Influencia de las anomalías faringolaríngeas diagnosticadas mediante laringoscopia indirecta en la predicción de la dificultad de intubación / Influence of pharyngolaryngeal anomalies diagnosed through indirect laryngoscopy in the prediction of difficult intubation

Objetivo: Detectar anomalías faringolaríngeas no valoradas habitualmente en la evaluación de la vía aérea difícil mediante la realización en el preoperatorio de una laringoscopia indirecta con el laringoscopio rígido e investigar su influencia en la predicción de la dificultad de intubación traqueal (DIT). Métodos: Estudio observacional prospectivo en 300 pacientes consecutivos sometidos a intervenciones quirúrgicas programadas bajo anestesia general. Además de evaluar los predictores demográficos y clínicos comunes de la vía aérea difícil, les fue practicada en el preoperatorio una laringoscopia indirecta con el laringoscopio rígido para diagnosticar las anomalías faringolaríngeas. Después, bajo anestesia general y laringoscopia directa comprobamos en qué pacientes existía DIT. Se investigó la asociación de todas las variables anteriores con la DIT, se confeccionó un modelo de regresión logística con fines predictivos y su poder de discriminación se consiguió valorando el área bajo la curva ROC obtenida. Resultados: Se contabilizaron 46 anomalías: 31 alteraciones de la epiglotis (22 epiglotis abarquilladas, 9 epiglotis flácidas o hipertrofiadas), 6 amígdalas linguales hipertróficas, 3 tumores en la vía aérea superior y 6 alteraciones de la lengua. Se encontró DIT en 14 casos (4,66%). El modelo elaborado y sus coeficientes para confeccionarlo fueron: f(x) = 1,322 + (2,173 distancia tiromentoniana < 6,5 cm) + (1,813 epiglotis abarquillada) - (1,310* cm abertura boca). El poder global de discriminación era 0,83 (IC 95%: 0,70-0,95). Conclusiones: La laringoscopia indirecta permitió el diagnóstico de las anomalías faringolaríngeas, y de ellas la epiglotis abarquillada fue una de las variables incluidas en el modelo de regresión logística (AU)

Objective: To determine the pharyngolaryngeal anomalies not usually included in the evaluation of difficult airway, in order to investigate the influence of these anomalies in the prediction of difficult intubation. To do this, indirect laryngoscopy with a 70° rigid laryngoscope was performed on all patients during the preoperative period. Methods: This is an observational, prospective study on 300 consecutive patients who were scheduled for endotracheal intubation under general anesthesia. In addition to assessing the airway in the preoperative period by demographic and clinical predictors of difficult airway, rigid indirect laryngoscopy was performed to diagnose pharyngolaryngeal anomalies. Later, under general anesthesia and direct laryngoscopy it was checked to see if there was difficulty in intubating the larynx, and its association with all previous variables was investigated. A logistic regression model for prediction purposes was developed, and its power of discrimination was achieved by assessing the area under the curve. Results: During the examination by indirect laryngoscopy 46 anomalies were found, which were as follows: 31 abnormalities of the epiglottis (22 omega epiglottis, 9 flaccid or hypertrophic epiglottis); 6 findings of hypertrophic lingual tonsils, 3 cases of upper airway tumors, and 6 patients with tongue disorders. Intubation difficulty was found in 14 cases (4.66%). The regression model found, and its coefficients to develop it were: f(x) = 1.322 + (2.173 thyromental distance < 6.5 cm) + (1.813 omega epiglottis) - (1.310*cm opening mouth). Global power of discrimination was 0.83, with a 95% confidence interval from 0.709 to 0.952). Conclusion: Indirect laryngoscopy allowed pharyngolaryngeal anomalies to be diagnosed, including omega epiglottis, which was one of the variables included in the logistic regression model (AU)

Influence of pharyngolaryngeal anomalies diagnosed through indirect laryngoscopy in the prediction of difficult intubation.

OBJECTIVE: To determine the pharyngolaryngeal anomalies not usually included in the evaluation of difficult airway, in order to investigate the influence of these anomalies in the prediction of difficult intubation. To do this, indirect laryngoscopy with a 70° rigid laryngoscope was performed on all patients during the preoperative period. METHODS: This is an observational, prospective study on 300 consecutive patients who were scheduled for endotracheal intubation under general anesthesia. In addition to assessing the airway in the preoperative period by demographic and clinical predictors of difficult airway, rigid indirect laryngoscopy was performed to diagnose pharyngolaryngeal anomalies. Later, under general anesthesia and direct laryngoscopy it was checked to see if there was difficulty in intubating the larynx, and its association with all previous variables was investigated. A logistic regression model for prediction purposes was developed, and its power of discrimination was achieved by assessing the area under the curve. RESULTS: During the examination by indirect laryngoscopy 46 anomalies were found, which were as follows: 31 abnormalities of the epiglottis (22 omega epiglottis, 9 flaccid or hypertrophic epiglottis); 6 findings of hypertrophic lingual tonsils, 3 cases of upper airway tumors, and 6 patients with tongue disorders. Intubation difficulty was found in 14 cases (4.66%). The regression model found, and its coefficients to develop it were: f(x)=1.322+(2.173 thyromental distance <6.5 cm)+(1.813 omega epiglottis)-(1.310*cm opening mouth). Global power of discrimination was 0.83, with a 95% confidence interval from 0.709 to 0.952). CONCLUSION: Indirect laryngoscopy allowed pharyngolaryngeal anomalies to be diagnosed, including omega epiglottis, which was one of the variables included in the logistic regression model.

Confirmation of oxidative stress and fatty acid disturbances in two further Papillon-Lefèvre syndrome families with identification of a new mutation.

BACKGROUND: We have previously reported oxidative and fatty acids disturbances in one Papillon-Lefèvre syndrome (PLS) family. This Mendelian condition characterized by palmar plantar keratosis and severe aggressive periodontitis, is caused by mutations in the cathepsin C (CTSC) gene. In this study, we have analysed two further unrelated PLS families to confirm this association. METHODS: Mutations were identified by direct sequencing of CTSC. Biochemical analyses were performed in probands and their relatives in order to determine plasma levels of vitamin E, CoQ10 , lipid hydroperoxides (HP) and fatty acid patterns. RESULTS: Pathogenic CTSC mutations were identified in both families including a new mutation (c504C>G). Both probands showed low levels of vitamin E and CoQ10 , and high levels of lipid HP, and also very low levels of docohexaenoic acid. CONCLUSIONS: The previously reported oxidative and fatty acids disturbances were confirmed as a feature of this condition in two further families. There are low levels of antioxidant markers and high levels of oxidative markers, in addition of low levels of some anti-inflammatory fatty acids in persons suffering PLS and some of their relatives.

El hallazgo de glucosa en el fluido obtenido por el catéter epidural después de su inserción durante la anestesia combinada intradural-epidural realizada con bupivacaína hiperbara es un suceso habitual / The finding of glucose in the fluid obtained by epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine is a usual occurrence

Objetivos. Evaluar si la aparición de glucosa en el fluido obtenido espontáneamente del catéter epidural tras su inserción, durante la anestesia combinada intradural-epidural realizada con bupivacaína hiperbara, es un suceso habitual. Pacientes y métodos. Estudio observacional prospectivo en 34 pacientes con anestesia combinada intradural-epidural a los que después de localizar el espacio epidural con solución salina, insertar la aguja espinal e inyectar bupivacaína hiperbara, se les introdujo un catéter epidural. Tras observar si goteaba espontáneamente algún fluido por él, se determinó si este contenía glucosa. Retirada la aguja epidural y lavada su luz con solución salina, se comprobó si en el lavado existía glucosa. Las muestras se analizaron con un glucómetro. Cuando desapareció el bloqueo motor se administró una dosis de anestésico local por el catéter epidural. Se valoró la asociación de los parámetros demográficos con el goteo espontáneo por el catéter epidural. Resultados. En 22 pacientes se produjo goteo espontáneo por el catéter epidural tras su inserción. Todas las muestras obtenidas contenían glucosa. En 9 de 34 muestras del lavado de aguja epidural existía glucosa. Ningún paciente sufrió bloqueo sensitivomotor excesivo. Se encontró asociación estadísticamente significativa (p<0,05) de la edad con el goteo espontáneo por el catéter (a más edad, más goteo). Conclusión. El hallazgo de glucosa en el fluido obtenido por el catéter epidural es un suceso frecuente y sin significación clínica. Proponemos que pudo deberse a fuga de líquido cefalorraquídeo por el agujero de punción dural durante o después de la administración de la bupivacaína hiperbara y al derrame de esta en el espacio epidural(AU)

Objectives. To determine whether the appearance of glucose in the fluid spontaneously obtained by the epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine is a usual occurrence. Patients and methods. A prospective, observational study was conducted on 34 patients with combined intradural-epidural anaesthesia in whom an epidural catheter was introduced, after locating the epidural space with a saline solution, inserting a spinal needle and injecting hyperbaric bupivacaine. After observing whether any fluid was spontaneously dripping from it, it was determined if this contained glucose. Withdrawal of the needle and washing its lumen with saline solution, it was checked whether there was glucose in washout. The samples were analysed using a glucose meter. When the motor block disappeared a dose of local anaesthetic was administered through the epidural catheter. The relationship of the demographic parameters with the spontaneous dripping of the epidural catheter was evaluated. Results. Spontaneous dripping by the epidural catheter after its insertion was observed in 22 patients. All the samples obtained contained glucose. There was glucose in 9 out of 34 epidural needle wash samples. None of the patients suffered from excessive motor-sensory block. There was a statistically significant relationship between patient age (P<.05) and spontaneous dripping by the catheter (the higher the age, more dripping). Conclusion. The finding of glucose in the fluid obtained by the epidural catheter is a frequent occurrence and is of no clinical significance. We propose that it could be due to a leak of cerebrospinal fluid by the dural puncture needle during or after the administering of the hyperbaric bupivacaine and the spillage of this into the epidural space(AU)

[The finding of glucose in the fluid obtained by epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine is a usual occurrence]. / El hallazgo de glucosa en el fluido obtenido por el catéter epidural después de su inserción durante la anestesia combinada intradural-epidural realizada con bupivacaína hiperbara es un suceso habitual.

OBJECTIVES: To determine whether the appearance of glucose in the fluid spontaneously obtained by the epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine is a usual occurrence. PATIENTS AND METHODS: A prospective, observational study was conducted on 34 patients with combined intradural-epidural anaesthesia in whom an epidural catheter was introduced, after locating the epidural space with a saline solution, inserting a spinal needle and injecting hyperbaric bupivacaine. After observing whether any fluid was spontaneously dripping from it, it was determined if this contained glucose. Withdrawal of the needle and washing its lumen with saline solution, it was checked whether there was glucose in washout. The samples were analysed using a glucose meter. When the motor block disappeared a dose of local anaesthetic was administered through the epidural catheter. The relationship of the demographic parameters with the spontaneous dripping of the epidural catheter was evaluated. RESULTS: Spontaneous dripping by the epidural catheter after its insertion was observed in 22 patients. All the samples obtained contained glucose. There was glucose in 9 out of 34 epidural needle wash samples. None of the patients suffered from excessive motor-sensory block. There was a statistically significant relationship between patient age (P<.05) and spontaneous dripping by the catheter (the higher the age, more dripping). CONCLUSION: The finding of glucose in the fluid obtained by the epidural catheter is a frequent occurrence and is of no clinical significance. We propose that it could be due to a leak of cerebrospinal fluid by the dural puncture needle during or after the administering of the hyperbaric bupivacaine and the spillage of this into the epidural space.

Alteración de la actividad de la butirilcolinesterasa en pacientes con enfermedad de Alzheimer tratados con inhibidores de la acetylcolinesterasa / Changes in butyrylcholinesterase activity in patients with Alzheimer disease treated with acetylcholinesterase inhibitors

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