The real-world use and effectiveness of avacopan in routine practice for the treatment of ANCA vasculitis. First experiences in Spain.

OBJECTIVES: ANCA-associated vasculitis (AAV) are chronic diseases with relapses that associate organic damage because of the disease and its treatment. Avacopan is a new treatment indicated for AAV. We present the first experiences with avacopan in Spain as part of an Early Access program. METHODS: Patients with AAV who started avacopan between June 2022-September 2023 were included. For comparison, a historical cohort of patients diagnosed with AAV around the same time and treated without avacopan was also included. RESULTS: 29 patients treated with avacopan were analyzed. Twelve patients (41.4%) were male, median age was 56 years. Most of patients were ANCA MPO positive (21/29, 72.4%). The most frequently affected organ was the kidney (23/29, 79.31%), with a mean eGFR of 23.2 ml/minMedian follow-up was 456.8 ± 181.7 days with a remission rate of 86.2%. eGFR increased from 23.2 ± 11.2-38.38 ± 18.55 ml/min after 12 months of diagnosis.2 patients had Adverse Events related to avacopan as severe neutropenia and a gastrointestinal affectation , 13 infections were reported and 1 death.Patients treated with avacopan received a significantly lower cumulative dose of prednisone at 6 and 12 months (p-values of 0.02 and <0.01, respectively) compared with historical controls. The evolution of GFR at 1 year of follow-up and the incidence of relapse were similar in both groups. CONCLUSION: The combination of avacopan in clinical practice presents a good safety profile and provides added value by contributing to the control of AAV activity, increase GFR, and removal of steroids.

Digestion of cattle manure under mesophilic and thermophilic conditions: characterization of organic matter applying thermal analysis and 1H NMR.

Digestion of cattle manure collected from a livestock farm together with bedding material (straw) has been studied under mesophilic and thermophilic conditions in batch reactors. The digestion was carried out for a prolonged period with the aim of evaluating the changes undergone by the organic matter. The mesophilic digestion carried out revealed a greater capacity to produce gas and transform organic matter, while a higher conversion rate, but a lower gas yield, was obtained under thermophilic conditions. Degradation of the organic matter was evaluated by means of thermal analysis and (1)H NMR. Stabilisation through anaerobic digestion (either mesophilic or thermophilic) resulted in an increase in the quality of the organic matter, as characterised by an enrichment in thermostable compounds, and an accumulation of long chain aliphatic materials. The experiments performed demonstrated the transformation of organic matter into complex materials under anaerobic conditions with an accumulation of aliphatic components under both types of conditions tested. Degradation through mesophilic digestion, in comparison to the thermophilic process, resulted in a greater destruction of straw particles.

Influence of design, physico-chemical and environmental parameters on pharmaceuticals and fragrances removal by constructed wetlands.

The ability of several mesocosm-scale and full-scale constructed wetlands (CWs) to remove pharmaceuticals and personal care products (PPCPs) from urban wastewater was assessed. The results of three previous works were considered as a whole to find common patterns in PPCP removal. The experiment took place outdoors under winter and summer conditions. The mesocosm-scale CWs differed in some design parameters, namely the presence of plants, the vegetal species chosen (Typha angustifolia versus Phragmites australis), the flow configuration (surface flow versus subsurface flow), the primary treatment (sedimentation tank versus HUSB), the feeding regime (batch flow versus continuous saturation) and the presence of gravel bed. The full-scale CWs consisted of a combination of various subsystems (ponds, surface flow CWs and subsurface flow CWs). The studied PPCPs were ketoprofen, naproxen, ibuprofen, diclofenac, salicylic acid, carbamazepine, caffeine, methyl dihydrojasmonate, galaxolide and tonalide. The performance of the evaluated treatment systems was compound dependent and varied as a function of the CW-configuration. In addition, PPCP removal efficiencies were lower during winter. The presence of plants favoured naproxen, ibuprofen, diclofenac, salicylic acid, caffeine, methyl dihydrojasmonate, galaxolide and tonalide removal. Significant positive correlations were observed between the removal of most PPCPs and temperature or redox potential. Accordingly, microbiological pathways appear to be the most likely degradation route for the target PPCPs in the CWs studied.

Chemical composition of rainwater under two events of aerosol transport: A Saharan dust outbreak and wildfires.

A one-year campaign of joint sampling of aerosols and precipitation, carried out in León, Spain, allowed to study the impact of two special events that affected the air quality in the north of the country, on rainfall in the city: a period with wildfires and a Saharan dust intrusion. The wildfires that occurred in northern Portugal and northwestern Spain in August 2016 affected the chemistry of rainfall on 15 August 2016, causing an increase in concentrations of NH4+, Na+, Cl-, K+, Mg2+, Ca2+, SO42- and NO3- and in the concentrations of organic acids, which was reflected in the levels of soluble and insoluble organic carbon. This led to acidification of rainwater (pH = 4.8). The second precipitation event was registered between 11 and 14 February 2017, during which the rainwater was collected in four daily fractions (P1, P2, P3 and P4). The rain sample of 12 February (P2) coincided with a Saharan dust intrusion that reached northern Iberia that day. The chemical composition of P2 showed an increase in the Ca2+ (>800%), Mg2+ (71%), Cl- (62%), and SO42- (33%) concentrations, with respect to P1. The input of crustal elements to the atmosphere helped to neutralize the P2 rainwater, causing pH values higher than 6.5. Once the dust intrusion left the north of the Peninsula, the composition of rainwater P3 and P4 revealed a mixture of marine contribution with local anthropogenic emissions, as well as a decrease in ion concentrations and conductivity, and an increase in pH values.

Determinants of renal and patient outcomes in a Spanish cohort of patients with ANCA-associated vasculitis and renal involvement.

The classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains controversial. The main objective of this study was to define the respective values of ANCA serotype-based classification, clinicopathological classification, and histopathological classification in predicting patient and renal outcomes in a Spanish cohort of patients with ANCA with specificity for myeloperoxidase, MPO-ANCA, versus ANCA with specificity for proteinase 3, PR3-ANCA. Two hundred and forty-five patients with ANCA-AAV and biopsy-proven renal involvement diagnosed between 2000 and 2104 were recruited in 12 nephrology services. Clinical and histologic data, renal outcomes, and mortality were analyzed. We applied the Chapel Hill Consensus Conference definition with categories for granulomatosis with the polyangiitis (GPA) and microscopic polyangiitis (MPA), the classification based on ANCA specificity, and the histopathological classification proposed in 2010. Eighty-two percent were MPO-ANCA positive and 18.0% PR3-ANCA positive. Altogether, 82.9% had MPA and 17.1% GPA. The median follow-up was 43.2 months (0.1-169.3). Neither ANCA-based serological nor clinical classification was predictive of renal outcomes or patient survival on bivariate or multivariate Cox regression analysis. Histopathological classification was found to predict development of end-stage renal disease (p = 0.005) in Kaplan-Meier analysis. ANCA specificity was more predictive of relapse than clinicopathological classification in multivariate analysis (HR 2.086; 95% CI 1.046-4.158; p = 0.037). In our Spanish cohort, a majority of patients had an MPO-ANCA-AAV. A classification based on ANCA specificity has a higher predictive value for relapse occurrence and could be used for decision-making with respect to induction treatment and maintenance therapies.

Síndrome de tolosa hunt: presentación de caso clínico / Tolosa Hunt syndrome: case report

El síndrome de Tolosa-Hunt es una entidad poco frecuente cuya etiopatogenia y mecanismos fi- siopatológicos son controversiales, se caracteri- za por cefalea asociada a parálisis de uno o más nervios craneales, diplopía, estrabismo y ptosis palpebral, ocasionados por el compromiso del seno cavernoso o la fisura orbitaria superior. Su diagnóstico es un reto y se aborda dentro de los diagnósticos diferenciales de las oftalmoplejías dolorosas. Con el objetivo de describir y actua- lizar el conocimiento sobre esta enfermedad se presenta el caso de una paciente de 14 años que acudió a consulta por cefalea intensa, dolor ocu- lar y afección de nervios craneales. Los hallazgos clínicos y la resonancia magnética confirmaron el diagnóstico del síndrome de Tolosa Hunt...(AU)

Double chromosome anomaly: interstitial deletion 5q and reciprocal translocation (1;11)(p22;q21).

We describe a girl with multiple congenital abnormalities and developmental delay; her karyotype showed an apparently balanced translocation between the short arm of chromosome 1 and the long arm of chromosome 11, and an interstitial deletion of the long arm of chromosome 5 (q15q31). The clinical findings are compared with those described in other cases of 5q deletion, and the origin of the chromosome rearrangements is briefly discussed.

Design of an enzymatic hybrid system: a useful strategy for the biosynthesis of benzylpenicillin in vitro.

A hybrid (prokaryotic-eukaryotic) enzyme system leading to the production of benzylpenicillin has been developed. In vitro synthesis of penicillin G was achieved by incubating 6-aminopenicillanic acid, CoA, phenylacetic acid, homogeneously pure phenylacetyl-CoA ligase (PA-CoA ligase) from Pseudomonas putida and acyl-CoA:6-APA acyltransferase (AT) from Penicillium chrysogenum. Benzylpenicillin was also obtained when AT was coupled with PA-CoA ligase and isopenicillin N-synthetase (IPNS). This is the first description of an in vitro assay that, using enzymes of different microbial origin, mimics the three last enzymatic steps leading to the biosynthesis of penicillin G in P. chrysogenum.

Synthesis of 3-furylmethylpenicillin using an enzymatic procedure.

3-Furylmethylpenicillin was synthesized in vitro from 3-furylacetic acid, 6-aminopenicillanic acid (6-APA), CoA, ATP and Mg2+. The reaction was catalyzed in two steps by the enzymes phenyl-acetyl-CoA ligase (PCL) from Pseudomonas putida and acyl-CoA: 6-APA acyltransferase (AT) from Penicillium chrysogenum. PCL catalyzes the activation of 3-furylacetic acid to 3-furylacetyl-CoA (3-F-CoA) and AT acylates the amino group of 6-APA with the 3-furylacetyl moiety of 3-F-CoA, releasing CoA and 3-furylmethylpenicillin.

Quantitative determination of semisynthetic cephamycins in human serum and urine by ion-exchange, reversed-phase and ion-pair chromatography.

High-performance liquid chromatographic methods have been developed for the determination of semisynthetic cephamycins: cefoxitin, cefmetazole and cefminox in human serum and urine samples. Serum samples spiked with each cephamycin were combined with an equal volume of methanol to remove proteins and, after centrifugation, and aliquot of the supernatant was analysed by ion-exchange, reversed-phase and ion-pair chromatography with hexadecyltrimethylammonium bromide as the ion-pairing agent. Urine samples were diluted, filtered and analysed by same chromatographic procedure. The cephamycins were detected by their ultraviolet absorbance (265-272 nm). It was possible to determine concentrations of cephamycins to 0.2 micrograms/ml in serum 2 micrograms/ml in urine samples with a good level of reproducibility and accuracy.

Determination of piperacillin and mezlocillin in human serum and urine by high-performance liquid chromatography after derivatisation with 1,2,4-triazole.

High-performance liquid chromatographic methods have been developed for the determination of piperacillin and mezlocillin in human serum and urine samples. The methods involve ultrafiltration of samples followed by reaction with 1.5 M 1, 2, 4-triazole and 0.5 x 10(-3) M mercury (II) chloride in solution (pH 8.50) at 50 degrees C for 15 min. The resulting products were separated on a C18 column following stabilisation in an eluent containing sodium thiosulphate. They were detected at 323 nm for both penicillins. The methods have been applied to assays applied to assays of these penicillins in human serum and urine samples. The procedures, which permit the determination of penicillin concentration down to 0.1 microgram m1-1 in serum and 1 microgram m1-1 in urine samples, are specific to intact penicillins without interference from corresponding penicilloates [see J. Haginaka et al., Anal. Sci. 1 (1985) 73]. At concentrations of 1-500 micrograms ml-1 for each compound, the within- and between-day precisions were 1.8-4.8 and 3.7-6.9, respectively. The accuracy was ca. 100% for all samples assayed.

IV. Acyl-CoA: 6-APA acyltransferase of Penicillium chrysogenum: studies on substrate specificity using phenylacetyl-CoA variants.

Two different penicillins (p- and m-methylbenzylpenicillin) were obtained "in vitro" by direct enzymatic synthesis, using homogeneously pure acyl-CoA: 6-aminopenicillanic acid (6-APA) acyltransferase from Penicillium chrysogenum, 6-APA and p- or m-tolylacetyl-CoA. The Km for these substrates were 6 and 15 mM, respectively, indicating that the affinity of the enzyme for these two molecules is much lower that shown by phenylacetyl-CoA (0.55 mM). Furthermore, acyltransferase does not recognize o-tolylacetyl-CoA as a substrate suggesting that the position of the methyl group on the aromatic moiety may have a very important role in the formation of the enzyme-substrate complex.

Acyl-CoA: 6-APA acyltransferase from Penicillium chrysogenum studies on its hydrolytic activity.

Acyl-CoA: 6-APA acyltransferase (AT) from Penicillium chrysogenum Wis 54-1255 catalyzes the hydrolysis of different acyl-CoA derivatives generating, in the absence of 6-APA, free acid and CoA. The hydrolytic efficiency of AT is highest for acyl-CoA variants in which the acyl-moiety is higher than six carbon atoms. The maximal rate of catalysis was achieved in 50 mM Tris-HCl buffer, pH 8.5 at 35 degrees C. Unlike the AT activity, the acylase activity has a different optimum temperature and substrate specificity and dithiothreitol is not required for the reaction.

Aliphatic molecules (C-6 to C-8) containing double or triple bonds as potential penicillin side-chain precursors.

Three different hexenoyl-CoA derivatives (trans-2-hexenoyl-CoA, trans-3-hexenoyl-CoA and trans-trans-2,4-hexadienoyl-CoA), two octenoyl-CoA (trans-2-octenoyl-CoA, trans-3-octenoyl-CoA) and 2-octynoyl-CoA were tested as substrates of the enzyme acyl-CoA: 6-Aminopenicillanic acid acyltransferase (AT) from Penicillium chrysogenum. Only trans-3-hexenoyl-CoA and trans-3-octenoyl-CoA were recognized by AT and efficiently converted into penicillin F and octenoylpenicillin, respectively. The Km values for these substrates were 0.6 and 0.5 mM, suggesting that the affinity of AT for these molecules is similar to that reported for phenyl acetyl-CoA, octanoyl-CoA and hexanoyl-CoA (0.5, 0.6, and 1 mM, respectively). The absence of enzymatic activity shown by AT with the other acyl-CoA derivatives tested is due to the different position of the double or triple bond(s) in their aliphatic chains. The influence of the free rotation round the bond C-2-C-3 and possibility of planar conformation in such molecules and the importance in the formation of the enzyme-substrate complex is discussed.

Biosynthesis of benzylpenicillin (G), phenoxymethylpenicillin (V) and octanoylpenicillin (K) from glutathione S-derivatives.

"In vitro" synthesis of benzylpenicillin and phenoxymethylpenicillin has been carried out by direct N-acylation of 6-aminopenicillanic acid (6-APA) with S-phenylacetyl- and (S-phenoxyacetyl)glutathione. The reactions were catalyzed by the enzyme acyl-CoA: 6-APA acyltransferase (AT) from Penicillium chrysogenum and in both cases the synthesis of antibiotics was enhanced by CoA. Penicillin K, a natural penicillin, was also synthesized "in vitro" by incubating (S-octanoyl)glutathione, 6-APA and AT, but in this case the formation of antibiotic required the presence of CoA. Furthermore, benzylpenicillin was obtained from (S-phenylacetyl)cysteinylglycine and 6-APA, suggesting that some intermediates of the gamma-glutamyl cycle are directly involved in the biosynthesis of penicillins. To explain "in vivo" formation of this beta-lactam antibiotic, a biosynthetic pathway which includes several glutathione-S-derivatives and a non-enzymatic reaction, is proposed.

Dye adsorption by sewage sludge-based activated carbons in batch and fixed-bed systems.

The present research work deals with the production of activated carbons by chemical activation and pyrolysis of sewage sludges. The adsorbent properties of these sewage sludges based activated carbons were studied by liquid-phase adsorption tests. Dyes removal from colored wastewater being a possible application for sludge based adsorbents, methylene blue and saphranine removing from solution was studied. Pure and binary adsorption assays were performed in batch and fixed bed systems. In all cases studied, the adsorbents produced from sewage sludges were able to adsorb both the compounds considered here. Nevertheless, time required for reaching equilibrium, adsorptive capacity and fixed bed characteristic parameters were different for these two compounds. Methylene blue adsorption occurred faster than that of saphranine, and it was preferably adsorbed when treating binary solutions. It could be concluded that the sewage sludge-based activated carbons may be promising for dyes removal from aqueous streams.

Influence of the application of sewage sludge on the degradation of pesticides in the soil.

A study was made of the influence of the application of sewage sludge on the degradation of pesticides in the soil. Two kinds of sludge were used, with different characteristics, one from an urban treatment plant and one from a food processing plant. Three organophosphorus insecticides, fenitrothion, diazinon and dimethoate, were studied. The relative importance was determined of the chemical and biological degradation processes, which involved experiments on soil and sterile soil samples. A comparative study was also made of the degradation of pesticide residues and the evolution of the microbial population. The application of sludge seems to have a complex effect on the degradation of pesticides, determined by the bioavailability and biodegradability of their active ingredient. The biodegradation of pesticide residues brings about alterations in the microorganism population of the soil.

[Biliary calculi resistant to dissolution with bile acids: their heterogeneous composition and diversity of treatment response]. / Calculos biliares resistentes a la disolución con ácidos biliares: composición heterogenea y diversidad de respuesta al tratamiento.

We have studied thirteen biliary stones resistant to biliary acids, using technical methods of stereomicroscopy, scanning electronic microscopy and EDX analyses. We have investigated changes on surface. Three biliary stones did not change and were considered resistant. Seven biliary stones appear partially dissolved and we observed many irregularities on surface and/or concentric dips in relation with cholesterol dissolution. In six cases, biliary pigment alternates with cholesterol. In three cases we observed a calcium carbonate coat on surface. One case included organic fibers. One biliary stone showed cholesterol with spherical bodies of calcium carbonate and pigment. It was a relapsed case of combined treatment. Three stones are composed of small black portions of polymerized calcium bilirubinate, rich in copper and iron. Our results demonstrate that biliary stones previously selected for treatment are a heterogeneous group. Because of this fact we get variable and unpredictable results.

[Fusarium pleural effusion after a ventricular assist device]. / Pleurésie à Fusarium compliquant une implantation de ventricule artificiel.

We report the case of a 36-year-old man with a pleural effusion that complicates the postoperative period after the implantation of a ventricular assist device (VAD). The epidemiological, etiologic and therapeutic features of Fusarium infections were reviewed. Complete recovery of the infection was obtained after a treatment by liposomal amphotericine B (AmBisome) and 5 fluorocytosine.