Greener approaches for chemical synthesis – ball mill and microwave assisted synthesis of fluoxetine and duloxetine and enantioselective catalysed addition of organometallic reagents to aldehydes

This PhD thesis focuses on the development of “greener” synthetic methodologies in organic synthesis. Turning chemical production into a more sustainable industry - by reducing the waste generated and the electricity consumption - is highly desired in a world with limited resources and increasing population. This thesis, in particular, focuses on three of the ‘12 Principles of Green Chemistry’, reducing the amount of solvent and energy consumption in a chemical process, and the use of catalytic reagents instead of stoichiometric. In the first chapter of this thesis, a greener synthetic route for the preparation of the antidepressant fluoxetine (Prozac) was developed. The use of ball milling allowed a decrease of the solvent used in the process, furthermore, microwave assisted heating provided a more efficient method compared to the traditional heating using an oil bath. Fluoxetine was synthesised with 47% yield through two different synthetic routes (3 and 4 steps respectively). In addition, the scope of the developed methodologies was tested by the attempted synthesis of the antidepressant duloxetine. The second chapter of this thesis focuses on the catalytic enantioselective synthesis of chiral alcohols. More specifically, two different methodologies for the catalytic enantioselective addition of organolithium reagents to aldehydes were successfully developed, achieving excellent yields and enantioselectivities. Furthermore, a new methodology for the use of organozirconium reagents as nucleophiles in the catalytic enantioselective 1,2-addition of alkenes to aldehydes was also developed. Last, the implementation of a catalytic enantioselective step to the previous syntheses of fluoxetine was attempted

The Impact Of Rituximab Infusion Protocol On The Long-term Outcome In Anti-musk Myasthenia Gravis

Objective: To evaluate whether the clinical benefit and relapse rates in anti-muscle-specific kinase (MuSK) myasthenia gravis (MG) differ depending on the protocol of rituximab followed. Methods: This retrospective multicentre study in patients with MuSK MG compared three rituximab protocols in terms of clinical status, relapse, changes in treatment, and adverse side effects. The primary effectiveness endpoint was clinical relapse requiring a further infusion of rituximab. Survival curves were estimated using Kaplan-Meier methods and survival analyses were undertaken using Cox proportional-hazards models. Results: Twenty-five patients were included: 11 treated with protocol 4 + 2 (375 mg/m(2)/4 weeks, then monthly for 2 months), five treated with protocol 1 + 1 (two 1 g doses 2 weeks apart), and nine treated with protocol 4 (375 mg/m(2)/4 weeks). Mean follow-up was 5.0 years (SD 3.3). Relapse occurred in 18.2%, 80%, and 33.3%, and mean time to relapse was 3.5 (SD 1.5), 1.1 (SD 0.4), and 2.5 (SD 1.4) years, respectively. Based on Kaplan-Meier estimates, patients treated with protocol 4 + 2 had fewer and later relapses than patients treated with the other two protocols (log-rank test P = 0.0001). Patients treated with protocol 1 + 1 had a higher risk of relapse than patients treated with protocol 4 + 2 (HR 112.8, 95% CI, 5.7-2250.4, P = 0.002). Patients treated with protocol 4 showed a trend to a higher risk of relapse than those treated with protocol 4 + 2 (HR 9.2, 95% CI 0.9-91.8, P = 0.059). InterpretationThis study provides class IV evidence that the 4 + 2 rituximab protocol has a lower clinical relapse rate and produces a more durable response than the 1 + 1 and 4 protocols in patients with MuSK MG

Drug-refractory myasthenia gravis : Clinical characteristics, treatments, and outcome

Altres ajuts: R. Alvarez-Velasco was supported by grant SLT008/18/00207 from the Health Research and Innovation Strategic Plan (PERIS). The NMD-ES Project and F. PlaJunca (data curator) are partially funded by the Centro de Investigacion Biomédica en Red de Enfermedades Raras (CIBERER).To describe the clinical characteristics and outcomes in patients with refractory myasthenia gravis (MG) and to determine the effectiveness and side effects of the drugs used for their treatment. This observational retrospective cross-sectional multicenter study was based on data from the Spanish MG Registry (NMD-ES). Patients were considered refractory when their MG Foundation of America post-interventional status (MGFA-PIS) was unchanged or worse after corticosteroids and two or more other immunosuppressive agents. Clinical and immunologic characteristics of drug-refractory patients, efficiency and toxicity of drugs used, and outcome (MGFA-PIS) at end of follow-up were studied. We included 990 patients from 15 hospitals. Eighty-four patients (68 of 842 anti-acetylcholine receptor [AChR], 5 of 26 anti-muscle-specific tyrosine kinase [MusK], 10 of 120 seronegative, and 1 of 2 double-seropositive patients) were drug refractory. Drug-refractory patients were more frequently women (p < 0.0001), younger at onset (p < 0.0001), and anti-MuSK positive (p = 0.037). Moreover, they more frequently presented a generalized form of the disease, bulbar symptoms, and life-threatening events (p < 0.0001; p = 0.018; and p = 0.002, respectively) than non-drug-refractory patients. Mean follow-up was 9.8 years (SD 4.5). Twenty-four (50%) refractory patients had side effects to one or more of the drugs. At the end of follow-up, 42.9% of drug-refractory patients (42.6% of anti-AChR, 100% of anti-MuSK, and 10% of seronegative patients) and 79.8% of non-drug-refractory patients (p < 0.0001) achieved remission or had minimal manifestations. Eighty percent of drug-refractory-seronegative patients did not respond to any drug tested. In this study, 8.5% of MG patients were drug-refractory. New more specific drugs are needed to treat drug-refractory MG patients

Clinical characteristics and outcomes of thymoma-associated myasthenia gravis

[Background and purpose] Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG.[Methods] This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18 years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed.[Results] We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6 years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95–4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15–2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43–3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47–4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up.[Conclusions] Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.This work is supported by Fondo de Investigaciones Sanitarias (FIS) grant FIS19/01774, Instituto de Salud Carlos III and cofunded by the European Union (ERDF/ESF, A Way to Make Europe/Investing in Your Future). Rodrigo Álvarez-Velasco was supported by a PhD for Medical Doctors grant from the Pla Estratègic de Recerca i Innovació en Salut (PERIS), Generalitat de Catalunya (SLT008/18/00207). Elena Cortés-Vicente was supported by a Juan Rodés grant (JR19/00037) from the Fondo de Investigación en Salud, Instituto de Salud Carlos III, Ministry of Health (Spain).Peer reviewe

Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain

Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT

EBM in primary care: a qualitative multicenter study in Spain

<p>Abstract</p> <p>Background</p> <p>Evidence based medicine (EBM) has made a substantial impact on primary care in Spain over the last few years. However, little research has been done into family physicians (FPs)' attitudes related to EBM. The present study investigates FPs' perceptions of EBM in the primary care context.</p> <p>Methods</p> <p>This study used qualitative methodology. Information was obtained from 8 focus groups composed of 67 FPs from 47 health centers in 4 autonomous regions in Spain. Intentional sampling considered participants' previous education in EBM, and their experience as tutors in family medicine or working groups' members of the Spanish Society of Family Practice. Sociological discourse analysis was used with the support of the MAXqda software. Results were validated by means of triangulation among researchers and contrast with participants.</p> <p>Results</p> <p>Findings were grouped into three main areas: 1) The tug-of-war between the "science" of EBM and "experience" in the search for good clinical practice in primary care; 2) The development of EBM sensemaking as a reaction to contextual factors and interests; 3) The paradox of doubt and trust in the new EBM experts.</p> <p>The meaning of EBM was dynamically constructed within the primary care context. FPs did not consider good clinical practice was limited to the vision of science that EBM represents. Its use appeared to be conditioned by several factors that transcended the common concept of barriers. Along with concerns about its objectivity, participants showed a tendency to see EBM as the use of simplified guidelines developed by EBM experts.</p> <p>Conclusions</p> <p>The identification of science with EBM and its recognition as a useful but insufficient tool for the good clinical practice requires rethinking new meanings of evidence within the primary care reality. Beyond the barriers related to accessing and putting into practice the EBM, its reactive use can determine FPs' questions and EBM development in a direction not always centred on patients' needs. The questioning of experts' authority as a pillar of EBM could be challenged by the emergence of new kinds of EBM texts and experts to believe in.</p

Effect of sex and RYR1 gene mutation on the muscle proteomic profile and main physiological biomarkers in pigs at slaughter

Gender and RYR1 gene mutation might have an effect on the muscle metabolic characteristics and on the animal's stress at slaughter, which could influence the process of muscle-to-meat conversion. Forty-eight pigs were distributed in a design including two factors: sex (male/female) and RYR1 genotype (NN/Nn). At slaughter, physiological blood biomarkers and muscle proteome were analyzed and carcass and meat quality traits were registered. Females had higher serum levels of glucose, urea, C-reactive protein "CRP", Pig-MAP and glutation-peroxidase "GPx" and lower levels of lactate, showed faster muscle pH decline and higher meat exudation. RYR1 mutation increased serum creatinine, creatine kinase and CRP and decreased GPx. The proteomic study highlighted significant effects of gender and RYR1 genotype on proteins related to fibre composition, antioxidant defense and post mortem glycolytic pathway, which correlate to differences of meat quality. This study provides interesting information on muscle biomarkers of the ultimate meat quality that are modulated by the animal's individual susceptibility to stress at slaughter.info:eu-repo/semantics/acceptedVersio

J Clin Psychiatry

To assess the utility of prophylactic administration of antidepressants in preventing a major depressive episode during antiviral treatment for chronic hepatitis C. A computerized literature search was conducted in MEDLINE, PsycINFO, EMBASE, the Cochrane Library, and ClinicalTrials.gov to locate articles published in any language from the earliest available online year until October 2012, using the following phrase and Boolean logic algorithm: "hepatitis and c and (interferon-alpha OR peginterferon OR (pegylated and interferon)) and (depression OR mood) and (prevention OR prophylactic OR prophylaxis OR antidepressant)." Double-blind, randomized, placebo-controlled trials using antidepressants prophylactically before starting antiviral therapy for chronic hepatitis C were included. At baseline, none of the patients in the trials presented depression (DSM-IV-TR criteria). Using keywords and cross-referenced bibliographies, 144 studies were identified and examined in depth. 137 articles were rejected because inclusion criteria were not met. Finally, 7 studies were included. Data were extracted independently by 2 investigators. The primary outcome measure was the onset of a major depressive episode during the antiviral treatment. Depressive symptoms, other side effects, and sustained virologic response were also examined. A full review and meta-analysis were performed. Odds ratios (ORs), mean differences, and estimated numbers needed to treat (NNTs) with 95% confidence intervals (CIs) were calculated. 591 patients were randomly assigned to antiviral treatment and another intervention: escitalopram (n = 197), paroxetine (n = 42), citalopram (n = 53), or placebo (n = 299). Selective serotonin reuptake inhibitors (SSRIs), as a group, reduced the incidence of a major depressive episode during antiviral treatment (OR = 0.53; 95% CI, 0.33 to 0.84). The NNT was 12 (95% CI, 7.0 to 37.9). SSRIs reduced depressive symptoms at 24 weeks of treatment (mean difference -2.18; 95% CI, -4.25 to -0.10). With regard to side effects, only dizziness was associated with administration of antidepressants (OR = 2.65; 95% CI, 1.46 to 4.80). There were no differences in sustained virologic response (OR = 1.22; 95% CI, 0.58 to 2.57). Administration of SSRIs before starting antiviral treatment reduces the incidence of interferon-induced depression, with a relatively moderate prophylactic impact and good tolerability

Exploring the influence of land use on the urban carbonyl sulfide budget : a case study of the Metropolitan Area of Barcelona

Altres ajuts: acords transformatius de la UABUnidad de excelencia María de Maeztu CEX2019-000940-MCarbonyl sulfide (OCS) is used to quantify the carbon capture potential of the biosphere because of its direct correlation with CO2 uptake during photosynthesis. However, to constrain the urban biosphere signal, it is necessary to evaluate potential anthropogenic sources. We conducted two sampling campaigns in the Metropolitan Area of Barcelona (AMB), Spain, during May (full COVID lockdown) and October 2020 to measure the spatial distribution and variability of OCS in four urban land uses as follows: built, urban forest, urban park, and peri-urban agriculture. The OCS background levels determined at Tibidabo (442 m asl) were approximately 484 ± 20 ppt and 407 ± 8 ppt for May and October 2020, respectively, and agreed with other seasonal surveys conducted in Europe during that same period. Averaged emissions were in the range of +Δ12 ± 40 ppt for the city and were +Δ9.4 ± 40.9 ppt for urban +Δ22.1 ± 48 ppt for urban green +Δ20.7 ± 42.9 ppt for agricultural and −Δ4.8 ± 19.6 ppt for forest. The urban values ranged from neutral to above background, suggesting nearby anthropogenic and marine emissions such as +Δ150 ppt in Montjuic, which is downwind of Barcelona's harbor. During the crop-growing season in May, the agricultural areas consistently showed values below the background (up to −Δ76 ppt in Gavà, uptake) at 7:00 UTC when the land breezes were dominant, while later in the morning, when the sea breeze are developed, the plant sink is masked by the transport of marine emissions. Urban forests located north of Tibidabo showed OCS values up to −Δ70 ppt, suggesting significant uptake by urban forests. We conclude that determining the urban biosphere signal using OCS as a tracer is more complex than expected because the marine and anthropogenic emissions from the port strongly impact the spatial-temporal distribution of OCS

Psychoneuroendocrinology

Cytokines and serotonin neurotransmission may play an important role on the development of psychopathological symptoms during interferon (IFN) treatment. The aim of the present study was to investigate the association between IFN-induced depression, anxiety and fatigue and functional genetic variants at the interleukin-6 gene (IL-6) and serotonin transporter gene (SERT). 385 consecutive Caucasian outpatients with chronic hepatitis C initiating treatment with IFN-alpha and ribavirin were included. All patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV (SCID-I) and those with a current major depressive disorder or anxiety disorder before starting treatment were excluded. Depression and anxiety were assessed at baseline during the treatment (at 4, 12, 24 and 48 weeks) using the Hospital Anxiety and Depression Scale and fatigue was evaluated using a visual analogue scale. The 5-HTTLPR region of SERT gene and the functional polymorphism located at the promoter region of IL-6 gene (rs1800795) were genotyped. Genotypic distribution was in the Hardy-Weinberg equilibrium for SERT (p=0.41) and for IL-6 (p=0.72) polymorphisms. At baseline we found only a significant effect of IL-6 polymorphism on fatigue symptoms. During antiviral treatment we reported that subjects with CC genotype (IL-6) presented significantly lower changes from baseline in IFN-induced depression (p=0.005) and IFN-induced anxiety (p=0.004). We did not find statistically significant differences on depression (p=0.21) or anxiety (p=0.15) between SS/SL and LL genotypes of SERT. Genetic variations in the IL-6 gene increase the risk of IFN-induced depression and anxiety. The IL-6 polymorphism was associated with fatigue rates in patients with chronic hepatitis C before treatment. Our study confirms the role of inflammatory mechanisms in IFN-induced psychopathological symptoms