Melhoria de processos de produção e operações numa empresa farmacêutica

Perante a conjuntura de instabilidade vivida a nível europeu e, principalmente, a nível nacional, a Industria Farmacêutica vê-se obrigada a fazer frente a certas dificuldades. Para tal, dá início a reduções orçamentais de grande dimensão, que requerem uma melhor e maior gestão e racionalização dos seus recursos. Deste modo, para a criação de vantagens competitivas, as Industrias devem focar-se na totalidade do seu negócio, desde a pesquisa de novos fármacos, ao desenvolvimento de processos de fabrico mais eficientes. O Laboratório Edol, como Pequena e Média Empresa nacional, detém um papel fundamental na economia portuguesa. Assim, de forma a manter a sua importância no dinamismo da economia, necessita de ajuda no desenvolvimento de linhas de produção mais eficazes. Perante isto, o Laboratório propôs a melhoria do processo de fabrico do creme hidratante ATL, uma vez que este produto, em especial, é líder em vendas e contém alguns constrangimentos na sua produção. Havia portanto, a necessidade de melhoria do processo com vista a um aumento significativo da sua produção. É neste contexto, que a aplicação de metodologias como o Lean e o Six Sigma se enquadram na perfeição nesta dissertação, que tem como objetivo eliminar fontes de desperdício e acrescentar valor aos produtos, em particular, no dermocosmético proposto por esta empresa. Ambas as filosofias demonstraram grande capacidade na melhoria do sistema, que levaram a propostas de sucesso e que atingiram as metas estipuladas – aumento de eficiência e produtividade do creme ATL. Para além disto, ainda foram descritas diversas ideias para projetos futuros de melhoria continua. De salientar que numa época de crescimento a nível de exportações, as empresas a nível nacional ou global, necessitam de otimizar as suas linhas para conseguirem dar vazão aos mercados internacionais. Como tal, o Lean e o Six Sigma, representam esse potencial. Dado isto, os objetivos propostos foram atingidos na íntegra, com o acrescento de novas soluções para a linha de produção e com uma gestão mais racional dos recursos humanos.

Technical optimization of the synthesis of flavours

The goal of this thesis is the investigation and optimization of the synthesis of potential fragrances. This work is projected as collaboration between the University of Applied Sciences in Merseburg and the company Miltitz Aromatics GmbH in Bitterfeld‐Wolfen (Germany). Flavoured compounds can be synthesized in different ways and by various methods. In this work, methods like the phase transfer catalysis and the Cope‐rearrangement were investigated and applied, for getting a high yield and quantity of the desired substances and without any by‐products or side reactions. This involved the study of syntheses with different process parameters such as temperature, solvent, pressure and reaction time. The main focus was on Cope‐rearrangement, which is a common method in the synthesis of new potential fragrance compounds. The substances synthesized in this work have a hepta‐1,5‐diene‐structure and that is why they can easily undergo this [3,3]‐sigma tropic rearrangement. The lead compound of all research was 2,5‐dimethyl‐2‐vinyl‐4‐hexenenitrile (Neronil). Neronil is synthesized by an alkylation of 2‐methyl‐3‐butenenitrile with prenylchloride under basic conditions in a phase‐transfer system. In this work the yield of isolated Neronil is improved from about 35% to 46% by according to the execution conditions of the reaction. Additionally the amount of side product was decreased. This synthesized hexenenitrile involved not only the aforementioned 1,5‐diene‐structure, but also a cyano group, that makes this structure a suitable base for the synthesis of new potential fragrance compounds. It was observed that Neronil can be transferred into 2,5‐dimethyl‐2‐vinyl‐4‐hexenoic acid by a hydrolysis under basic conditions. After five hours the acid can be obtained with a yield of 96%. The following esterification is realized with isobutanol to produce 2,5‐dimethyl‐2‐vinyl‐4‐hexenoic acid isobutyl ester with quantitative conversion. It was observed that the Neronil and the corresponding ester can be converted into the corresponding Cope‐product, with a conversion of 30 % and 80%. Implementing the Cope‐rearrangement, the acid was heated and an unexpected decarboxylated product is formed. To achieve the best verification of reaction development and structure, scrupulous analyses were done using GC‐MS, 1H‐NMR and 13C‐ NMR.

Valorization of olive pomace through combination of biocatalysis with supercritical fluid technology

A supercritical carbon dioxide (scCO2) based oil extraction method was implemented on olive pomace (alperujo), and an oil yield of 25,5 +/- 0,8% (goil/gdry residue) was obtained. By Soxhlet extraction with hexane, an oil extraction yield of 28,9 +/- 0,8 % was obtained, which corresponds to an efficiency of 88,4 +/- 4,8 % for the supercritical method. The scCO2 extraction process was optimized for operating conditions of 50 MPa and 348,15 K, for which an oil loading of 32,60 g oil/kg CO2 was calculated. As a proof of concept, olive pomace was used as feedstock for biodiesel production, in a process combining the use of lipase as a catalyst with the use of scCO2 as a solvent, and integrating the steps of oil extraction, oil to biodiesel transesterification and subsequent separation of the latter. In the conducted experiments, FAME (fatty acid methyl ester) purities of 90% were obtained, with the following operating parameters: an oil:methanol molar ratio of 1:24; a residence time of 7,33 and 11,6 mins; a pressure of 40 MPa; a temperature of 313,15 K; and Lipozyme (Mucor miehei; Sigma-Aldritch) as an enzyme. However, oscillations of FAME purity were registered throughout the experiments, which could possibly be due to methanol accumulation in the enzymatic reactor. Finally, the phenolic content of olive pomace, and the effect of the drying process – oven or freeze-drying – and the extraction methods – hydro-alcoholic method and supercritical method – on the phenolic content were analysed. It was verified that the oven-drying process on the olive pomace preserved 90,1 +/- 3,6 % of the total phenolic content. About 62,3 +/- 5,53% of the oven-dried pomace phenolic content was extracted using scCO2 at 60 MPa and 323,15 K. Seven individual phenols – hydroxytyrosol, tyrosol, oleuropein, quercetin, caffeic acid, ferulic acid and p-coumaric acid – were identified and quantified by HPLC.

Urinary tract infection in full-term newborn infants: risk factor analysis

OBJECTIVE: To analyze the correlation of risk factors to the occurrence of urinary tract infection in full-term newborn infants. PATIENTS AND METHODS: Retrospective study (1997) including full-term infants having a positive urine culture by bag specimen. Urine collection was based on: fever, weight loss > 10% of birth weight, nonspecific symptoms (feeding intolerance, failure to thrive, hypoactivity, debilitate suction, irritability), or renal and urinary tract malformations. In these cases, another urine culture by suprapubic bladder aspiration was collected to confirm the diagnosis. To compare and validate the risk factors in each group, the selected cases were divided into two groups: Group I - positive urine culture by bag specimen collection and negative urine culture by suprapubic aspiration, and Group II - positive urine culture by bag specimen collection and positive urine culture by suprapubic aspiration . RESULTS: Sixty one infants were studied, Group I, n = 42 (68.9%) and Group II, n = 19 (31.1%). The selected risk factors (associated infectious diseases, use of broad-spectrum antibiotics, renal and urinary tract malformations, mechanical ventilation, parenteral nutrition and intravascular catheter) were more frequent in Group II (p<0.05). Through relative risk analysis, risk factors were, in decreasing importance: parenteral nutrition, intravascular catheter, associated infectious diseases, use of broad-spectrum antibiotics, mechanical ventilation, and renal and urinary tract malformations. CONCLUSION: The results showed that parenteral nutrition, intravascular catheter, and associated infectious diseases contributed to increase the frequency of neonatal urinary tract infection, and in the presence of more than one risk factor, the occurrence of urinary tract infection rose up to 11 times.

Immunoglobulin E-rheumatoid factor in juvenile rheumatoid arthritis

OBJECTIVES: To determine the presence of immunoglobulin E-rheumatoid factor in patients with juvenile rheumatoid arthritis and to correlate it with clinical and laboratory parameters. METHODS: A multicenter prospective study was carried out from January 1993 to January 1999 with the enrollment of 3 centers of pediatric rheumatology. Ninety-one children with juvenile rheumatoid arthritis diagnosed according to the American College of Rheumatology criteria were studied: 38 (42%) with systemic, 28 (31%) with pauciarticular, and 25 (27%) with polyarticular onset. Ages ranged from 2.1 years to 22.6 years (mean 10.5 ± 4.7), with 59 (65%) girls. The control group consisted of 45 healthy children. The detection of immunoglobulin E-rheumatoid factor was carried out utilizing an enzyme-linked immunosorbent assay. Associations of immunoglobulin E-rheumatoid factor with immunoglobulin M-rheumatoid factor (latex agglutination test), total serum immunoglobulin E, erythrocyte sedimentation rate, antinuclear antibody, and functional and radiological classes III or IV were analyzed. RESULTS: Positive immunoglobulin E-rheumatoid factor was found in 15 (16.5%) of the 91 children with juvenile rheumatoid arthritis: 7 (18.5%) with systemic, 5 (18%) with pauciarticular, and 3 (12%) with polyarticular onset. A significant correlation was observed between immunoglobulin E-rheumatoid factor and total serum immunoglobulin E in the juvenile rheumatoid arthritis patients. No correlation was found between immunoglobulin E-rheumatoid factor and positive latex agglutination slide test, erythrocyte sedimentation rate, antinuclear antibody, or the functional and radiological classes III or IV in any disease onset group. In 4 out of 45 control children (8.9%), immunoglobulin E-rheumatoid factor was positive but with no correlation with total serum immunoglobulin E levels. CONCLUSIONS: Immunoglobulin E-rheumatoid factor could be detected in 16.5% of juvenile rheumatoid arthritis patients, particularly in those with high levels of total serum immunoglobulin E, and immunoglobulin E-rheumatoid factor appears not to be associated with disease activity or severity.

Adrenocortical tumors: results of treatment and study of Weiss's score as a prognostic factor

PURPOSE: The differential diagnosis between benign and malignant adrenal cortical tumors circumscribed to the gland is controversial. One hundred and seven patients with adrenal cortex tumors (excluding those with primary hyperaldosteronism) were studied to assess the 5-year survival rate of adults, children, patients stratified by pathological stage, and patients stratified according to Weiss's score of <3 or >3. METHODS: The patients were evaluated both clinically and biochemically. One hundred and five patients underwent surgery and were classified pathologically as stages I, II, III, or IV. The tumors were weighed, measured, and classified according to Weiss's criteria and divided into 2 groups: <3 and >3. RESULTS: After 5 years, the survival rate was 77.5% for the whole group, 74.61% for the adults, 84.3% for the children, 100% for stage I, 83.9% for stage II, 33% for stage III, and 11.7% for stage IV groups. Additionally, after 5 years, 100% of the patients with tumors with Weiss's score <3 were alive compared to 61.65% of those with Weiss's score >3. The average weights of the tumors of score <3 and >3 were 23.38 g ± 41.36 g and 376.3 ± 538.76 g, respectively, which is a statistically significant difference. The average sizes of tumors of Weiss's score <3 and >3 were 3.67 ± 2.2 cm and 9.64 ± 5.8 cm, respectively, which is also a statistically significant difference. CONCLUSIONS: Weiss's score may be a good prognostic factor for tumors of the adrenal cortex. Additionally, there was a statistically significant difference between the average weight and size of tumors with benign behavior (Weiss's score <3) and those with malignant behavior (Weiss's score >3).

Um Stibadium com mosaico na Villa Romana do Rabaçal. De cenário áulico a chão de culto cemiterial – de chão agricultado às primícias arqueológicas

A nossa reflexão abordará a questão da presença de um stibadium, leito semicircular com mesa, construído em alvenaria no interior de um ninfeu decorado com mosaico, numa posição frontal, simétrica e sobreelevada em relação ao ingresso na sala do triclinium, bem como a sua ligação com o ritual do conuiuium, na pars urbana da Villa romana do Rabaçal. Estas estruturas, descobertas nas campanhas de trabalhos arqueológicos aqui realizados entre 1986 e 1992, foram desde então interpretadas como fazendo parte de um jardim interior, dado terem sido nelas assinalada a existência, a um nível inferior, de um conjunto de cinco canaletas ligadas, aparentemente, a um tanque exterior. Inconformados com esta interpretação, observámos de novo em 1997, ao pormenor, esta construção absidal, tendo em conta a sua axialidade e o facto de nela ter sido incorporado um sistema de canalizações que permitiam, porventura, ou espalhar água por todo o pavimento de mosaico do triclinium, sala rectangular de maior aparato decorativo da pars urbana da Villa, ou, pelo contrário, melhor isolar da humidade o interior do pavimento da sala em sigma. Esta discussão será o ponto central da nossa comunicação. Serão ainda abordadas, em jeito de epílogo, questões relacionadas com a continuidade da ocupação da Villa na Antiguidade Tardia, sua provável ocupação em época suévica e a continuidade da utilização do local como espaço de habitação e de culto cemiterial até ao século XVI.

Ensaio exploratório de um modelo TLS num sistema produtivo Lean: caso Equipar

O setor da cortiça representa no panorama industrial português um lugar de grande destaque devido à imagem de excelência e de rigor que os fabricantes nacionais transmitem ao mundo. As rolhas, produto originado por esta matéria-prima, encontram-se sujeitas a novas pressões do mercado pelo aparecimento de produtos alternativos que fornecem a mesma utilidade. O caso de Estudo é aplicado na Corticeira Amorim, atual líder mundial do setor, que utiliza a inovação e a melhoria dos seus processos e produtos como forma de manter o monopólio que atualmente possui. Faz parte da estratégia da Unidade Industrial Equipar, procurar as melhores práticas exploradas pelas empresas internacionais de topo. Atualmente a metodologia que apresenta melhor desempenho em termos de ganhos são os modelos que combinam a Teoria das Restrições com Lean e 6-Sigma, denominados pela sigla TLS. Foi desejado que se criasse um modelo com base nas filosofias anteriores e que fosse possível adaptar ao sistema produtivo de rolhas técnicas encontrado na secção Twin Top. Após uma revisão bibliográfica, construiu-se um modelo TLS com 5 fases com objetivo de atingir a melhoria contínua de um sistema produtivo. As fases do modelo proposto passam pela análise e identificação da restrição, exploração da mesma com as possíveis oportunidades de melhorias LSS, pela subordinação do sistema à restrição e por fim é feita uma reavaliação do desempenho da restrição, onde se a mesma estiver resolvida o ciclo fecha retornando ao primeiro passo novamente ou, caso contrário, é elevado o desempenho do processo com recurso a investimento monetário. Foram aplicados dois ciclos de melhoria contínua. Os resultados obtidos na resolução da primeira restrição foram extremamente satisfatórios onde o processo restritivo tornou-se o mais eficiente após as melhorias. Foi iniciada a exploração da restrição no segundo ciclo. Os objetivos definidos inicialmente na presente tese de mestrado foram alcançados.

Melhoramento de um processo de cromagem de segmentos de pistão

Neste trabalho estudam-se os parâmetros que influenciam o processo de cromagem de segmentos de pistão utilizado na MAHLE Componentes de Motores S.A., situada em Portugal na zona industrial de Murtede perto de Coimbra. Pretende-se identificar a influência dos vários parâmetros do processo de cromagem na dureza, com o intuito de otimizá-la. Estabelece-se como objetivo principal a identificação de fatores que permitam diminuir o aparecimento de lascas (objeto de estudo) no revestimento dos segmentos. Para além disso, pretende-se quantificar a dureza extremamente fragil do revestimento para futuramente melhorar o controlo de qualidade efetuado na fábrica e deste modo, reduzir a ocorrência de peças com defeito. Neste trabalho recorre-se à metodologia Seis Sigma, muito utilizada em engenharia no melhoramento contínuo de processos. Após a realização de ensaios e correspondente análise de resultados, obtêm-se os valores dos parâmetros do processo que permitem a redução dos defeitos na cromagem dos segmentos. Com os resultados deste estudo espera-se melhorar a qualidade dos produtos (segmentos de pistão), aumentar a produtividade e simultaneamente diminuir o refugo, com as vantagens económicas daí decorrentes.

Understanding multi-asset factor models: Factor exposure interpretation

Field lab: Business project

Acellular Gellan-gum based bilayered structures for the regeneration of osteochondral defects: a preclinical study

 In orthopaedics, the management and treatment of osteochondral (OC) defects remains an ongoing clinical challenge. Autologous osteochondral mosaicplasty has been used as a valid option for OC treatments although donor site morbidity remains a source of concern [1]. Engineering a whole structure capable of mimicking different tissues (cartilage and subchondral bone) in an integrated manner could be a possible approach to regenerate OC defects. In our group we have been proposing the use of bilayered structures to regenerate osteochondral defects [2,3]. The present study aims to investigate the pre-clinical performance of bilayered hydrogels and spongy-like hydrogels in in vivo  models (mice and rabbit, respectively), in both subcutaneous and orthotopic models. The bilayered structures were produced from Low Acyl Gellan Gum (LAGG) from Sigma-Aldrich, USA. Cartilage-like layers were obtained from a 2wt% LAGG solution. The bone-like layers were made of 2wt% LAGG with incorporation of hydroxyapatite at 20% and 30% (w/v). Hydrogels and spongy-like were subcutaneouly implanted in mice to evaluate the inflammatory response. Then, OC defects were induced in rabbit knee to create a critical size defect (4 mm diameter and 5 mm depth), and then hydrogels and sponges implanted. Both structures followed different processing methods. The hydrogels were injected allowing in situ  crosslinking. Unlike, the spongy-like were pre-formed by freeze-drying. The studies concerning subcutaneous implantation and critical size OC defect were performed for 2 and 4 weeks time, respectively. Cellular behavior and inflammatory responses were assessed by means of histology staining and biochemical function and matrix deposition by immunohistochemistry. Additionally, both OC structures stability and new cartilage and bone formation were evaluated by using vivo- computed tomography (Scanco 80). The results showed no acute inflammatory response for both approaches. New tissue formation and integration in the adjacent tissues were also observed, which present different characteristic behaviors when comparing hydrogels and sponges response. As future insights, a novel strategy for regeneration of OC defects can be designed encompassing both, hydrogels and spongy-like structures and cellular approaches. References: 1. Espregueira-Mendes J. et al. Osteochondral transplantation using autografts from the upper tibio-fibular joint for the treatment of knee cartilage lesions. Knee Surgery, Sports Traumatology, Arthroscopy 20,1136, 2012. 2. Oliveira JM. et al, Novel hydroxyapatite/chitosan bilayered scaffold for osteochondral tissue-engineering applications: Scaffold design and its performance when seeded with goat bone marrow stromal cells. Biomaterials 27, 6123, 2006. 3. Pereira D R. et al. Gellan Gum-Based Hydrogel Bilayered Scaffolds for Osteochondral Tissue Engineering. Key Engineering Materials 587, 255, 2013.

Measurements of the nuclear modification factor for jets in Pb+Pb collisions at sNN =2.76TeV with the ATLAS detector

Measurements of inclusive jet production are performed in pp and Pb+Pb collisions at sNN−−−√=2.76 TeV with the ATLAS detector at the LHC, corresponding to integrated luminosities of 4.0 pb−1 and 0.14 nb−1 , respectively. The jets are identified with the anti-kt algorithm with R=0.4, and the spectra are measured over the kinematic range of jet transverse momentum 32factor, RAA, is evaluated and jets are found to be suppressed by approximately a factor of two in central collisions compared to pp collisions. The RAA shows a slight increase with pT and no significant variation with rapidity.

Utilização de ferramentas da qualidade num sistema operacional numa empresa

Dissertação de mestrado integrado em Engenharia e Gestão Industrial

Lack of the transcription factor hypoxia-inducible factor (HIF)-1α in macrophages accelerates the necrosis of Mycobacterium avium-induced granulomas

Accepted Manuscript

Female hippocampus vulnerability to environmental stress, a precipitating factor in tau aggregation pathology

Tau-mediated neurodegeneration is a central event in Alzheimer's disease (AD) and other tauopathies. Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD pathology, we previously showed that stress triggers tau hyperphosphorylation and accumulation; however, little is known about the etiopathogenic interaction of chronic stress with other AD risk factors, such as sex and aging. This study focused on how these various factors converge on the cellular mechanisms underlying tau aggregation in the hippocampus of chronically stressed male and female (middle-aged and old) mice expressing the most commonly found disease-associated Tau mutation in humans, P301L-Tau. We report that environmental stress triggers memory impairments in female, but not male, P301L-Tau transgenic mice. Furthermore, stress elevates levels of caspase-3-truncated tau and insoluble tau aggregates exclusively in the female hippocampus while it also alters the expression of the molecular chaperones Hsp90, Hsp70, and Hsp105, thus favoring accumulation of tau aggregates. Our findings provide new insights into the molecular mechanisms through which clinically-relevant precipitating factors contribute to the pathophysiology of AD. Our data point to the exquisite sensitivity of the female hippocampus to stress-triggered tau pathology.