Production planning of biopharmaceutical manufacture.

Multiproduct manufacturing facilities running on a campaign basis are increasingly becoming the norm for biopharmaceuticals, owing to high risks of clinical failure, regulatory pressures and the increasing number of therapeutics in clinical evaluation. The need for such flexible plants and cost-effective manufacture pose significant challenges for planning and scheduling, which are compounded by long production lead times, intermediate product stability issues and the high cost - low volume nature of biopharmaceutical manufacture. Scheduling and planning decisions are often made in the presence of variable product titres, campaign durations, contamination rates and product demands. Hence this thesis applies mathematical programming techniques to the planning of biopharmaceutical manufacture in order to identify more optimal production plans under different manufacturing scenarios. A deterministic mixed integer linear programming (MILP) medium term planning model which explicitly accounts for upstream and downstream processing is presented. A multiscenario MILP model for the medium term planning of biopharmaceutical manufacture under uncertainty is presented and solved using an iterative solution procedure. An alternative stochastic formulation for the medium term planning of biomanufacture under uncertainty based on the principles of chance constrained programming is also presented. To help manage the risks of long term capacity planning in the biopharmaceutical industry, a goal programming extension is presented which accounts for multiple objectives including cost, risk and customer service level satisfaction. The model is applied to long term capacity analysis of a mix of contractors and owned biopharmaceutical manufacturing facilities. In the final sections of this thesis an example of a commercial application of this work is presented, followed by a discussion on related validation issues in the biopharmaceutical industry. The work in this thesis highlighted the benefits of applying mathematical programming techniques for production planning of biopharmaceutical manufacturing facilities, so as to enhance the biopharmaceutical industry's strategic and operational decision-making towards achieving more cost-effective manufacture

New insights on the relative sea level change during Holocene along the coasts of Tunisia and western Libya from archaeological and geomorphological markers

New data of sea level changes for the Mediterranean region along the coasts of northern Africa are presented. Data are inferred from archaeological sites of Punic-Roman age located along the coast of Tunisia, between Tunis and Jerba island and along the western coast of Libya, between Sabratha and Leptis Magna. Data are based on precise measures of presently submerged archaeological markers that are good indicators of past sea-level elevation. Nineteen selected archaeological sites were studied in Tunisia and four in Libya, all aged between w2.0 and w1.5 ka BP. The functional elevations of significant archaeological markers were measured with respect to the sea level at the time of measurements, applying corrections for tide and atmospheric pressure values. The functional elevations of specific architectural parts of the sites were interpreted, related to sea level at the time of their construction providing data on the relative changes between land and sea. Observations were compared against sea level change predictions derived from the glacio-hydro-isostatic model associated with the Last Glacial cycle. The results indicate that local relative sea level change along the coast of Tunisia and Libya, has increased 0.2 O 0.5 m since the last w2 ka. Besides minor vertical tectonic movements of the land, the observed changes are produced by eustatic and glacio-hydro-isostatic variations acting in the Mediterranean basin since the end of the last glacial maximum

Organisation et fonctionnement d’un écosystème côtier du Maroc : la lagune de Khnifiss

La lagune de Khnifiss, située au sud du Maroc, est une réserve biologique d’intérêt mondial pour l’avifaune. Des études pluridisciplinaires portant sur la physico-chimie des eaux, la biologie, la sédimentologie et les courants ont été réalisées par l’INRH dans la lagune en septembre 1998 et février 2001. Les résultats du courant obtenus montrent que la circulation des eaux à l’intérieur de la lagune est gérée par un courant alternatif et bidirectionnel : les courants du jusant sont plus importants que ceux du flot et varient également en fonction du rythme de la marée vive-eau/morte-eau. Ce mode de circulation des eaux attribue à la lagune une richesse en éléments azotés et phosphatés, surtout en période de vive-eau. La biomasse chlorophyllienne, assez importante dans la lagune, est causée par la richesse du milieu en éléments nutritifs et le phénomène d’upwelling qui se manifeste en été et au printemps dans la zone sud du Maroc. Ces études ont montré que la lagune de Khnifiss est un milieu propice à la conchyliculture. Néanmoins, l’installation de tout projet aquacole dans le site devra tenir compte de sa capacité trophique et de son équilibre écologique.The Moroccan coastal marine area has several zones that are targets for exploitation but must simultaneously be protected. Lagoons are considered to be among the most productive natural systems in the world, but they are also vulnerable systems due to natural and human constraints. Lagoons can also be a target of economic expansion. This is why an understanding about the state of these ecosystems is important in order to proceed with rational use of the resource. The Khnifiss lagoon, situated on the South Atlantic coast of Morocco, is a potential site for aquaculture and tourism if planned with an ecological awareness. The large surface area and high biological production for the avifauna qualify it to be among the four protected sites by the RAMSAR convention for humid zone conservation (lagoons of Khnifiss and Moulay Bousselham, lakes of Sidi Boughaba and Afennourir). The objective of this work was to complete previous studies and to estimate the nutritive richness of the Khnifiss lagoon. To understand the spatio-temporal variability in the water currents, and the physico-chemical and biological and characteristics of this lagoon, two surveys were organized in September 1998 and February 2001.The Khnifiss lagoon (20 km long and 65 km2 surface area) is situated between Tantan and Tarfaya (28°02'54'' N, 12°13'66'' W). It opens up into the Atlantic ocean by a narrow inlet called ''Foum Agouitir'', about 100 m wide. The lagoon continues upstream beyond a salt marsh, called "Sebkha Tazra". Physical, chemical and biological variables were monitored: temperature and salinity; dissolved oxygen, nitrates and phosphates; chlorophyll a. The current (direction and intensity) and the sediment were also studied. Samples were collected four times from the surface and bottom waters during spring tide (ST), neap tide (NT), low tide (LT) and high tide (HT) during two seasons (September 1998 and February 2001). Seven hydrological stations were sampled, representing the lagoon system and one reference station in a neighbouring zone (Hréf), which represents the marine zone of the lagoon. Temperature and salinity were measured with a multi-sensor probe. The chemical analyses were carried out according to methods suggested by AMINOT & CHAUSSEPIED (1983). Thirty (30) sediment samples were also collected. Currents were measured at two fixed points by two current-meters.Based on the hydrological characteristics of the lagoon, especially temperature, salinity, water circulation and the nature of sediment, three zones were identified :1. Zone I (downstream from the lagoon) was dominated by the ocean’s influence and included the Hréf, H1 and H2 stations. Maximum depths varied from 2.5 to 6.6 m, depending on the tide and location. The concentrations of the different hydrological parameters were controlled by the plug effect of the oceanic environment. The most important current in the lagoon was recorded in this zone in the spring tide (ST: 110 cm.s-1). The sediment was coarse and important water - sediment exchange was caused by the strong current recorded in this zone.2. Zone II (middle of the lagoon) was a transition zone with an intermediate oceanic influence. It was situated between the H3 and H5 stations. The size of the inlet and the important exchanges governed by currents caused by strong tides resulted in concentrations of the various parameters being similar to those in Zone I. Depths varied from 2.64 to 8.7 m. Waters were more saline during the LT and NT periods (36-41 practical salinity unit, or psu). The current decreased relative to that is zone I (56 cm.s-1 in September 1998 and 78 cm.s-1 in February 2001). In this zone the current moved preferentially towards the right strand at high tide and toward the left strand at low tide.3. Zone III (upstream in the lagoon) covered a different biotope compared to the first two zones. The waters were less deep (2.64 to 5.3 m) and included the stations H6, H7 and the upper part of the lagoon. This zone was characterized by a very low oceanic influence. Water temperature and salinity were higher, 24-26°C and 41-44 psu respectively, during the LT and NT periods.On the basis of the hydrological zonation, the conjunction of the climate descriptors (moderate wind, rare precipitation, absence of storms, moderate air temperature) of the lagoon and the strong hydrodynamic influence in the lagoon suggest that the Knifiss lagoon is a relatively unconfined ecosystem. The hydrodynamics of this lagoon permit a fast water renewal rate and insure a good environmental quality. In addition, studies carried out on the healthiness of this lagoon demonstrated not only a healthy environment, but also healthy shellfish. This diagnosis seemed to be related to the geographical location and important rates of water exchange. However, the absence of continental freshwater sources leads to an important increase in salinity and temperature at the level of the upstream zone (zone III). Zone III therefore cannot be considered for shellfish breeding.On the basis of the biological zones: With respect to the bathymetry of the lagoon (depths varied from 2.5 to 8.7 m), shellfish, in contrast to fish, require less water depth. Therefore, it is sufficient to search for a less turbulent zone, which offers sufficient planktonic food for the shellfish growth. In the Khnifiss lagoon, the taxonomy of the phytoplankton has not been yet studied. However, BENNOUNA (1999) demonstrated that the phytoplankton community was dominated by dinoflagellates and diatoms in the Oualidia and Sidi Moussa lagoons. RHARBI (2000) found that picophytoplankton were the principal breeding food source of oysters and clams in Oualidia lagoon. The source of shellfish for breeding is located in the neighbouring upwelling marine waters. Development projects planned for the lagoon must include an awareness programme for fishermen about the role that moderate and responsible shellfish breeding programs can play in the preservation and reconstitution of the marine resource as well as in the improvement of their incomes

Low-temperature rate constants for rotational excitation and de-excitation of C3 (X 1∑g +) by collisions with He (1S)

The low-temperature rotational (de-) excitation of C3 (X 1∑g 1) by collisions with He (1S) is studied using an ab initio potential energy surface (PES). This PES has been calculated using the single- and double-excitation coupled-cluster approach with noniterative perturbational treatment of triple excitations [CCSD(T)] and the augmented correlation-consistent triple-ζ basis set (aug-cc-pVTZ) with bond functions. This PES is then incorporated in full close-coupling quantum scattering calculations for collision energies between 0.1 and 50 cm -1 in order to deduce the rate constants for rotational levels of C3 up to j = 10, covering the temperature range 5-15 K. © 2008. The American Astronomical Society. All rights reserved.The Agencia Española de Cooperación Internacional (project A/8083/07, CSIC-Université Tunis El Manar) and the Spanish Ministerio de Educación y Ciencia (project AYA 2005-00702) are thanked for financial supportPeer Reviewe

Kyste neurentérique intra dural extra médullaire: à propos d’un cas

Le kyste neurentérique (KNE) est une malformation congénitale rare du système nerveux central (SNC) entrant dans le cadre des notochordodysraphies. Nous rapportons un nouveau cas de KNE de localisation intra durale extra médullaire chez un patient de 16 ans, admis dans un tableau de compression médullaire cervicale haut évoluant depuis 4 mois. L’imagerie a objectivé une lésion kystique pré médullaire en regardde C1-C2-C3. Le patient a bénéficié d’une évacuation kystique et l’histologie avait conclu à un kyste neurentérique. L’évolution était marquée par le décès du patient par des complications neurovégétatives graves. Malgré sa bénignité histologique, le kyste neurentérique de localisation cervicale haute peut se compliquer de troubles neurovégétatifs parfois imprévisibles pouvant aboutir à une évolution dramatique

Cavernome intramedullaire: a propos d’un cas

Le cavernome intramédullaire, malformation vasculaire rare, représente environ 5 à 12 % des malformations vasculaires spinales et 3 % des malformations vasculaires intra-durales. Il peut être longtemps asymptomatique ou se manifester par une altération brutale ou progressive des fonctions médullaires. Le diagnostic repose sur l’imagerie par résonance magnétique (IRM) médullaire et l’anatomopathologie. La chirurgie représente l’essentiel de la prise en charge, néanmoins elle n’est pas dénudée de complications. Nous rapportons un cas de cavernome intramédullaire chez une patiente de 24 ans, admise dans un tableau de compression médullaire dorsale lente avec une paraparésie évoluant depuis 2 ans. L’IRM médullaire a objectivé une lésion intramédullaire en regard deT7-T8. La patiente a bénéficié d’une exérèse totale de la tumeur et l’histologie a confirmé le cavernome intramédullaire. L’évolution a été marquée par une aggravation partielle du déficit moteur. A travers cette observation, les auteurs discutent les aspects cliniques, radiologiques ainsi que la prise en charge de cette pathologie rare.Mots clés: Cavernome, intramédullaire, malformation vasculair

Nouvelle approche géologique et géodinamique du Complexe Hydrothermal de Moulay Yacoub, bordure septentrionale du Sillon Sud Rifain

As águas termais de Moulay Yacoub surgem em formações miocénicas do Sulco Sul do Rife. São caracterizadas por forte mineralização, relacionada com a natureza do seu local de armazenamento e circulação em reservatórios de litologias variadas. Apresentam duas fácies químicas principais: uma Cl-Na, pouco diluída, e outra, Cl-Ca-Mg, dominada por águas imaturas. A comparção geoquímica e geotermométrica com outras fontes regionais sugere uma origem mais profunda que o reservatório liássico. A recente descoberta de extrusões de blocos de calcário liássico, de magmatitos paleozóicos, de metassedimentos e de grandes massas de doleritos triássicos, sugere a existência de formações permeáveis sob a cobertura margosa do Miocénico. Os acidentes profundos NE-SW, associados a um cavalgamento cego, sugerem uma relação estreita entre estas águas termais e as extrusões do soco ante-neogénicos. Durante a sua passagem para a superfície, as águas termais de Moulay Yacoub terão sido diluídas através de misturas ocorridas principalmente no reservatório liássico

Target repurposing for neglected diseases

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Future Science for personal use, not for redistribution. The definitive version was published in Future Medicinal Chemistry 3 (2011): 1307-1315, doi:10.4155/fmc.11.92.Infectious diseases are an enormous burden to global health, and since drug discovery is costly, those infectious diseases that affect the developing world are often not pursued by commercial drug discovery efforts. Therefore, pragmatic means by which new therapeutics can be discovered are needed. One such approach is target repurposing, where pathogen targets are matched with homologous human targets that have been pursued for drug discovery for other indications. In many cases, the medicinal chemistry, structural biology, and biochemistry knowledge around these human targets can be directly repurposed to launch and accelerate new drug discovery efforts against the pathogen targets. This article describes the overarching strategy of target repurposing as a tool for initiating and prosecuting neglected disease drug discovery programs, highlighting this approach with three case studies.Support from the National Institutes of Health (R01 AI082577) is gratefully acknowledged.2012-08-0