From data to models : reducing uncertainty in benefit risk assessment : application to chronic iron overload in children

Growing awareness about the relevance of formal evaluation of the efficacy and safety in children has resulted into important changes in the requirements for the approval of medicines for children. In this thesis a model-based approach is proposed to ensure more efficient use of the evidence available from historical data. The work presented provides a quantitative framework for the assessment of the benefit-risk balance prior to drug approval. Three central questions are addressed, which refer to the need to ensure that accurate inferences are made about the safety and efficacy of a therapeutic intervention, especially when considering long-term outcome. In brief, we demonstrate how modelling and simulations can be applied together with multi-criteria decision analysis to address essential clinical, scientific and regulatory questions. Focus is given to the opportunity for optimising experimental protocol design (evidence generation) and integrating existing knowledge about the drug and the disease in the target population (evidence synthesis). These concepts are illustrated by real-life examples on the treatment of transfusion-dependent haemoglobinopathies, but the proposed framework can be extrapolated to a broader range of diseases and conditions. We anticipate that some of the meta-analytical elements presented here will become embedded into daily practice in pharmaceutical R&D.UBL - phd migration 201

The mediterranean diet slows down the progression of aging and helps to prevent the onset of frailty: A narrative review

The aging population is rapidly increasing all over the world. This results in significant implications for the planning and provision of health and social care. Aging is physiologically characterized by a decrease in lean mass, bone mineral density and, to a lesser extent, fat mass. The onset of sarcopenia leads to weakness and a further decrease in physical activity. An insufficient protein intake, which we often observe in patients of advanced age, certainly accelerates the progression of sarcopenia. In addition, many other factors (e.g., insulin resistance, impaired protein digestion and absorption of amino acids) reduce the stimulation of muscle protein synthesis in the elderly, even if the protein intake is adequate. Inadequate intake of foods can also cause micronutrient deficiencies that contribute to the development of frailty. We know that a healthy eating style in middle age predisposes to so-called “healthy and successful” aging, which is the condition of the absence of serious chronic diseases or of an important decline in cognitive or physical functions, or mental health. The Mediterranean diet is recognized to be a “healthy food” dietary pattern; high adherence to this dietary pattern is associated with a lower incidence of chronic diseases and lower physical impairment in old age. The aim of our review was to analyze observational studies (cohort and case–control studies) that investigated the effects of following a healthy diet, and especially the effect of adherence to a Mediterranean diet (MD), on the progression of aging and on onset of frailty

Ecopharmacology: Deliberated or casual dispersion of pharmaceutical principles, phytosanitary, personal health care and veterinary products in environment needs a multivariate analysis or expert systems for the control, the measure and the remediation

.The increasing human and animal use and abuse of drugs as well as of personalhealthcare and gross domestic products, involve disposal and waste problems and, as a consequence, affect the environmental condition. Actually most of the active principles are complex synthesised organic molecules that react, inside human or animal body, by specific biochemical reactions that in no case can reach a 100% yield and produce residues that could be more noxious of the starting compounds. Just reading the indication sheet accompanying any drugs, it is easy to state that no drug can be considered healthy, so, their use constitutes a serious pollution source. The full awareness of this relatively new environmental problem let many researchers to face it from different point of view. Current studies are considering the sources of these substances in the environment, the effects on human health as well as on the flora and fauna species, the recalcitrance and possible degradation methods, analytical techniques able to determine them and their metabolites even at low concentrations and in complex matrices. Literature on the subject continuously increases and a comparison of all data became more and more difficult both for a single drug and for different ones based on the same or different active principles. This is a typical case in which chemometrics can extract a full information in the easier way, so the design of a European database coupled to suitable expertsystem software should be strongly suggested

Molecular Aspects and Treatment of Iron Deficiency in the Elderly

Iron deficiency (ID) is the most frequent nutritional deficiency in the whole population worldwide, and the second most common cause of anemia in the elderly. The prevalence of anemia is expecting to rise shortly, because of an ageing population. Even though WHO criteria define anemia as a hemoglobin serum concentration <12 g/dL in women and <13 g/dL in men, several authors propose different and specific cut-off values for the elderly. Anemia in aged subjects impacts health and quality of life, and it is associated with several negative outcomes, such as longer time of hospitalization and a higher risk of disability. Furthermore, it is an independent risk factor of increased morbidity and mortality. Even though iron deficiency anemia is a common disorder in older adults, it should be not considered as a normal ageing consequence, but a sign of underlying dysfunction. Relating to the molecular mechanism in Iron Deficiency Anemia (IDA), hepcidin has a key role in iron homeostasis. It downregulates the iron exporter ferroportin, inhibiting both iron absorption and release. IDA is frequently dependent on blood loss, especially caused by gastrointestinal lesions. Thus, a diagnostic algorithm for IDA should include invasive investigation such as endoscopic procedures. The treatment choice is influenced by the severity of anemia, underlying conditions, comorbidities, and the clinical state of the patient. Correction of anemia and iron supplementation should be associated with the treatment of the causal disease

PEMODELAN KONEKTIVITAS SPASIAL TROTOAR BERKELANJUTAN ANTAR ZONA DI KOTA TUA JAKARTA

Kota Tua Jakarta adalah objek wisata sejarah di Kota Jakarta. Wilayah Kota Tua Jakarta terbagi ke dalam lima zona, yaitu Zona 1 Sunda Kelapa (Masjid Luar Batang, Museum Bahari, Menara Syahbandar, Gudang VOC, dll), Zona 2 Fatahillah (Museum Bank Mandiri, Museum Bank Indonesia, Museum Sejarah Jakarta, Alun-alun Fatahillah, Museum Wayang, Museum Seni, Stasiun Jakarta Kota, dll), Zona 3 Pecinan (Komunitas Pelukis Jalanan, Pusat Obat Tradisional Cina, Pusat Perniagaan, dll), Zona 4 Pekojan (Kampung Arab, Langgar Tinggi, Mesjid An-Nawier, dll), dan Zona 5 Peremajaan (Pusat Perniagaan, Bangunan Cina, Gedung Tua, Wisata Kuliner). Namun, sebagian besar wisatawan—domestik dan mancanegara—hanya berkunjung ke Zona 2 sehingga penyampaian sejarah Kota Tua Jakarta menjadi kabur dan distribusi pendapatan pariwisata Kota Tua Jakarta juga tidak merata. Ketidakmerataan distribusi pendapatan menimbulkan berbagai permasalahan ekonomi dan sosial di Zona 1. Untuk menganalisis isu tersebut, metode yang digunakan pada penelitian ini adalah wawancara tidak terstruktur dan observasi partisipatori yang berorientasi spasial. Berdasarkan hasil wawancara, observasi, dan analisis spasial yang dilakukan, wisatawan hanya mengunjungi Zona 2 karena kemudahan aksesibilitas di Zona 2 dibandingkan dengan zona lainnya serta buruknya kondisi trotoar yang menghubungkan Zona 2 dengan zona lainnya. Lebih dalam, buruknya kondisi trotoar berimplikasi pada terbentuknya area-area ruang mati (death space) di Jalan Kakap dan Ekor Kuning. Kehadiran ruang mati (death space) di Jalan Kakap dan Ekor Kuning mengundang terjadinya tindak kriminal dan masalah sosial lainnya di wilayah tersebut. Oleh karena itu, tulisan ini mencoba menawarkan solusi perbaikan pada trotoar-trotoar yang mengonekasikan zona-zona di Kota Tua Jakarta, khususnya Zona 1 dan Zona 2. Konsep desain yang digunakan pada perbaikan tersebut adalah Green-sidewalks

Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury