Chaperones and proteases: cellular fold-controlling factors of proteins in neurodegenerative diseases and aging.

The formation of toxic protein aggregates is a common denominator to many neurodegenerative diseases and aging. Accumulation of toxic, possibly infectious protein aggregates induces a cascade of events, such as excessive inflammation, the production of reactive oxygen species, apoptosis and neuronal loss. A network of highly conserved molecular chaperones and of chaperone-related proteases controls the fold-quality of proteins in the cell. Most molecular chaperones can passively prevent protein aggregation by binding misfolding intermediates. Some molecular chaperones and chaperone-related proteases, such as the proteasome, can also hydrolyse ATP to forcefully convert stable harmful protein aggregates into harmless natively refoldable, or protease-degradable, polypeptides. Molecular chaperones and chaperone-related proteases thus control the delicate balance between natively folded functional proteins and aggregation-prone misfolded proteins, which may form during the lifetime and lead to cell death. Abundant data now point at the molecular chaperones and the proteases as major clearance mechanisms to remove toxic protein aggregates from cells, delaying the onset and the outcome of protein-misfolding diseases. Therapeutic approaches include treatments and drugs that can specifically induce and sustain a strong chaperone and protease activity in cells and tissues prone to toxic protein aggregations.

Quality of Learners' Time and Learning Performance Beyond Quantitative Time-on-Task

Peer-reviewed

Baerveldt implant in refractory glaucoma: long-term results and factors influencing outcome.

PURPOSE: To evaluate the clinical outcome of patients who received a Baerveldt implant for refractory glaucoma and to identify factors which may influence the outcome. METHODS: Retrospective study including 51 eyes of 51 patients with medically uncontrolled glaucoma who underwent Baerveldt implant surgery between June 1994 and December 1998. Criteria for success were intraocular pressure (IOP) < or = 21 mmHg and > 6 mmHg, necessity of further antiglaucoma medications, absence of additional glaucoma surgery and no loss of light perception. RESULTS: Over a mean follow-up of 37.6 (SD: +/-18.8) months, the mean intraocular pressure decreased from 34.8 (+/-12.5) mmHg to 14.0 (+/-4.3) mmHg at month 60. Qualified success rate, achieved when IOP was below 21 mmHg and higher than 6 mmHg with medications was 25/48 (52%), complete success rate (same IOP limits without medication) was 14/48 (29%). Seven eyes had major complications or lost light perception. Postoperative visual acuity improved or remained within one Snellen line of the preoperative visual acuity in 35 patients (73%). Factors associated with a better prognosis were a preoperative visual acuity better than 20/400 and etiology of glaucoma. CONCLUSION: The Baerveldt implant is effective in lowering intraocular pressure in most patients with refractory glaucoma. Long-term results are promising with satisfactory IOP control.

Critères de qualité en radiothérapie des cancers de la tête et du cou sous l'égide de l'Intergroupe ORL Quality criteria in radiotherapy for head and neck cancers under the aegis of Head and Neck Intergroup.

The aim of radiotherapy is to deliver enough radiation to the tumor in order to achieve maximum tumour control in the irradiated volume with as few serious complications as possible with an irradiation dose as low as possible to normal tissue. The quality of radiotherapy is essential for optimal treatment and quality control is to reduce the bias in clinical trials avoiding possible major deviations. The assurance and quality control programs have been developed in large european (EORTC, GORTEC) and american cooperative groups (RTOG) of radiation oncology since the 1980s. We insist here on the importance of quality assurance in radiotherapy and the current status in this domain and the criteria for quality control especially for current clinical trials within GORTEC are discussed here.

Effect of prestorage curing on storage life, internal and external qualities of sweet orange (Citrus sinensis)

Orange fruits from two seasons, in April and August 2006 representing late 2005 and early 2006 harvests respectively were cured in hot air at 36-37(0)C to 1%, 3%, 5% and 7% weight loss before storage at 28(0)C and 86% relative humidity (RH). The fruits were observed for incidence of decay, further weight loss, juice content, firmness or softening of the peel, total soluble solids (TSS), pH, titratable acidity, and colour during storage. Curing reduced the incidence of decay. All control fruits were rotten by day 21 in August harvest while 22.5% of the control was rotten by day 56 in the April harvest. Storage life was extended beyond 56 days in fruits cured with 1, 3, 5 and 7% in April harvest as there was no decay throughout, while decay incidence in August harvest was 88.9, 61.1, 22.2 and 31.3% in 1, 3, 5 and 7% respectively. Penicillium digitatum, Phytophthora sp., Alternaria citri and Collectotrichum gloeosporioides were among decay causing moulds detected. Control fruits lost more weight during storage than cured fruits did. Fruit rind hardening was more noticed in the control and those cured to 1% weight loss, especially from the April harvest. It was insignificant in other treatments in both trials. Titratable acidity, pH, juice content and TSS were not affected by the treatment. Colour change to yellow was however retarded by curing. Curing to 5% weight loss was best for decay control and quality retention.

Quality and safety requirements for sustainable phage therapy products.

The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allowsa timely supplying of phage therapy products for 'personalized therapy' or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.

Targeted inactivation of hypocretin receptors in dopaminergic and noradrenergic systems alters brain activity in wakefulness

Since the discovery of hypocretins/orexins (Hcrt/Ox) in 1998, several narcoleptic mouse models, such as Hcrt-KO, Hcrtrl-KO, Hcrtr2-KO and double receptors KO mice, and orexin-ataxin transgenic mice were generated. The available Hcrt mouse models do not allow the dissection of the specific role of Hcrt in each target region. Dr. Anne Vassalli generated loxP-flanked alleles for each Hcrt receptor, which are manipulated by Cre recombinase to generate mouse lines with disrupted Hcrtrl or Hcrtr2 (or both) in cell type-specific manner. The role of noradrenaline (NA) and dopamine (OA) in ttie regulation of vigilance states is well documented. The purpose of this thesis is to explore the role of the Hcrt input into these two monoaminergic systems. Chronic loss of Hcrtrl in NA neurons consolidated paradoxical sleep (PS), and altered wakefulness brain activity in baseline, during the sleep deprivation (SD), and when mice were challenged by a novel environment, or exposed to nest-building material. The analysis of alterations in the sleep EEG delta power showed a consistent correlation with the changes in the preceding waking quality in these mice. Targeted inactivation of Hcrt input into DA neurons showed that Hcrtr2 inactivation present the strongest phenotype. The loss of Hcrtr2 in DA neurons caused modified brain activities in spontaneous wakefulness, during SD, and in novel environmental conditions. In addition to alteration of wakefulness quality and quantity, conditional inactivation of Hcrtr2 in DA neurons caused an increased in time spent in PS in baseline and a delayed and less complete PS recovery after SD. In the first 30 min of sleep recovery, single (i.e. for Hcrtrl or Hcrtr2) conditional knockout receptor mice had opposite changes in delta activity, including an increased power density in the fast delta range with specific inactivation of Hcrtr2, but a decreased power density in the same range with specific inactivation of Hcrtrl in DA cells. These studies demonstrate a complex impact of Hcrt receptors signaling in both NA and DA system, not only on quantity and quality of wakefulness, but also on PS amount regulation as well as on SWS delta power expression. -- Depuis la découverte des hypocrétines/orexines (Hcrt/Ox) en 1998, plusieurs modèles de souris, narcoleptiques telles que Hcrt-KO, Hcrtr2-KO et récepteurs doubles KO et les souris transgéniques orexine-ataxine ont été générés. Les modèles de souris Hcrt disponibles ne permettaient pas la dissection du rôle spécifique de l'Hcrt dans chaque noyau neuronal cible. Notre laboratoire a généré des allèles loxP pour chacun des 2 gènes codant pour les récepteurs Hcrtr, qui sont manipulés par recombinase Cre pour générer des lignées de souris avec Hcrtrl inactivé, ou Hcrtr2 inactivé, (ou les deux), spécifiquement dans un type cellulaire particulier. Le rôle de la noradrénaline (NA) et la dopamine (DA) dans la régulation des états de vigilance est bien documentée. Le but de cette thèse est d'étudier le rôle de l'afférence Hcrt dans ces deux systèmes monoaminergiques au niveau de l'activité cérébrale telle qu'elle apparaît dans l'électroencéphalogramme (EEG). Mon travail montre que la perte chronique de Hcrtrl dans les neurones NA consolide le sommeil paradoxal (PS), et l'activité cérébrale de l'éveil est modifiée en condition spontanée, au cours d'une experience de privation de sommeil (SD), et lorsque les souris sont présentées à un nouvel environnement, ou exposées à des matériaux de construction du nid. Ces modifications de l'éveil sont corrélées à des modifications de puissance de l'activité delta du sommeil lent qui le suit. L'inactivation ciblée des Hcrtrs dans les neurones DA a montré que l'inactivation Hcrtr2 conduit au phénotype le plus marqué. La perte de Hcrtr2 dans les neurones DA mène à des modification d'activité cérébrale en éveil spontané, pendant SD, ainsi que dans des conditions environnementales nouvelles. En plus de l'altération de la qualité de l'éveil et de la quantité, l'inactivation conditionnelle de Hcrtr2 dans les neurones DA a provoqué une augmentation du temps passé en sommeil paradoxal (PS) en condition de base, et une reprise retardée et moins complète du PS après SD. Dans les 30 premières minutes de la récupération de sommeil, les modèles inactivés pour un seul des récepteurs (ie pour Hcrtrl ou Hcrtr2 seulement) montrent des changements opposés en activité delta, en particulier une densité de puissance accrue dans le delta rapide avec l'inactivation spécifique de Hcrtr2, mais une densité de puissance diminuée dans cette même gamme chez les souris inactivées spécifiquement en Hcrtrl dans les neurones DA. Ces études démontrent un impact complexe de l'inactivation de la neurotransmission au niveau des récepteurs d'Hcrt dans les deux compartiments NA et DA, non seulement sur la quantité et la qualité de l'éveil, mais aussi sur la régulation de quantité de sommeil paradoxal, ainsi que sur l'expression de la puissance delta pendant le sommeil lent.

Describing and Analyzing Information Technology through Total Quality Management and Process Management: Case Stora Enso Newsprint

Laatu on osaltaan vahvistamassa asemaansa liike-elämässä yritysten kilpaillessa kansainvälisillä markkinoilla niin hinnalla kuin laadulla. Tämä suuntaus on synnyttänyt useita laatuohjelmia, joita käytetään ahkerasti yritysten kokonais- valtaisen laatujohtamisen (TQM) toteuttamisessa. Laatujohtaminen kattaa yrityksen kaikki toiminnot ja luo vaatimuksia myös yrityksen tukitoimintojen kehittämiselle ja parantamiselle. Näihin lukeutuu myös tämän tutkimuksen kohde tietohallinto (IT). Tutkielman tavoitteena oli kuvata IT prosessin nykytila. Tutkielmassa laadittu prosessikuvaus pohjautuu prosessijohtamisen teoriaan ja kohdeyrityksen käyttämään laatupalkinto kriteeristöön. Tutkimusmenetelmänä prosessin nykytilan selvittämiseksi käytettiin teemahaastattelutta. Prosessin nykytilan ja sille asetettujen vaatimusten selvittämiseksi haastateltiin IT prosessin asiakkaita. Prosessianalyysi, tärkeimpien ala-prosessien tunnistaminen ja parannusalueiden löytäminen ovat tämän tutkielman keskeisemmät tulokset. Tutkielma painottui IT prosessin heikkouksien ja parannuskohteiden etsimiseen jatkuvan kehittämisen pohjaksi, ei niinkään prosessin radikaaliin uudistamiseen. Tutkielmassa esitellään TQM:n periaatteet, laatutyökaluja sekä prosessijohtamisen terminologia, periaatteet ja sen systemaattinen toteutus. Työ antaa myös kuvan siitä, miten TQM ja prosessijohtaminen niveltyvät yrityksen laatutyössä.

Meaning in life and perceived quality of life in Switzerland: results of a representative survey in the German, French and Italian regions.

BACKGROUND: The concept of meaning in life (MIL) has become a central one in recent years, particularly in psycho-oncology and palliative care. The Schedule for Meaning in Life Evaluation (SMILE) has been developed to allow individuals to choose the life areas that they consider to be important for their own MIL. This approach relates to the "World Health Organisation" definition of quality of life (QOL) as an individual's perception of his own position. The aims of this study were (i) to assess MIL in a representative sample of the Swiss population according to the three linguistic regions and (ii) to evaluate whether MIL constitutes a significant determinant of the perceived QOL. METHODS: A telephone survey of the Swiss population, performed by a professional survey company, was conducted between November and December 2013. The interview included the SMILE, perceived QOL (0-10) and health status (1-5), and various sociodemographic variables. In the SMILE, an index of weighting (IOW, 20-100), an index of satisfaction (IOS, 0-100), and a total SMILE index (IOWS, 0-100) are calculated from the areas mentioned by the participants as providing MIL. RESULTS: Among the 6671 telephonic contacts realized, 1015 (15 %) participants completed the survey: 405 French, 400 German and 210 Italian participants. "Family" (80.2 %), "occupation/work" (51 %), and "social relations" (43.3 %) were the most cited MIL-relevant categories. Italian participants listed "health" more frequently than German and French participants (50.4 % vs 31.5 % and 24.8 % respectively, χ(2) = 12.229, p = .002). Age, gender, education, employment, and marital status significantly influenced either the MIL scores or the MIL-relevant categories. Linear regression analyses indicate that 24.3 % of the QOL variance (p = .000) is explained by health status (B = .609, IC = .490-.728, p = .000), MIL (B = .034, IC = .028-.041, p = .000) and socioeconomic status (F = 11.01, p = .000). CONCLUSION: The major finding of our analysis highlights the positive and significant influence of MIL on the perceived QOL in a representative sample of a general, multilingual and multicultural population. This result indicates that the existential dimension is not only determinant for QOL in some critical life events, as shown e.g. in psycho-oncology and palliative care, but also in everyday life.

(210)Po poisoning as possible cause of death: forensic investigations and toxicological analysis of the remains of Yasser Arafat.

The late president of the Palestinian Authority, Yasser Arafat, died in November 2004 in Percy Hospital, one month after having experienced a sudden onset of symptoms that included severe nausea, vomiting, diarrhoea and abdominal pain and which were followed by multiple organ failure. In spite of numerous investigations performed in France, the pathophysiological mechanisms at the origin of the symptoms could not be identified. In 2011, we found abnormal levels of polonium-210 ((210)Po) in some of Arafat's belongings that were worn during his final hospital stay and which were stained with biological fluids. This finding led to the exhumation of Arafat's remains in 2012. Significantly higher (up to 20 times) activities of (210)Po and lead-210 ((210)Pb) were found in the ribs, iliac crest and sternum specimens compared to reference samples from the literature (p-value <1%). In all specimens from the tomb, (210)Po activity was supported by a similar activity of (210)Pb. Biokinetic calculations demonstrated that a (210)Pb impurity, as identified in a commercial source of 3MBq of (210)Po, may be responsible for the activities measured in Arafat's belongings and remains 8 years after his death. The absence of myelosuppression and hair loss in Mr Arafat's case compared to Mr Litvinenko's, the only known case of malicious poisoning with (210)Po, could be explained by differences in the time delivery-scheme of intake. In conclusion, statistical Bayesian analysis combining all the evidence gathered in our forensic expert report moderately supports the proposition that Mr Arafat was poisoned by (210)Po.

Calidad de vida y cáncer de próstata: un programa progresivo de fuerza-resistencia = Quality of life and prostate cancer: a progressive resistance strength program

This article presents the design and implementation of a progressive resistance strength program adapted to prostate cancer. The initial model corresponds to the guide of the American College Sports Medicine Position Stand (ACSM, 2009). This program includes the most habitual symptoms related to the illness and its treatments. The study design is quasi-experimental. The sample is 33 subjects in treatment phase. Study variables are tumour classification TNM, anthropometric measures, resistance strength, hypertension, fatigue, incontinence, pain and quality of life. After 24 weeks a significant improvement on resistance strength capacity is observed. This result is more consistent in lower extremities. Also improves hypertension, urinary incontinence, pain and quality of life. As conclusion, the improvement of the quality of life is mediated by the functional and physical capacity of the ill person

Standard care practices and psychosocial interventions aimed at reducing parental distress following stillbirth: A systematic narrative review

Objective: To summarise and critically evaluate the evidence informing the provision of standard care practices and psychosocial interventions following stillbirth. Background: Stillbirth is increasingly recognised as a significant bereavement experience with the potential to cause substantial psychological distress for parents. Standard care practices and psychosocial interventions to support parents have undergone dramatic changes, with limited basis in evidence. Methods: A systematic narrative review was conducted of quantitative studies examining interventions designed to reduce psychological distress in parents following the loss of a stillborn baby. Results: Twenty-five studies met the inclusion criteria for the review. Substantial methodological weaknesses were identified among reviewed studies, including small and heterogeneous loss samples, weak study designs and lack of clarity in reported methods and outcomes. Inadequate replication of many findings substantially limits the generalisability of the evidence. Conclusion: Tentative evidence was found for the provision of mementoes of the baby and information regarding the cause of the loss, support group attendance, and cognitive behavioural interventions for parents identified with clinical levels of distress. Contradictory findings for the impact of contact with the baby prevent the formation of clear conclusions for this practice. Due to the methodological weaknesses prevalent in the research identified, the current evidence base is not considered sufficiently able to reliably inform care practices and intervention approaches. High-quality research evidence in this field is urgently required.

A feasability study of the analysis of the economic outcomes of specialized nutrition in obesity and weight management in Switzerland

The increasing prevalence of obesity and its associated complications requires specialized care to improve outcomes and control health care costs. Obesity is associated with numerous serious and costly medical problems requiring specialized care in managing health. The economic burden of obesity includes increased inpatient and outpatient medical expenditures as well as employer-related issues of absenteeism and associate costs. The objectives of this study are: - To describe the health consequences and the economic burden of obesity, - To review the existing treatment - To argue in favor of a specialized nutritional intervention that has shown to improve health and reduce obesity related health care costs. Therefore, expose the possibility of introducing the specialized nutrition in Switzerland and the feasibility of this project considering the medical trends and reimbursement system in Switzerland The benefits and outcomes for the patients will be the significant weight loss which reduces the severity and risk factors for complications and the improved health and quality of life. Weight loss will be a combination of a diet, exercise and behavioral interventions which are the basic recommendations for obesity treatment in addition to the specialized nutritional support. By nutritional support, we mean products that are intended to provide nutritional support in the dietary management of people with specific diseases and conditions when adequate intake of regular foods is compromised. These products are called, Food for special medical purposes FSMP. They are not intended to treat, cure, prevent, mitigate or have a direct impact on disease in a manner similar to drugs or other medical treatments and should be used under medical supervision. They also provide a low cost alternative to surgery. From a health care system perspective, the specialized nutrition will drive its advantage by reducing the utilization of medical services for obesity associated complications like medication, physician's consultations and surgical interventions arriving to a cost effective care for the hospitals, the health care organizations and the third party payers which are the health insurances. [Author, p. 4]

Quality of beans stored under hermetic conditions

This study aimed to evaluate the quality of beans (Phaseolus vulgaris L.) stored with different moisture contents under hermetic conditions. Beans with 12.3%, 15.7%, and 17.8% moisture content were used in the experiment. They were packed in bag type silos (3 kg), PET bottles (1.5 L), and glass containers (3 L), covered with organza fabric (control), and stored at 25 ºC and 70±5% relative humidity, for 120 days. The evaluated characteristics included moisture content, apparent density, electrical conductivity, germination percentage, cooking time, and bean classification, every 30 days. Except for the electrical conductivity and cooking time, the other characteristics were kept for 120 days in the stored product with moisture contents of 12.3% and 15.7% in hermetic conditions. Beans with 17.8% of the moisture content, electrical conductivity and cooking time increased, and apparent density and germination were reduced. Beans stored in the control, with any of the moisture contents, showed high quality loss during the long storage. It was concluded that it is possible to storage beans with moisture contents of 12.3% and 15.7%, with quality, for until 120 days, in hermetic conditions.

The role of glyphosate in RR soybean production and seed quality

This study aimed to evaluate the production components and quality of RR soybean seeds (Roundup Ready®), after application of increasing rates of gliphosate. Field experiments were conducted in Mandaguari, Paraná, during two seasons. Treatments consisted of five doses of glyphosate. All applications were performed once, between development stages V4 and V5. The experiment was arranged in a completely randomized block design, with four replicates. Data were subjected to analysis of variance, and when significant, t-tests and a regression analysis were applied to verify the behavior of the treatments. The physiological and sanitary quality, yield and mass of one thousand seeds were evaluated. The results indicated that seed quality can be adversely affected by glyphosate, and also showed a probable reduction in yield components with increasing rates of application.