Psychosocial group intervention to enhance self-management skills of people with dementia and their caregivers: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: After diagnosis of a dementing illness patients and their spouses have many concerns related to the disease and their future. This often leads to poor psychological well-being and reduced health related quality of life (HRQoL) of the family. Support for self-management skills has been proven to be an effective method to improve prognosis of asthma, heart failure and osteoarthritis. However, self-management interventions have not been studied in dementia. Therefore, our aim was to examine in an objective-oriented group intervention the efficacy of self-management support program (SMP) on the HRQoL of dementia patients and their spousal caregivers as well as on the sense of competence and psychological well-being of care-givers. METHODS: During the years 2011-12, 160 dementia patients and their spouses will be recruited from memory clinics and randomized into two arms: 80 patients for group-based SMP sessions including topics selected by the participants, 80 patients will serve as controls in for usual community care. Sessions may include topics on dementia, community services, active lifestyle and prevention for cognitive decline, spousal relationship, future planning and emotional well-being. The patients and spouses will have their separate group sessions (10 participants/group) once a week for 8 weeks. Main outcome measures will be patients' HRQoL (15D) and spousal caregivers' HRQoL (RAND-36), and sense of competence (SCQ). Secondary measures will be caregivers' psychological well-being (GHQ-12) and coping resources, patients' depression, cognition and signs of frailty. Data concerning admissions to institutional care and the use and costs of health and social services will be collected during a two year follow-up. DISCUSSION: This is a "proof -of-concept" study to explore the efficacy of group support for self-management skills among dementia families. It will also provide data on cost-effectiveness of the intervention.     

Exploiting drug-disease relationships for computational drug repositioning

Finding new uses for existing drugs, or drug repositioning, has been used as a strategy for decades to get drugs to more patients. As the ability to measure molecules in high-throughput ways has improved over the past decade, it is logical that such data might be useful for enabling drug repositioning through computational methods. Many computational predictions for new indications have been borne out in cellular model systems, though extensive animal model and clinical trial-based validation are still pending. In this review, we show that computational methods for drug repositioning can be classified in two axes: drug based, where discovery initiates from the chemical perspective, or disease based, where discovery initiates from the clinical perspective of disease or its pathology. Newer algorithms for computational drug repositioning will likely span these two axes, will take advantage of newer types of molecular measurements, and will certainly play a role in reducing the global burden of disease.     

Interferon-induced versus chemokine transcripts as lupus biomarkers

Compelling support for a central role for interferon-alpha in lupus pathogenesis has led to a new focus on the role of innate immune system activation in the generation of pathogenic mediators. These insights have been extended in translational studies of patients with well-characterized disease activity and clinical manifestations in order to identify informative molecular biomarkers. Chemokines are among the interferon-inducible genes, and new data support an association between the expression of chemokines and both lupus disease activity and organ damage. Longitudinal studies that relate molecular biomarkers to disease activity will be needed to validate these promising data and establish a sensitive measure of change for interventional studies and patient care.     

Influence of Body Mass Index and Albumin on Perioperative Morbidity and Clinical Outcomes in Resected Pancreatic Adenocarcinoma

Obesity is a known risk factor for PDA and recent reports suggest obesity has a negative impact on clinical outcomes in patients with PDA. Pretreatment body mass index (BMI) and serum albumin (SA) have been shown to be associated with worse overall survival in patients with advanced and metastatic PDA. However, minimal data exists on the impact of BMI and SA on perioperative and long-term clinical outcomes in patients with early-stage resected PDA. Herein, we report on the impact of these variables on perioperative clinical outcomes, overall survival (OS) and disease free survival (DFS) in patients with resected PDA. With IRB approval, we evaluated 1,545 patients with PDA treated at a single institution from 2007–2013 and identified 106 patients who underwent upfront resection with curative intent. BMI and SA were calculated preoperatively and at the time of last clinical evaluation. Influence of preoperative BMI, SA, change in either variable, and influence of other clinical and pathologic variables on perioperative morbidity and mortality was assessed. The impact of these variables on DFS and OS was assessed with cox regression modeling and ANOVA. Actuarial estimates for DFS and OS were calculated using Kaplan-Meier methods. Median follow up time was 16 months (3–89). Mean age was 68 years. Median survival was 14 months (3–65) and median time to recurrence was 11 months (1–79). Length of hospital stay was associated with BMI (p = .023), change in BMI (p = .003) and SA (p = .004). Post-operative transfusion rate was associated with SA (p = .021). There was a strong correlation between BMI change and positive margin (p = .04) and lymph node status (p = .01). On multivariate analysis, change in SA (p = .03) and node positivity (p = .008) were associated with decreased DFS. Additionally, preoperative SA (p = .023), node positivity (p = .026) and poor differentiation (p = .045) were associated with worse OS on multivariate analysis. Low preoperative SA was associated with worse DFS and OS in patients with resected PDA. Lower BMI and SA were associated with longer post-operative hospital stay. Our study is one of the first to describe how pre-operative BMI and SA and post-operative changes in these variables impact clinical and perioperative outcomes. This data supports nutritional status and weight loss as predictors of outcome in resected pancreatic cancer patients and warrants further prospective investigation.     

OCP3 is an important modulator of NPR1-mediated jasmonic acid-dependent induced defenses in <Emphasis Type="Italic">Arabidopsis</Emphasis>

Background  

Upon appropriate stimulation, plants increase their level of resistance against future pathogen attack. This phenomenon, known as induced resistance, presents an adaptive advantage due to its reduced fitness costs and its systemic and broad-spectrum nature. In Arabidopsis, different types of induced resistance have been defined based on the signaling pathways involved, particularly those dependent on salicylic acid (SA) and/or jasmonic acid (JA).     

The Complement Anaphylatoxin C3a Receptor (C3aR) Contributes to the Inflammatory Response in Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice

Inflammatory bowel diseases are a critical public health issue, and as treatment options remain limited, there is a need to unravel the underlying pathomechanisms in order to identify new therapeutic targets. Complement activation was found in patients suffering from inflammatory bowel disease, and the complement anaphylatoxin C5a and its receptor C5aR have been implicated in disease pathogenesis in animal models of bowel inflammation. To further characterize complement-related pathomechanisms in inflammatory bowel disease, we have investigated the role of the anaphylatoxin C3a receptor in acute dextran sulfate sodium-induced colitis in mice. For this, colitis was induced in C3a receptor-deficient BALB/c and C57BL/6 mice, and disease severity was evaluated by clinical and histological examination, and by measuring the mRNA expression or protein levels of inflammatory mediators in the tissue. C3a receptor deficiency was partially protective in BALB/c mice, which had significantly reduced weight loss, clinical and histological scores, colon shortening, and CXCL-1/KC mRNA, myeloperoxidase and interleukin-6 tissue levels compared to the corresponding wild type mice. In C57BL/6 mice the differences between wild type and C3a receptor-deficient animals were much smaller and reached no significance. Our data demonstrate that the contribution of C3a receptor to disease pathogenesis and severity of dextran sulfate sodium-induced colitis in mice depends on the genetic background. Further studies will be required to clarify whether targeting of C3a receptor, possibly in combination with C5a receptor, might be considered as a therapeutic strategy for inflammatory bowel disease.     

The ARTS (Arterial Revascularization Therapies Study): Background,goals and methods

BACKGROUND: The rising costs of healthcare have forced policy makers to make choices, and new treatments are increasingly assessed in terms of the balance between additional costs and additional effects. The recent recognition that stenting has a major and long-lasting effect enhancing balloon PTCA procedure has made it imperative to compare in patients with multivessel disease the standard surgical procedure with multiple stenting in a large-scale multinational and multicenter approach (19 countries, 68 sites). METHODS: Selection and inclusion of patients is based on a consensus of the cardiac surgeon and interventional cardiologist on equal 'treatability' of patients by both techniques with analysis of clinical follow-up (event-free survival) on the short (30 days), medium (1 year), and long term (3 and 5 years) with analysis of cost-effectiveness and quality of life (EuroQol and SF-36). Of the entire trial, the primary null hypothesis which needs to be rejected is that there will be no difference in event-free survival or effectiveness (E), at 1 year and also that the direct and indirect costs (C) per event-free year are not different between surgery or stenting. For this to become significant with a power of 90% requires 1200 patients. Between April 97 and June 98, 1205 patients have been randomized with a monthly recruitment of 83 patients; the one year follow-up will thus be completed in June 1999. Expected costs, effects and cost-effectiveness ratio (CE ratio) for stents are: Stent: high-cost estimate, 2 vessel disease (C 3 $19,297, E 3 81%, CE ratio 3 $23,876); 3 vessel disease (C 3 $24,566, E 3 81%, CE ratio 3 $30,397) low-cost estimate, 2 vessel disease (C 3 $16,638, E 3 81%, CE ratio 3 $20,586); 3 vessel disease (C 3 $20,456, E 3 81%, CE ratio 3 $25,322) Compared with CABG (C 3 $21,350, E 3 88%, CE ratio 3 $24,348) CONCLUSION: Clinically, stenting is not expected to be more effective than CABG, but should be cost-effective in both the 2- and 3-vessel disease groups when using the lower-cost estimate and in the 2 vessel group when using the higher-cost assumptions. (Int J Cardiovasc     

Opciones terapéuticas para el tratamiento antifúngico en el paciente crítico

Invasive fungal infections, especially in the critical care setting, have become an excellent target for prophylactic, empiric, and pre-emptive therapy interventions due to their associated high morbidity, mortality rate, increased incidence, and healthcare costs. For these reasons, new studies and laboratory tests have been developed over the last few years in order to formulate an early therapeutic intervention strategy in an attempt to reduce the high mortality rate associated with these infections. In recent years, evidencebased studies have shown the roles that the new antifungal drugs play in the treatment of invasive mycosis in seriously ill and complex patients, although data from critically ill patients are more limited. New antifungal agents have been analyzed in different clinical situations in critical care units, and the increasing number of non-Candida albicans species suggest that the application of early echinocandin therapy in critically ill patients with invasive candidiasis is a good option. Voriconazole should be recommended for invasive aspergillosis as a first line option.     

New insights in the genetics of adrenocortical tumors, pheochromocytomas and paragangliomas.

Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counselling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific hereditary cancer susceptibility syndromes. In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors.The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and somatic PRKAR1A mutations in secreting adrenocortical adenomas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocytoma and paraganglioma, the demonstration that three genes encoding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary paraganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at-risk of disease by the presymptomatic genetic testing.     

Botrytis cinerea manipulates the antagonistic effects between immune pathways to promote disease development in tomato

Plants have evolved sophisticated mechanisms to sense and respond to pathogen attacks. Resistance against necrotrophic pathogens generally requires the activation of the jasmonic acid (JA) signaling pathway, whereas the salicylic acid (SA) signaling pathway is mainly activated against biotrophic pathogens. SA can antagonize JA signaling and vice versa. Here, we report that the necrotrophic pathogen Botrytis cinerea exploits this antagonism as a strategy to cause disease development. We show that B. cinerea produces an exopolysaccharide, which acts as an elicitor of the SA pathway. In turn, the SA pathway antagonizes the JA signaling pathway, thereby allowing the fungus to develop its disease in tomato (Solanum lycopersicum). SA-promoted disease development occurs through Nonexpressed Pathogen Related1. We also show that the JA signaling pathway required for tomato resistance against B. cinerea is mediated by the systemin elicitor. These data highlight a new strategy used by B. cinerea to overcome the plant's defense system and to spread within the host.     

Revolutionizing medicine in the 21(st) century through systems approaches

Personalized medicine is a term for a revolution in medicine that envisions the individual patient as the central focus of healthcare in the future. The term "personalized medicine", however, fails to reflect the enormous dimensionality of this new medicine that will be predictive, preventive, personalized, and participatory-a vision of medicine we have termed P4 medicine. This reflects a paradigm change in how medicine will be practiced that is revolutionary rather than evolutionary. P4 medicine arises from the confluence of a systems approach to medicine and from the digitalization of medicine that creates the large data sets necessary to deal with the complexities of disease. We predict that systems approaches will empower the transition from conventional reactive medical practice to a more proactive P4 medicine focused on wellness, and will reverse the escalating costs of drug development an will have enormous social and economic benefits. Our vision for P4 medicine in 10 years is that each patient will be associated with a virtual data cloud of billions of data points and that we will have the information technology for healthcare to reduce this enormous data dimensionality to simple hypotheses about health and/or disease for each individual. These data will be multi-scale across all levels of biological organization and extremely heterogeneous in type - this enormous amount of data represents a striking signal-to-noise (S/N) challenge. The key to dealing with this S/N challenge is to take a "holistic systems approach" to disease as we will discuss in this article.     

Cardiomyocyte differentiation from embryonic and adult stem cells

In recent years multiple reports indicating that embryonic as well as adult stem cells can differentiate to cardiomyocytes have ignited discussions on whether these stem cells could lead to new therapies for patients with heart disease. Recent developments have been made in the generation of cardiomyocytes from both embryonic and adult stem cells, and progress towards clinical applications in patients with heart failure has been made. Nevertheless, controversies surrounding safety and transdifferentiation issues will need to be overcome before these stem cell approaches can reach their full potential.     

Elevated cell-specific microparticles are a biological marker for cerebral dysfunctions in human severe malaria

Cerebral malaria (CM) and severe anemia (SA) are the most severe complications of Plasmodium falciparum infections. Although increased release of endothelial microparticles (MP) correlates with malaria severity, the full extent of vascular cell vesiculation remains unknown. Here, we characterize the pattern of cell-specific MP in patients with severe malaria. We tested the hypothesis that systemic vascular activation contributes to CM by examining origins and levels of plasma MP in relation to clinical syndromes, disease severity and outcome. Patients recruited in Douala, Cameroon, were assigned to clinical groups following WHO criteria. MP quantitation and phenotyping were carried out using cell-specific markers by flow cytometry using antibodies recognizing cell-specific surface markers. Platelet, erythrocytic, endothelial and leukocytic MP levels were elevated in patients with cerebral dysfunctions and returned to normal by discharge. In CM patients, platelet MP were the most abundant and their levels significantly correlated with coma depth and thrombocytopenia. This study shows for the first time a widespread enhancement of vesiculation in the vascular compartment appears to be a feature of CM but not of SA. Our data underpin the role of MP as a biomarker of neurological involvement in severe malaria. Therefore, intervention to block MP production in severe malaria may provide a new therapeutic pathway.     

Quality control of human tissues-experience from the Indiana University Cancer Center-Lilly Research Labs human tissue bank

The success of molecular research and its applications in both the clinical and basic research arenas is strongly dependent on the collection, handling, storage, and quality control of fresh human tissue samples. This tissue bank was set up to bank fresh surgically obtained human tissue using a Clinical Annotated Tissue Database (CATD) in order to capture the associated patient clinical data and demographics using a one way patient encryption scheme to protect patient identification. In this study, we determined that high quality of tissue samples is imperative for both genomic and proteomic molecular research. This paper also contains a brief compilation of the literature involved in the patient ethics, patient informed consent, patient de-identification, tissue collection, processing, and storage as well as basic molecular research generated from the tissue bank using good clinical practices. The current applicable rules, regulations, and guidelines for handling human tissues are briefly discussed. More than 6,610 cancer patients have been consented (97% of those that were contacted by the consenter) and 16,800 tissue specimens have been banked from these patients in 9 years. All samples collected in the bank were QC’d by a pathologist. Approximately 1,550 tissue samples have been requested for use in basic, clinical, and/or biomarker cancer research studies. Each tissue aliquot removed from the bank for a research study were evaluated by a second H&E, if the samples passed the QC, they were submitted for genomic and proteomic molecular analysis/study. Approximately 75% of samples evaluated were of high histologic quality and used for research studies. Since 2003, we changed the patient informed consent to allow the tissue bank to gather more patient clinical follow-up information. Ninety two percent of the patients (1,865 patients) signed the new informed consent form and agreed to be re-contacted for follow-up information on their disease state. In addition, eighty five percent of patients (1,584) agreed to be re-contacted to provide a biological fluid sample to be used for biomarker research.     

T rypanosoma cruzi trans-sialidase as a multifunctional enzyme in Chagas' disease

Trypanosoma cruzi trans‐sialidase (TS) was identified three decades ago. TS catalyses a trans‐glycosylation reaction, transferring SA from sialylated donors to the terminal galactose mucin‐glycoconjugates, or non‐mucin galactyosyl‐glycoconjugates. It is an external surface protein that is also released from the parasite, displaying several binding properties in addition to its enzymatic function. TS structure has been solved and its catalytic properties are well known, providing tools for development of new inhibitors, as potential chemotherapeutic agents against Chagas’ disease. However, there are still several unsolved questions regarding TS role in the biology of T. cruzi and in the pathology of Chagas’ disease. In this review, we will describe the multifunctional roles of TS regarding the development of Chagas’ disease and propose that these multiple functions have to be considered in future investigations aiming to use TS as a drug target.     

Pharmacogenetics in drug development

Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx-the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success--the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines.     

Diagnostic and economic evaluation of new biomarkersfor Alzheimer¿s disease: the research protocol of a prospective cohort study

ABSTRACT: BACKGROUND: New research criteria for the diagnosis of Alzheimer's disease (AD) have recently been developed to enable an early diagnosis of AD pathophysiologyby relying on emerging biomarkers. To enable efficient allocation of health care resources, evidence is needed to support decision makers on the adoption of emerging biomarkers in clinical practice. The research goals are to 1) assess the diagnostic test accuracy of current clinical diagnostic work-up and emerging biomarkers in MRI, PET and CSF, 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model.Methods/designIn a cohort design 223 consecutive patients suspected of having a primary neurodegenerative disease are approached in four academic memory clinics and followed for two years. Clinical data and data on quality of life, costs and emerging biomarkers are gathered.Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to the reference diagnosis. The clinical practice diagnosis at baseline is reflected by a consensus procedure among experts using clinical information only (no biomarkers). The diagnosis based on the new research criteria is reflected by decision rules that combine clinical and biomarker information. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period.A decision analytic model is built combining available evidence from different resources among which (accuracy) results from the study, literature and expert opinion to assess long-term cost-effectiveness of the emerging biomarkers. DISCUSSION: Several other multi-centre trials study the relative value of new biomarkers for early evaluation of AD and related disorders. The uniqueness of this study is the assessment of resource utilization and quality of life to enable an economic evaluation. The study results are generalizable to a population of patients who are referred to a memory clinic due to their memory problems.Trial registrationNCT01450891.     

Enhanced Disease Susceptibility 1 and Salicylic Acid Act Redundantly to Regulate Resistance Gene-Mediated Signaling

Resistance (R) protein–associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA) and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1), non–race-specific disease resistance 1 (NDR1), phytoalexin deficient 4 (PAD4), senescence associated gene 101 (SAG101), and EDS5, have been identified as components of resistance derived from many R proteins. Here, we show that EDS1 and SA fulfill redundant functions in defense signaling mediated by R proteins, which were thought to function independent of EDS1 and/or SA. Simultaneous mutations in EDS1 and the SA–synthesizing enzyme SID2 compromised hypersensitive response and/or resistance mediated by R proteins that contain coiled coil domains at their N-terminal ends. Furthermore, the expression of R genes and the associated defense signaling induced in response to a reduction in the level of oleic acid were also suppressed by compromising SA biosynthesis in the eds1 mutant background. The functional redundancy with SA was specific to EDS1. Results presented here redefine our understanding of the roles of EDS1 and SA in plant defense.     

Toward the complete genomic map and molecular pathology of human chromosome 4

The identification of disease genes via molecular DNA cloning has revolutionized human genetics and medicine. Both the candidate gene approach and positional cloning have been used successfully. The defects causing Huntington's disease, facioscapulohumeral muscular dystrophy, piebaldism, Hurler/Scheie syndrome, one form of autosomal recessive retinitis pigmentosa, and a second locus for autosomal dominant polycystic kidney disease have recently been localized to chromosome 4. In addition to the rapid progress in the cloning of the 203-megabase chromosome, the presence of more than 60 closely spaced microsatellites on this chromosome will undoubtedly lead to the localization of additional disease genes. In order to consider cloned genes as potential candidates for disorders assigned to chromosome 4, it is important to collect and order all genes with respect to their chromosomal localization. Analysis of cytogenetically visible interstitial and terminal deletions should also be helpful in defining new disease gene loci and in mapping novel genes. These data represent the status quo of the integrated molecular map for chromosome 4.