Empirical validation of a rat in vitro organ slice model as a tool for in vivo clearance prediction

Tissue slices have been shown to be a valuable tool to predict metabolism of novel drugs. However, besides the numerous advantages of their use for this purpose, some potential drawbacks also exist, including reported poor penetration of drugs into the inner cell layers of slices and loss of metabolic capacity during prolonged incubation, leading to underprediction of metabolic clearance. In the present study, we empirically identified ( and quantified) sources of underprediction using rat tissue slices of lung, intestine, kidney, and liver and found that thin liver slices ( +/- 100 mu m) metabolized model substrates ( 7- hydroxycoumarin, testosterone, warfarin, 7- ethoxycoumarin, midazolam, haloperidol, and quinidine) as rapidly as isolated hepatocytes. Furthermore, it was found that organ slices remain metabolically active for sufficient periods of incubation, enabling study of the kinetics of low clearance compounds. In addition, we determined the influence of albumin on the clearance prediction of six model substrates. For three of these substrates, the intrinsic clearance in the presence of albumin was approximately 3 times higher than that obtained from incubations without albumin, but corrected for unbound fraction. This resulted in a much more accurate prediction of in vivo whole body metabolic clearance for these compounds. Collectively, these results show that drawbacks of the use of slices for clearance prediction are largely surmountable. Provided that thin liver slices and physiological albumin concentration are used, whole body metabolic clearance is predicted with acceptable ( 2- fold) accuracy with organ slices. These results emphasize the applicability of organ slices in this field of research

Can AMP induce sputum eosinophils, even in subjects with complete asthma remission?

<p>Abstract</p> <p>Background</p> <p>The definition of <b>"</b>clinical asthma remission" is based on absence of symptoms and use of medication. However, in the majority of these subjects airway inflammation is still present when measured. In the present study we investigated whether "complete asthma remission", additionally defined by the absence of bronchial hyperresponsiveness (BHR) and the presence of a normal lung function, is associated with the absence of airway inflammation.</p> <p>Methods</p> <p>Patients with a former diagnosis of asthma and a positive histamine provocation test were re-examined to identify subjects with complete asthma remission (no asthma symptoms or medication, PC₂₀histamine > 32 mg/ml, FEV₁> 90% predicted). Patients with PC₂₀histamine ≤ 32 mg/ml were defined as current asthmatics and were divided in two groups, i.e. asthmatics with and without BHR to adenosine 5'monophoshate (AMP). Sputum induction was performed 1 week before and 1 hour after AMP provocation. Sputum induction and AMP provocation were previously shown to be sensitive markers of airway inflammation.</p> <p>Results</p> <p>Seven patients met criteria for complete asthma remission. Twenty-three were current asthmatics, including twelve without hyperresponsiveness to AMP. Subjects with complete asthma remission showed no AMP-induced sputum eosinophilia (median (range) 0.2 (0 - 4.6)% at baseline and 0.2 (0 - 2.6)% after AMP). After AMP, current asthmatics had a significant increase in sputum eosinophils (0.5 (0 - 26.0)% at baseline and 2.6 (0 - 32.0) % after AMP), as had the subgroup of current asthmatics without hyperresponsiveness to AMP (0.2 (0 - 1.8)% at baseline and 1.3 (0 - 6.3)% after AMP).</p> <p>Conclusions</p> <p>Subjects with complete asthma remission, in contrast to subjects with current asthma, do not respond with eosinophilic inflammation in sputum after AMP provocations. These data lend support to the usefulness of the definition of complete asthma remission.</p

Impact of exercise training on oxidative stress in individuals with a spinal cord injury

Individuals with a spinal cord injury (SCI) have an increased cardiovascular risk. We hypothesize that (anti)oxidative imbalance is associated with the increased cardiovascular risk in SCI, while exercise can reverse this status. The aim of the study is to compare baseline levels of oxidative stress and antioxidative capacity between individuals with SCI and able-bodied (AB) subjects, and to assess acute and long-term effects of functional electrical stimulation (FES) exercise on oxidative stress and antioxidative capacity in SCI. Venous blood was taken from subjects with an SCI (n = 9) and age- and gender-matched AB subjects (n = 9) to examine oxidative stress through malondialdehyde (MDA) levels, while superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme levels represented anti-oxidative capacity. Subsequently, subjects with an SCI performed an 8-week FES exercise training period. Blood was taken before and after the first exercise bout and after the last FES session to examine the acute and chronic effect of FES exercise, respectively. Baseline levels of MDA, SOD and GPx were not different between individuals with SCI and AB subjects. SCI demonstrated a correlation between initial fitness level and MDA (R = −0.83, P = 0.05). MDA, SOD and GPx levels were neither altered by a single FES exercise bout nor by 8 weeks FES training. In conclusion, although individuals with an SCI demonstrate a preserved (anti)oxidative status, the correlation between fitness level and (anti)oxidative balance suggests that higher fitness levels are related to improved (anti)oxidative status in SCI. Nonetheless, the FES exercise stimulus was insufficient to acutely or chronically change (anti)oxidative status in individuals with an SCI

Pelvic organ prolapse and collagen-associated disorders

Contains fulltext : 109010.pdf (publisher's version ) (Open Access)INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) and other disorders, such as varicose veins and joint hypermobility, have been associated with changes in collagen strength and metabolism. We hypothesized that these various disorders were more prevalent in both POP patients and their family members. METHODS: In this study, the prevalence of various collagen-associated disorders, including POP, was compared between POP patients (n = 110) and control patients (n = 100) and their first and second degree family members. RESULTS: POP patients reported a higher prevalence of varicose veins, joint hypermobility and rectal prolapse and were more likely to have family members with POP as compared to the control group (p < 0.01). In contrast, the family members of the POP group did not report a higher prevalence of collagen-associated disorders compared to the family members of the control group (p = 0.82). CONCLUSIONS: POP and other collagen-associated disorders may have a common aetiology, originating at the molecular level of the collagens.1 maart 201

Internet-based treatment for adults with depressive symptoms: the protocol of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Depression is a highly prevalent condition, affecting more than 15% of the adult population at least once in their lives. Guided self-help is effective in the treatment of depression. The purpose of this study is to investigate the effectiveness of two Internet-based guided self-help treatments with adults reporting elevated depressive symptoms. Other research questions concern the identification of potential mediators and the search for subgroups who respond differently to the interventions.</p> <p>Methods</p> <p>This study is a randomized controlled trial with three conditions: two treatment conditions and one waiting list control group. The two treatment conditions are Internet-based cognitive behavior therapy and Internet-based problem-solving therapy. They consist of 8 and 5 weekly lessons respectively. Both interventions are combined with support by e-mail. Participants in the waiting list control group receive the intervention three months later.</p> <p>The study population consists of adults from the general population. They are recruited through advertisements in local and national newspapers and through banners on the Internet. Subjects with symptoms of depression (≥ 16 on the Center for Epidemiological Studies Depression scale) are included. Other inclusion criteria are having sufficient knowledge of the Dutch language, access to the Internet and an e-mail address.</p> <p>Primary outcome is depressive symptoms. Secondary outcomes are anxiety, quality of life, dysfunctional cognitions, worrying, problem solving skills, mastery, absence at work and use of healthcare. We will examine the following variables as potential mediators: dysfunctional cognitions, problem solving skills, worrying, anxiety and mastery. Potential moderating variables are: socio-demographic characteristics and symptom severity. Data are collected at baseline and at 5 weeks, 8 weeks, 12 weeks and 9 months after baseline. Analyses will be conducted on the intention-to-treat sample.</p> <p>Discussion</p> <p>This study evaluates two Internet-based treatments for depression, namely cognitive behavioral therapy and problem-solving therapy. The effectiveness of Internet-based problem-solving therapy suggest that this may be a worthwhile alternative to other more intensive treatment options. Strengths and limitations of this study are discussed.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN16823487</p

Collaborative Care for patients with severe borderline and NOS personality disorders: A comparative multiple case study on processes and outcomes

<p>Abstract</p> <p>Background</p> <p>Structured psychotherapy is recommended as the preferred treatment of personality disorders. A substantial group of patients, however, has no access to these therapies or does not benefit. For those patients who have no (longer) access to psychotherapy a Collaborative Care Program (CCP) is developed. Collaborative Care originated in somatic health care to increase shared decision making and to enhance self management skills of chronic patients. Nurses have a prominent position in CCP's as they are responsible for optimal continuity and coordination of care. The aim of the CCP is to improve quality of life and self management skills, and reduce destructive behaviour and other manifestations of the personality disorder.</p> <p>Methods/design</p> <p>Quantitative and qualitative data are combined in a comparative multiple case study. This makes it possible to test the feasibility of the CCP, and also provides insight into the preliminary outcomes of CCP. Two treatment conditions will be compared, one in which the CCP is provided, the other in which Care as Usual is offered. In both conditions 16 patients will be included. The perspectives of patients, their informal carers and nurses are integrated in this study. Data (questionnaires, documents, and interviews) will be collected among these three groups of participants. The process of treatment and care within both research conditions is described with qualitative research methods. Additional quantitative data provide insight in the preliminary results of the CCP compared to CAU. With a stepped analysis plan the 'black box' of the application of the program will be revealed in order to understand which characteristics and influencing factors are indicative for positive or negative outcomes.</p> <p>Discussion</p> <p>The present study is, as to the best of our knowledge, the first to examine Collaborative Care for patients with severe personality disorders receiving outpatient mental health care. With the chosen design we want to examine how and which elements of the CC Program could contribute to a better quality of life for the patients.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2763">NTR2763</a></p

Collaborative Care for patients with severe borderline and NOS personality disorders: A comparative multiple case study on processes and outcomes

<p>Abstract</p> <p>Background</p> <p>Structured psychotherapy is recommended as the preferred treatment of personality disorders. A substantial group of patients, however, has no access to these therapies or does not benefit. For those patients who have no (longer) access to psychotherapy a Collaborative Care Program (CCP) is developed. Collaborative Care originated in somatic health care to increase shared decision making and to enhance self management skills of chronic patients. Nurses have a prominent position in CCP's as they are responsible for optimal continuity and coordination of care. The aim of the CCP is to improve quality of life and self management skills, and reduce destructive behaviour and other manifestations of the personality disorder.</p> <p>Methods/design</p> <p>Quantitative and qualitative data are combined in a comparative multiple case study. This makes it possible to test the feasibility of the CCP, and also provides insight into the preliminary outcomes of CCP. Two treatment conditions will be compared, one in which the CCP is provided, the other in which Care as Usual is offered. In both conditions 16 patients will be included. The perspectives of patients, their informal carers and nurses are integrated in this study. Data (questionnaires, documents, and interviews) will be collected among these three groups of participants. The process of treatment and care within both research conditions is described with qualitative research methods. Additional quantitative data provide insight in the preliminary results of the CCP compared to CAU. With a stepped analysis plan the 'black box' of the application of the program will be revealed in order to understand which characteristics and influencing factors are indicative for positive or negative outcomes.</p> <p>Discussion</p> <p>The present study is, as to the best of our knowledge, the first to examine Collaborative Care for patients with severe personality disorders receiving outpatient mental health care. With the chosen design we want to examine how and which elements of the CC Program could contribute to a better quality of life for the patients.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2763">NTR2763</a></p