Facilitators and Barriers of Adherence to Multi-Disease Exacerbation Action Plans in COPD Patients - A Qualitative Study.

Whereas exacerbation action plans to self-manage Chronic Obstructive Pulmonary Disease (COPD) significantly improve health outcomes, patients' adherence to those action plans is often poor. This study aimed to identify facilitators and barriers of adherence to tailored multi-disease exacerbation action plans. We also explored patients' perspectives toward disease management roles. Individual semi-structured interviews were conducted with a sample of COPD patients who completed a Dutch-Australian self-management intervention evaluating tailored exacerbation action plans for COPD and relevant comorbidities. Interviews were thematically analyzed using a deductive approach guided by the Capability, Opportunity and Motivation of Behavior (COM-B) model. In 2016, ten patients (5 Australian; 5 Dutch; 6 men; age 59-83 years) were interviewed at the end of their one-year follow-up. Facilitators of adherence included improved patients' comprehension of disease and treatment, positive feelings about the intervention, improved self-confidence, and professional support. Barriers included difficulties to recognize symptoms, dislike toward daily symptom monitoring, negative feelings about the intervention, negative mood state, and complexity of symptom diaries and action plans. Patients indicated three distinctive perspectives of their own and their healthcare professional's role in their disease management: 1) patients felt mainly responsible; 2) patients felt shared responsibility with their healthcare professional; and 3) patients felt not responsible as they perceived their healthcare professional to be mainly responsible. We successfully used the COM-B model as a guide to identify facilitators and barriers of patients' adherence to multi-disease exacerbation action plans. Improving patients' adherence in future self-management interventions by targeting specific facilitators or barriers should be considered.

Clinical evaluation of a deep-learning-based computer-aided detection system for the detection of pulmonary nodules in a large teaching hospital.

AIM: To evaluate a deep-learning-based computer-aided detection (DL-CAD) software system for pulmonary nodule detection on computed tomography (CT) images and assess its added value in the clinical practice of a large teaching hospital. MATERIALS AND METHODS: A retrospective analysis was performed of 145 chest CT examinations by comparing the output of the DL-CAD software with a reference standard based on the consensus reading of three radiologists. For every nodule in each scan, the location, composition, and maximum diameter in the axial plane were recorded. The subgroup of chest CT examinations (n = 97) without any nodules was used to determine the negative predictive value at the given clinical sensitivity threshold setting. RESULTS: The radiologists found 91 nodules and the CAD system 130 nodules of which 80 were true positive. The measured sensitivity was 88% and the mean false-positive rate was 1.04 false positives/scan. The negative predictive value was 95%. For 23 nodules, there was a size discrepancy of which 19 (83%) were measured smaller by the radiologist. The agreement of nodule composition between the CAD results and the reference standard was 95%. CONCLUSIONS: The present study found a sensitivity of 88% and a false-positive rate of 1.04 false positives/scan, which match the vendor specification. Together with the measured negative predictive value of 95% the system performs very well; however, these rates are still not good enough to replace the radiologist, even for the specific task of nodule detection. Furthermore, a surprisingly high rate of overestimation of nodule size was observed, which can lead to too many follow-up examinations.

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by demyelination, inflammation and neurodegeneration throughout the central nervous system. Although spinal cord pathology is an important factor contributing to disease progression, few studies have examined MS lesions in the spinal cord and how they differ from brain lesions. In this study we have compared brain and spinal cord white (WM) and grey (GM) matter from MS and control tissues, focusing on small heat shock proteins (HSPB) and HSP16.2. Western blotting was used to examine protein levels of HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 in brain and spinal cord from MS and age-matched non-neurological controls. Immunohistochemistry was used to examine expression of the HSPs in MS spinal cord lesions and controls. Expression levels were quantified using ImageJ. Western blotting revealed significantly higher levels of HSPB1, HSPB6 and HSPB8 in MS and control spinal cord compared to brain tissues. No differences in HSPB5 and HSP16.2 protein levels were observed, although HSPB5 protein levels were higher in brain WM versus GM. In MS spinal cord lesions, increased HSPB1 and HSPB5 expression was observed in astrocytes, and increased neuronal expression of HSP16.2 was observed in normal-appearing GM and type 1 GM lesions. The high constitutive expression of several HSPBs in spinal cord and increased expression of HSPBs and HSP16.2 in MS illustrate differences between brain and spinal cord in health and upon demyelination. Regional differences in HSP expression may reflect differences in astrocyte cytoskeleton composition and influence inflammation, possibly affecting the effectiveness of pharmacological agents.

The association of haemophilic arthropathy with Health-Related Quality of Life: a post hoc analysis.

BACKGROUND: The aim of replacement therapy in haemophilia is to improve Health-Related Quality of Life (HRQoL) by preventing bleeding and arthropathy. However, the association of arthropathy with HRQoL is unknown. AIM: To explore the association of haemophilic arthropathy with HRQoL. METHODS: A post hoc analysis on patients with severe/moderate haemophilia with SF36 questionnaire (SF36) and X-rays of ankles, knees and elbows made within 2.5-years. The SF36 scores of 'physical functioning' (SF36-PF, range 0-100, optimum 100) and Utility (SF6D-Utility, range 0-1, optimum 1) and radiological Pettersson scores (PS, range 0-78, optimum 0) were calculated. The association of PS with reduced SF6D-Utility and SF36-PF ( 21 points, the risk of reduced SF6D-Utility was stable (OR 4.16; 95% CI: 2.03-8.51) but SF36-PF continued to decrease: compared to lowest PS, OR for reduced SF36-PF was 5.69 (95% CI: 1.62-20.06) for PS 22-39 and 25.15 (95% CI: 6.53-96.81) for PS 40-78. CONCLUSION: Health-Related Quality of Life only showed a significant deterioration in patients with a Pettersson score of >21 points. This suggests that HRQoL is relatively insensitive to early joint changes.

Safety and Tolerability of Nebulized Amoxicillin-Clavulanic Acid in Patients with COPD (STONAC 1 and STONAC 2).

The safety and tolerability of nebulized amoxicillin clavulanic acid were determined in patients with stable COPD and during severe exacerbations of COPD. Nine stable COPD patients received doses ranging from 50:10 mg up to 300:60 mg amoxicillin clavulanic acid and eight patients hospitalised for a COPD exacerbation received fixed doses 200/40 mg twice daily. Safety was evaluated by spirometry before and after inhalation. Tolerability was evaluated by questionnaire. Plasma and expectorated sputum samples were assayed for amoxicillin content. Seventeen patients underwent in total 100 nebulizations with amoxicillin clavulanic acid. In this safety and tolerability study no clinically relevant deteriorations in FEV1 were observed. Nebulized amoxicillin clavulanic acid produces sputum concentrations well above the Minimal Inhibiting Concentration of 90% for potential pathogenic micro-organisms, with low concentrations in the central compartment (low systemic exposure). Based on spirometry and reported side effects, inhalation of nebulized amoxicillin clavulanic acid seems to be safe and well tolerated, both in stable patients with COPD as in those experiencing a severe exacerbation. Levels of amoxicillin were adequate.

What drives MRI-measured cortical atrophy in multiple sclerosis?

BACKGROUND: Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown. OBJECTIVE: We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology. METHODS: MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model. RESULTS: Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 hours, and disease duration 35±15 years. MRI-measured regional cortical volumes varied depending on anatomical region. Neuronal density, neuronal size, and axonal density were significant predictors of GM volume. CONCLUSIONS: In patients with long-standing disease, neuronal and axonal pathology are the predominant pathological substrates of MRI-measured cortical volume in chronic MS.

Compact portable higher harmonic generation microscopy for the real time assessment of unprocessed thyroid tissue.

During thyroid surgery fast and reliable intra-operative pathological feedback has the potential to avoid a two-stage procedure and significantly reduce health care costs in patients undergoing a diagnostic hemithyroidectomy (HT). We explored higher harmonic generation (HHG) microscopy, which combines second harmonic generation (SHG), third harmonic generation (THG), and multiphoton excited autofluorescence (MPEF) for this purpose. With a compact, portable HHG microscope, images of freshly excised healthy tissue, benign nodules (follicular adenoma) and malignant tissue (papillary carcinoma, follicular carcinoma and spindle cell carcinoma) were recorded. The images were generated on unprocessed tissue within minutes and show relevant morphological thyroid structures in good accordance with the histology images. The thyroid follicle architecture, cells, cell nuclei (THG), collagen organization (SHG) and the distribution of thyroglobulin and/or thyroid hormones T3 or T4 (MPEF) could be visualized. We conclude that SHG/THG/MPEF imaging is a promising tool for clinical intraoperative assessment of thyroid tissue.

Implementation of a multi-institutional diffuse intrinsic pontine glioma autopsy protocol and characterization of a primary cell culture.

AIMS: Diffuse intrinsic pontine glioma (DIPG) is a fatal paediatric malignancy. Tumour resection is not possible without serious morbidity and biopsies are rarely performed. The resulting lack of primary DIPG material has made preclinical research practically impossible and has hindered the development of new therapies for this disease. The aim of the current study was to address the lack of primary DIPG material and preclinical models by developing a multi-institutional autopsy protocol. METHODS: An autopsy protocol was implemented in the Netherlands to obtain tumour material within a brief post mortem interval. A team of neuropathologists and researchers was available at any time to perform the autopsy and process the material harvested. Whole brain autopsy was performed and primary DIPG material and healthy tissue were collected from all affected brain areas. Finally, the study included systematic evaluation by parents. RESULTS: Five autopsies were performed. The mean time interval between death and time of autopsy was 3 h (range 2-4). All tumours were graded as glioblastoma. None of the parents regretted their choice to participate, and they all derived comfort in donating tissue of their child in the hope to help future DIPG patients. In addition, we developed and characterized one of the first DIPG cell cultures from post mortem material. CONCLUSION: Here we show that obtaining post mortem DIPG tumour tissue for research purposes is feasible with short delay, and that the autopsy procedure is satisfying for participating parents and can be suitable for the development of preclinical DIPG models.

Increased expression of distinct galectins in multiple sclerosis lesions.

AIMS: Multiple sclerosis (MS) is a chronic progressive degenerative disorder of the central nervous system, characterized by inflammation, demyelination, ultimate failure of remyelination and axonal loss. Current research identifies galectins, adhesion/growth-regulatory effectors binding ß-galactosides, peptide motifs and lipids, as important immunomodulators in diverse inflammatory diseases. However, little is known about their expression, cellular localization and role in human central nervous system tissue. To identify a potential role of galectins in MS, their expression and localization in control white matter (CWM) and demyelinated MS lesions were examined. METHODS: qPCR, Western blot and immunohistochemical analyses were performed on human post mortem CWM and MS lesions at different stages. Cultured astrocytes, derived from healthy subjects and MS patients, were analysed similarly. RESULTS: Among 11 different galectins tested, galectins-1, -3, -8 and -9 were present at detectable levels in CWM, and, interestingly, significantly enhanced in active MS lesions. On the cellular level, galectins localized to microglia/macrophages, astrocytes and endothelial cells. Intriguingly, galectin-9 displayed a distinctly different intracellular localization in microglia/macrophages when comparing active and inactive MS lesions, being restricted to the nuclei in active lesions, and primarily localizing in the cytoplasm in inactive lesions. Furthermore, enhanced levels of galectin-1, detected as dimers in Western blot analysis, were released by cultured astrocytes from MS patients. CONCLUSIONS: This study provides a detailed analysis of galectins in MS lesions and assigns distinct galectins to different aspects of the disease. Thus, besides being known as modulators of inflammatory processes, our findings suggest additional association of distinct galectins with MS pathology.

BLBP-expression in astrocytes during experimental demyelination and in human multiple sclerosis lesions.

Several lines of evidence indicate that remyelination represents one of the most effective mechanisms to achieve axonal protection. For reasons that are not yet understood, this process is often incomplete or fails in multiple sclerosis (MS). Activated astrocytes appear to be able to boost or inhibit endogenous repair processes. A better understanding of remyelination in MS and possible reasons for its failure is needed. Using the well-established toxic demyelination cuprizone model, we created lesions with either robust or impaired endogenous remyelination capacity. Lesions were analyzed for mRNA expression levels by Affymetrix GeneChip® arrays. One finding was the predominance of immune and stress response factors in the group of genes which were classified as remyelination-supporting factors. We further demonstrate that lesions with impaired remyelination capacity show weak expression of the radial-glia cell marker brain lipid binding protein (BLBP, also called B-FABP or FABP7). The expression of BLBP in activated astrocytes correlates with the presence of oligodendrocyte progenitor cells. BLBP-expressing astrocytes are also detected in experimental autoimmune encephalomyelitis during the remission phase. Furthermore, highest numbers of BLBP-expressing astrocytes were evident in lesions of early MS, whereas significantly less are present at the rim of (chronic)-active lesions from patients with long disease duration. Transfection experiments show that BLBP regulates growth factor expression in U87 astrocytoma cells. In conclusion, we provide evidence that expression of BLBP in activated astrocytes negatively correlates with disease duration and in parallel with remyelination failure.

The hippocampal fimbria of cuprizone-treated animals as a structure for studying neuroprotection in multiple sclerosis.

OBJECTIVE AND DESIGN: It has been demonstrated that changes in the normal-appearing white matter (NAWM) in multiple sclerosis precede the appearance of classical lesions. The understanding of NAWM biology in an established disease model might help to clarify why some of them progress to active demyelinating lesions. MATERIAL OR SUBJECTS: C57BL6 male mice (19-21 g) were used in this study. TREATMENT: Demyelination was induced by feeding mice a diet containing 0.2% cuprizone for up to 5 weeks. METHODS: Routine stainings (luxol fast blue, and hematoxylin and eosin) and immunohistochemistry were performed to assess myelin status and the inflammatory infiltrate. RESULTS: We demonstrated that, in the toxic demyelination cuprizone model, the corpus callosum is severely demyelinated after a 5-week cuprizone challenge (acute demyelination) whereas the fimbria of the hippocampus appear normal in routine myelin stainings. Microgliosis but not astrogliosis is evident after acute demyelination in the fimbria. Interestingly, both regions, the fimbria and the corpus callosum, demonstrated early oligodendrocyte apoptosis as well as intense microglia accumulation and activation. However, only the corpus callosum progresses to actively demyelination lesions whereas the fimbria does not. CONCLUSIONS: The applied model appears suitable for elucidating pathways which promote progression of affected tissue to an active lesion.

Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage.

The multidrug resistance protein 1 (MRP1) gene encodes a transporter protein that helps to protect cells against xenobiotics. Elevated levels of MRP1 in tumor cells can result in active extrusion of a wide range of (anticancer) drugs with different cellular targets, a phenomenon called multidrug resistance (MDR). To explore the protective function of the mouse mrp1 protein during drug treatment, we investigated the toxicity caused by the anticancer drug etoposide-phosphate (ETOPOPHOS) in mice lacking the mrp1 gene (mrp1(-/-) mice). We show here that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis. The high concentrations of mrp1 that we find in the basal layers of the oropharyngeal mucosa and in the basal membrane of the Sertoli cells in the testis apparently protect wild-type mice against this tissue damage. We also find drug-induced polyuria in mrp1(-/-) mice, which correlates with the presence of mrp1 protein in the urinary collecting tubules, the major site of kidney water reabsorption. Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus.

Molecular diagnostics of psoriasis, atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

BACKGROUND: Microarray studies on the epidermal transcriptome in psoriasis and atopic dermatitis (AD) have revealed genes with disease-specific expression in keratinocytes of lesional epidermis. These genes are possible candidates for disease-specific pathogenetic changes, but could also provide a tool for molecular diagnostics of inflammatory skin conditions in general. OBJECTIVES: To analyse if gene expression signatures as found in purified epidermal cells from AD are also present in other eczematous conditions such as allergic and irritant contact dermatitis. METHODS: We used real-time quantitative polymerase chain reaction, immunohistochemistry and bioinformatics to investigate gene expression in different forms of eczema. Normal epidermis and psoriatic epidermis were analysed for comparison. RESULTS: Carbonic anhydrase II was highly induced in epidermis from all forms of eczema but not in psoriasis. Remarkably, the presumed neuron-specific Nel-like protein 2 showed a strong induction only in AD epidermis. Interleukin-1F9, elafin, beta-defensin-2 and vanin-3 were strongly induced in psoriasis, but not in any type of eczema. High levels of the chemokines CCL17 and CXCL10 were predominantly found in epidermis of allergic contact dermatitis. The chemokine CXCL8 was highly expressed in psoriasis, AD and allergic contact dermatitis, but not in irritant contact dermatitis. Cluster analysis or multinomial logistic regression indicated that expression levels of a set of seven genes are a strong predictor of the type of inflammatory response. CONCLUSIONS: These observations contribute to molecular diagnostic criteria for inflammatory skin conditions.

(Cost)-effectiveness of self-treatment of exacerbations on the severity of exacerbations in patients with COPD: the COPE II study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic disease with a high prevalence and rapidly increasing incidence rates. The effect of self-treatment of COPD exacerbations on the severity of exacerbations during a 1-year period was examined and a cost-effectiveness analysis was performed. METHODS: Patients were randomly allocated to four 2-hour self-management sessions, with or without training in self-treatment of exacerbations. Patients in the self-treatment group received an action plan with the possibility to initiate a course of prednisolone (with or without antibiotics). During follow-up, all participants kept a daily symptom diary. These provided the data to calculate the frequency of exacerbations, the number of exacerbation days and mean daily severity scores. RESULTS: Data were analysed for 142 randomised patients (self-treatment: n = 70; control: n = 72). The frequency of exacerbations was identical in both study groups (mean (SD) 3.5 (2.7)). Patients in the self-treatment group reported fewer exacerbation days (median 31 (interquartile range (IQR) 8.9-67.5) in the self-treatment group vs 40 (IQR 13.3-88.2) in the control group; p = 0.064); the difference was significant in the group of patients with a high number of exacerbation days per year (>137 (90th percentile of the whole study population); p = 0.028). The mean severity score of an exacerbation day was equal in both groups. No between-group differences were found in health-related quality of life. Cost-effectiveness analyses showed that applying self-treatment saved euro154 per patient, with a trend towards a lower probability for hospital admissions (0.20/patient/year in the self-treatment group vs 0.33/patient/year in the control group; p = 0.388) and a significant reduction of health care contacts (5.37/patient/year in the self-treatment group vs 6.51/patient/year in the control group; p = 0.043). CONCLUSION: Self-treatment of exacerbations incorporated in a self-management programme leads to fewer exacerbation days and lower costs.

Abundant extracellular myelin in the meninges of patients with multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS) myelin debris has been observed within MS lesions, in cerebrospinal fluid and cervical lymph nodes, but the route of myelin transport out of the brain is unknown. Drainage of interstitial fluid from the brain parenchyma involves the perivascular spaces and leptomeninges, but the presence of myelin debris in these compartments has not been described. AIMS: To determine whether myelin products are present in the meninges and perivascular spaces of MS patients. METHODS: Formalin-fixed brain tissue containing meninges from 29 MS patients, 9 non-neurological controls, 6 Alzheimer's disease, 5 stroke, 5 meningitis and 7 leucodystrophy patients was investigated, and immunohistochemically stained for several myelin proteins [proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)]. On brain material from MS patients and (non)neurological controls, PLP immunostaining was used to systematically investigate the presence of myelin debris in the meninges, using a semiquantitative scale. RESULTS: Extensive extracellular presence of myelin particles, positive for PLP, MBP, MOG and CNPase in the leptomeninges of MS patients, was observed. Myelin particles were also observed in perivascular spaces of MS patients. Immunohistochemical double-labelling for macrophage and dendritic cell markers and PLP confirmed that the vast majority of myelin particles were located extracellularly. Extracellular myelin particles were virtually absent in meningeal tissue of non-neurological controls, Alzheimer's disease, stroke, meningitis and leucodystrophy cases. CONCLUSIONS: In MS leptomeninges and perivascular spaces, abundant extracellular myelin can be found, whereas this is not the case for controls and other neurological disease. This may be relevant for understanding sustained immunogenicity or, alternatively, tolerogenicity in MS.

Complications and failure of uterine artery embolisation for intractable postpartum haemorrhage.

OBJECTIVE: Primary postpartum haemorrhage (PPH) is a major cause of maternal morbidity and mortality around the world. Most patients can be managed conservatively, but patients with intractable bleeding require more aggressive treatment. In these cases uterine artery embolisation (UAE) has proven to be a useful tool to control PPH. The reported success rate of UAE is over 90% with only minor complications. In this case series we studied the effectiveness and complications of UAE. DESIGN: Retrospective analysis of a case series. SETTING: Case series in a large peripheral hospital in the Netherlands. SAMPLE: Eleven patients who were treated with UAE for intractable PPH from November 2004 to February 2008. METHODS: In this paper we review the results of all patients treated with UAE for intractable PPH in our hospital and focus on the two cases with adverse outcomes. MAIN OUTCOME MEASURES: Effectiveness, causes of failure of UAE, complications. RESULTS: Nine out of eleven patients were treated successfully with UAE. One patient needed an emergency hysterectomy for intractable bleeding. In the aftermath she developed a vesicovaginal fistula (VVF). Another patient suffered a major thrombo-embolic event of the right leg, for which she underwent embolectomies and despite fasciotomy a necrotectomy. CONCLUSIONS: UAE is a valuable tool in managing major PPH and in most cases it can replace surgery and thus prevent sacrification of the uterus. However, due to blood supply of the uterus by one of the ovarian or aberrant arteries, UAE might fail to control the bleeding. In addition, serious complications such as a thrombo-embolic event or VVF may occur. We hereby present a case of migration of an embolus from the site of re-embolisation into the femoral artery requiring immediate intervention to prevent the loss of the lower leg. This complication demonstrates that gelatine sponge particles could migrate from the internal iliac artery into the external iliac artery.

Translating pathology in multiple sclerosis: the combination of postmortem imaging, histopathology and clinical findings.

BACKGROUND: Studies combining postmortem magnetic resonance imaging (MRI) and histopathology have provided important insights into the abnormalities reflected by MRI. MATERIALS AND METHODS: A short overview of these studies applied to multiple sclerosis (MS) is provided in this review, and the Amsterdam postmortem imaging protocol is specifically highlighted. CONCLUSION: Postmortem MRI and histopathology correlation studies have enabled a direct translation of basic pathology in MS to the clinical setting, and have simultaneously served as a biological validation of new MRI techniques.