Self-assembly of ferria - nanocellulose composite fibres.

An environmentally benign synthesis of a magnetically responsive carboxymethylated cellulose nanofibril-based material is reported. Applied experimental conditions lead to the in-situ formation of magnetite nanoparticles with primary particle sizes of 2.0-4.0 nm or secondary particles of 3.6-16.4 nm depending on whether nucleation occurred between individual carboxymethylated cellulose nanofibrils, or on exposed fibril surfaces. The increase in magnetite particle size on the cellulose fibril surfaces was attributed to Ostwald ripening, while the small particles formed within the carboxymethyl cellulose aggregates were presumably due to steric interactions. The magnetite nanoparticles were capable of coordinating to carboxymethylated cellulose nanofibrils to form large "fibre-like" assemblies. The confinement of small particles within aggregates of reductive cellulose molecules was most likely responsible for excellent conservation of magnetic characteristics on storage of this material. The possibility for using the material in drug delivery applications with release rate controlled by daylight illumination is presented.

Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress.

BACKGROUND: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. OBJECTIVES: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. METHODS: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. RESULTS: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. CONCLUSIONS: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).

The biomarkers suPAR and blood eosinophils are associated with hospital readmissions and mortality in asthma - a retrospective cohort study.

INTRODUCTION: Prognostic biomarkers in asthma are needed. The biomarker soluble urokinase plasminogen activator receptor (suPAR) has been associated with asthma control and with prognosis in acutely admitted medical patients. We investigated if suPAR and blood eosinophil counts at the time of admission for asthma are associated with readmission and mortality. METHODS: Our cohort comprised 1341 patients (median age 45.3, IQR 30.1-63.1) acutely admitted with a diagnosis of asthma to Hvidovre Hospital, Denmark (November 2013 to March 2017). Patients had suPAR and blood eosinophils measured at admission. Outcomes were 365-day readmission and all-cause mortality. Logistic regression analysis adjusted for age, sex, C-reactive protein, and Charlson comorbidity score was used to assess the association of the two biomarkers with readmission and all-cause mortality. RESULTS: Compared to event-free patients, patients who were either readmitted (n = 452, 42.3%) or died (n = 57, 5.3%) had significantly higher suPAR concentrations (p < 0.0001) and lower eosinophil counts (p = 0.0031) at admission. The highest odds of readmission or mortality were observed for patients in either the 4th suPAR quartile (p < 0.0001) or with eosinophil counts < 150 cells/µL at admission. Increasing levels of suPAR were associated with 365-day readmission (OR 1.3 [1.0-1.6]; p = 0.05) and mortality (OR 2.9 [1.7-5.1]; p = 0.0002). Eosinophil count > 300 cells/µL was significantly associated with lower odds of readmission (OR 0.64 [0.5-0.9]; p = 0.005) and lower mortality (OR 0.7 [0.6-0.9]; p = 0.0007). CONCLUSIONS: In patients acutely admitted with asthma, elevated suPAR concentrations together with blood eosinophil count < 150 cells/µL at the time of hospital admission were associated with both 365-day all-cause readmission and mortality.

PET/CT prior to salvage surgery in recurrent head and neck squamous cell carcinoma.

PURPOSE: The purpose of this study was to assess the use of 18F-FDG PET/CT scans for detecting distant metastases in patients with recurrent head and neck squamous cell carcinoma (HNSCC) and investigate the treatment and survival of patients with recurrence. METHODS: In this retrospective study, consecutive head and neck cancer patients referred for FDG PET/CT scan between 2012 and 2014 were included. Patient records were reviewed and only patients with recurrence of HNSCC were enrolled for further analysis. Information on distant metastases, surgery and survival was collected. A Kaplan-Meier analysis was used to report survival. RESULTS: Overall 275 PET/CT scans were performed due to suspected recurrence, and in 166 scans (144 patients), recurrence of HNSCC was confirmed, making them eligible for further analysis. Distant metastases were revealed in 29.8% of the scans (n = 51) and the proportion of revealed metastases remained constant at approximately 30% each year. Although the number of performed scans increased twofold each year, there was no statistically significant change in the proportion of scans with distant metastasis (p = 0.55). The distant metastases were most often seen in the lungs (n = 44) and bone (n = 15). A few patients had widespread dissemination to other areas. Salvage surgery was performed following 81 of the 166 PET/CT scans. Seven of the patients who underwent salvage surgery had M-site oligo-metastases. Patients who underwent salvage surgery had a median survival of 22 months whereas patients not treated with salvage surgery had a median survival of 6 months. After 5 years, 21% of the patients selected for salvage surgery were alive. CONCLUSIONS: Distant metastases occur frequently in patients with recurrent HNSCC disease and the proportion of revealed distant metastases remained the same (30%). Imaging with FDG PET/CT can be recommended in patients with recurrent HNSCC prior to putative salvage surgery.

Risk profiling based on p16 and HPV DNA more accurately predicts location of disease relapse in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: In the era of precision medicine and HPV-related oropharyngeal squamous cell carcinoma (OPSCC), it is relevant to assess the risk of not only survival, but also the risk of local, regional, or distant treatment failure. The UICC 8th edition uses the surrogate marker p16 to stratify for HPV association but discordance between p16 status and HPV association has been shown. The purpose of this study was to develop a prognostic model to predict the risk of local, regional, and distant metastases and non-cancer-related death for patients with OPSCC, test the prognostic relevance of adding HPV DNA and p16 status, and validate the findings in an independent external dataset. PATIENTS AND METHODS: Consecutive patients diagnosed with OPSCC and treated with curative radiotherapy with or without cisplatin in eastern Denmark from 2000 to 2014 were included. Characteristics included age, gender, TNM stage, smoking habits, performance status, and HPV status assessed with p16 and HPV DNA. The information was used to develop a prognostic model for first site of failure with four competing events: recurrence in T-, N-, and M-site, and death with no evidence of disease. RESULTS: Overall 1243 patients were eligible for the analysis. A prognostic model with the four events was developed and externally validated in an independent dataset with a heterogeneously treated patient population from another institution. The individual prognostication from the competing risk analysis is displayed in a user friendly online tool (https://rasmussen.shinyapps.io/OPSCCmodelHPV_p16/). Replacing p16 status with the combined variable HPV/p16 status influenced the HR and patients with HPV-/p16+ had significantly higher HR of M-site recurrence than HPV+/p16+ with a HR = 2.56; CI [1.30; 5.02]; P = 0.006 (P = 0.013 in the validation cohort). CONCLUSION: Patients with HPV-/p16+ have significantly higher risk of M-site recurrence and could potentially be relevant candidates for clinical trials testing systemic treatments in combination with conventional treatments.

Exhaled and nasal nitric oxide in chronic rhinosinusitis patients with nasal polyps in primary care.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder associated with lower airway disease. However, only few studies of CRSwNP from outside secondary/tertiary care centres have been published. We recently reported an asthma frequency of 44% and 65% in primary and secondary care patients respectively. Therefore, we hypothesise that inflammation of the lower airways could be present in all CRSwNP patients, even without asthma. Here, we assessed the degree of lower and upper airway inflammation using exhaled and nasal nitric oxide (NO) in primary care CRSwNP patients with and without asthma. METHODS: Fifty-seven patients who met the EPOS criteria for CRSwNP were prospectively recruited from primary care ear, nose and throat clinics. Nasal endoscopy was performed by an ear, nose and throat specialist upon enrolment. Additionally, 30 healthy controls were enrolled. Expiratory and nasal NO measurements and thorough pulmonary evaluation were performed. Pulmonary disease was diagnosed by a respiratory physician. RESULTS: Fifty-nine percent of CRSwNP patients with asthma showed elevated expiratory NO; the same was seen in 29% of non-asthmatic CRSwNP patients. Compared with controls, a high level of exhaled NO was significantly more prevalent in CRSwNP irrespective of asthma-status. Nasal NO was significantly lower in patients with CRSwNP compared with controls. CONCLUSION: Subclinical eosinophilic lower airway inflammation is common in CRSwNP in the primary sector, even in the absence of asthma.

The risk of osteoporosis in oral steroid treatment for nasal polyposis: a systematic review.

BACKGROUND: Systemic glucocorticoids are often used in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), and osteoporosis is a well-known complication to steroid treatment, associated with significant morbidity. Nevertheless, the burden of steroid induced osteoporosis is unknown in patients with CRSwNP. We aimed to assess the risk of acquiring osteoporosis caused by oral steroids in patients with CRSwNP, and provide recommendations on future research and guidelines. METHODOLOGY: Cochrane Review Database, EMBASE, Ovid Medline, and PubMed were searched for studies including adult patients with CRSwNP treated with oral steroids. Outcomes were Bone Mineral Density (BMD) and prevalence of fractures in relation to dose and duration of oral steroids. In addition, we reviewed general guidelines for treatment with oral steroids. RESULTS: We identified two studies (n=243) that met the inclusion criteria. Doses and durations of oral steroids were over 5 mg/day for more than 3 months and 1 mg/kg body weight/day for 6 to 10 days for 4 or more courses/year. The prevalence of low bone mass was 39% and 61%, respectively. It was not possible to quantify the overall risk of osteoporosis induced by oral steroids from the studies. No studies evaluated prevalence of fracture. CONCLUSIONS: Registry studies and randomized controlled trials would be needed to assess the risk of osteoporosis in CRSwNP patients and future guidelines should include recommendations regarding preventive treatment and recommendations on doses and durations of oral steroids.

Surgical treatment of obesity in DM1--a case report and a review of the literature.

In patients with myotonic dystrophy type 1 overweight and obesity are frequent. When present this has further negative effects on the patients' pulmonary and muscle function as well as social participation. Anesthesia in myotonic dystrophy type 1 patients is associated with increased risks, especially in those who are obese. We describe the outcome of the first patient reported who has undergone gastric bypass surgery. The operation went without complications. Within two years after surgery she has lost 56.5 kg corresponding to 44% of her preoperative body weight (128.5 kg). She has lost muscle mass and muscle strength, but has gained somewhat in functional tests including pulmonary function and has no longer any need for nocturnal ventilation. Surgical treatment of obesity may be feasible in selected myotonic dystrophy type 1 patients but further studies are needed to determine appropriate criteria for surgery including body mass index limits and how pre- and post-operative follow-up should best be made.

A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality.

Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.

Budesonide in Crohn's disease: findings of a compassionate-use program.

BACKGROUND/AIMS: Budesonide controlled-release (CR) capsules are effective for inducing remission of Crohn's disease (CD) and are associated with fewer side effects than conventional corticosteroids. A compassionate-use program was implemented in countries where this treatment was unavailable. This paper reports the findings of this program. METHODOLOGY: Physicians were allowed to apply to AstraZeneca for a supply of budesonide CR capsules primarily for patients with CD who had experienced unacceptable side effects from conventional steroids or were unresponsive to other drugs. Physicians were requested to record adverse events (AEs) and patient response (1 = 'moderate'; 2 = 'well'; 3 = 'very well'). RESULTS: Four thousand and ninety-two patients were enrolled. There were 232 AE reports involving 326 different symptoms. There were 138 serious AEs (mainly gastrointestinal), and four deaths. Ten serious AEs were considered related to budesonide (no deaths). Budesonide was discontinued as a result of AEs in 147 patients (75 due to serious AEs, mainly gastrointestinal). Efficacy data were obtained from 1188 patients, with 943 (79%) responding 'well' or 'very well'. In the subgroups of patients that were young, elderly, or had unsuccessfully received immunosuppressants previously, the mean patient response score was >2. CONCLUSIONS: In a normal clinical setting, budesonide CR capsules were well tolerated by patients with ileocecal CD.

Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia.

Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002. During 3 weeks of treatment, l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, -47%; buspirone, -46%; riluzole, -33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of l-DOPA-induced dyskinesia.

Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Taking advantage of a monkey brain bank constituted to study the pathophysiology of levodopa-induced dyskinesia, we here report the changes affecting D1, D2 and D3 dopamine receptors within the striatum of four experimental groups of non-human primates: normal, parkinsonian, parkinsonian treated with levodopa without or with dyskinesia. We also report the possible role of arrestin and G protein-coupled receptor kinases.

Transdermal suctioning technique for serial sampling of interstitial fluid in newborn infants.

OVERVIEW: Use of a suction-induced epidermal mini-erosion for serial sampling of dermal interstitial fluid (IF) in 16 newborn infants with gestational age ranging from 24 to 42 weeks is reported. RESULTS: The mini-erosion formed reproducibly and electron microscopy showed that the split was located within the epidermis. IF was sampled serially by suctioning during 1-3 days without signs of stress or pain. IF sample volumes (10-50 microl) did not decrease with time. Glucose values in IF and blood were correlated (r(s) = 0.542; p = 0.000). IF glucose was lower than blood glucose on all 3 days. The epidermis regenerated within 4 +/- 0.9 days (mean, SD) after sampling was terminated. There were no complications. CONCLUSION: Serial transdermal sampling was performed without stress or pain in newborn infants. Systemic and temporal differences between glucose measured in IF and blood were observed.

Gene deletion of cystatin C aggravates brain damage following focal ischemia but mitigates the neuronal injury after global ischemia in the mouse.

Cystatin C is distributed in all human tissues and fluids with a particular abundance in the cerebrospinal fluid. Cystatin C is a strong endogenous inhibitor of lysosomal cysteine proteases, such as cathepsin B, L, H and S, that are involved in various biological processes such as degradation of cellular proteins and regulation of enzymes, as well as in pathological processes. Pharmacological inhibition of cathepsins has been shown to reduce neuronal damage after brain ischemia, suggesting that cystatin C is an endogenous neuroprotectant. Cystatin C has also amyloidogenic properties and is co-localized with beta-amyloid in degenerated neurons in Alzheimer's disease, suggesting a role in neuronal degeneration. To test the hypothesis that endogenous cystatin C is neuroprotective during brain ischemia, global and focal brain ischemia was induced in mice with the cystatin C gene knocked out. Following focal ischemia, larger brain infarcts were found in cystatin C knockout mice, probably due to a reduced inhibition of the cathepsins during ischemia. In contrast, brain damage after global ischemia was diminished in cystatin C knockout mice, suggesting that cystatin C has an aggravating effect on selective neuronal damage after global ischemia.

Homology modeling of Na,K-ATPase: a putative third sodium binding site suggests a relay mechanism compatible with the electrogenic profile of Na+ translocation.

Identification of the third Na(+) binding site would be crucial in interpretation of the electrophysiological behavior of Na,K-ATPase. To address this question a three-dimensional homology model of Na,K-ATPase was built from the known crystallographic structure of Ca-ATPase (1EUL). Phe760, which is conserved in virtually all Ca-ATPases, is replaced by Ser768 in Na,K-ATPase, resulting in a small cavity between M4, M5, and M6. A partially hydrated Na(+) ion can be bound at this third site on the cytoplasmic side of cation binding sites 1 and 2. This leads to the proposal that the conductance of the "third Na(+)" ion across approximately 70% of the membrane dielectric may be achieved by adding up the passage of one Na(+) ion from the described cytoplasmic cavity to cation site 1 and the further conductance of the previously bound Na(+) ion from cation site 1 to the extracellular phase. This relay mechanism may therefore be compatible with the electrogenic profile of Na(+) translocation.

On the appearance of bile in clinical MR cholangiopancreatography.

PURPOSE: To study the appearance of bile in clinical MR cholangiopancreatography (MRCP) with special reference to its chemical and physical properties. MATERIAL AND METHODS: Gallbladder bile was collected during surgery from 38 patients and studied with respect to chemical constituents. The relaxation rates 1/T1 and 1/T2 of bile were also determined in vitro. In 16 of these 38 patients, abdominal imaging was performed using MRCP as well as T1-weighted GE sequences. RESULTS: For 9 of the 13 chemical parameters studied, a positive significant correlation with 1/T1 as well as 1/T2 was found. The median relaxation rates 1/T1 and 1/T2 were 0.76 and 1.48 s-1, respectively. The corresponding ranges were 0.38-3.13 s-1 and 0.70-5.75 s-1, respectively. On the MRCP images a few patients showed gallbladder of poor visibility due to low signal-to-noise ratio. This coincided with a high relaxation rate 1/T2 of bile. On the T1-weighted GE sequences a few patients showed hyperintense gallbladder relative to liver, coinciding with high relaxation rates 1/T1 of bile. CONCLUSION: Bile was found to show a large interindividual variation with respect to relaxation rates 1/T1 and 1/T2. The relaxation rates increased with increasing amounts of substances in the bile. For some patients (11%) MRCP imaging is unsuccessful due to high relaxation rate of bile.

MR characteristics of acute cholangitis.

PURPOSE: To describe the MR appearance of acute cholangitis and discuss the role of MR imaging as a diagnostic method in this disease. MATERIAL AND METHODS: Of 60 patients with clinical acute cholangitis, 12 were examined with MR before endoscopic retrograde pancreatography (ERCP). A retrospective review was performed of MR and ERCP findings. The MR findings registered were presence of biliary duct dilatation, intraluminal filling defects due to stones or sludge, bands of mucosal oedema of the biliary ducts, intra- and retroperitoneal oedema/fluid, and definition of the cause of obstruction, e.g. stones, stenosis or tumour was made. RESULTS: Acute cholangitis was related to obstruction from choledocholithiasis (n=8), pancreatic cancer (n=1), benign biliary duct stricture (n=1), papillary stenosis (n=1) and without evidence of an obstructing cause (n=1). One patient had an acute obstructive suppurative (toxic) cholangitis. CONCLUSION: MR imaging has a role in the non-invasive radiographic arsenal of techniques to confirm or exclude the diagnosis of acute cholangitis, especially in older patients where the clinical symptoms may be vague.

MR and ultrasound in screening of patients with suspected biliary tract disease.

PURPOSE: The diagnostic value and cost-efficiency of MR imaging were compared with US before endoscopic retrograde cholangiopancreatography (ERCP) in patients with clinically suspected biliary tract disease. MATERIAL AND METHODS: In a prospective study of 219 patients, 85 were examined with both MR and US before ERCP. RESULTS: To find the correct diagnosis in the jaundiced patients the sensitivity of US, MR and ERCP was 53%, 93%, and 89%, respectively. In the patients with abdominal upper quadrant pain and normal serum bilirubin, the sensitivity of US, MR and ERCP was 50%, 100% and 70%, respectively. Examination with MR costs four times more than US. Screening with US and supplemental MR in non-diagnostic cases would cost 80% of the total amount compared to screening with MR only. CONCLUSION: MR had a higher sensitivity than US for diagnosing biliary tract disease and MR was superior to US in visualising stones in the common bile duct and in diagnosing the cause of cholestasis. However, screening with US and supplemental MR in non-diagnostic cases is at present most cost-effective. With increased accessibility and slightly lower costs, MR will probably replace US as screening method in patients with suspected biliary tract disease.