Knowledge, health beliefs and attitudes towards dementia and dementia risk reduction among descendants of people with dementia: a qualitative study using focus group discussions.

BACKGROUND: Individuals with a parental family history of dementia have an increased risk of developing dementia because they share their genes as well as their psychosocial behaviour. Due to this increased risk and their experience with dementia, they may be particularly eager to receive information regarding dementia risk reduction (DRR). This study evaluated the knowledge, beliefs and attitudes towards dementia and DRR among descendants of people with dementia. METHOD: Using a semi-structured topic guide, three focus group discussions were conducted consisting of 12 female (80%) and 3 male (20%) descendants of people with dementia with a mean (± SD) age of 48.8 (± 12) years. Focus group discussions were audio recorded and transcribed. Each transcript was analysed thoroughly, and where appropriate, a code was generated and assigned by two researchers independently. Then, similar codes were grouped together and categorized into themes. RESULTS: The items in the topic guide could only be addressed after participants had been given the opportunity to share their experiences of having a parent with dementia. Participants were unaware or uncertain about the possibility of reducing the risk of developing dementia and therefore hesitant to assess their dementia risk without treatment options in sight. Moreover, participants indicated that their general practitioner only gave some information on heritability, not on DRR. Although participants identified a large number of modifiable risk factors as a group during the group discussions, they were eager to receive more information on dementia and DRR. In the end, participants adopted a more positive attitude towards a DRR programme and provided suggestions for the development of future DRR programmes. CONCLUSIONS: Although the research aim was to evaluate the knowledge, beliefs and attitudes towards dementia and DRR, sharing experiences of having a parent with dementia seemed a prerequisite for considering participants' own risk of developing dementia and participating in a DRR programme. Knowledge of dementia and DRR was limited. Due to unawareness of the possibility of reducing dementia risk, participants were hesitant about assessing their dementia risk. Group discussions positively changed the perception of dementia risk assessment and participants' willingness to participate in a DRR programme.

Prediction model for pneumonia in primary care patients with an acute respiratory tract infection: role of symptoms, signs, and biomarkers.

BACKGROUND: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care. METHODS: From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model. RESULTS: Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics. CONCLUSIONS: Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.

Depression and anxiety as predictors of mortality among heart failure patients: systematic review and meta-analysis.

Several studies suggest that psychological factors are associated with negative outcomes and in particular higher mortality rates among heart failure (HF) patients. We aimed to evaluate the effect sizes of depression and anxiety on all-cause mortality in HF patients. We conducted a systematic review according to the PRISMA methodology. We searched for studies on depression or anxiety effects on all-cause mortality among HF patients published up to June 2015. A number of 26 and 6 articles met inclusion criteria for depression (total 80,627 patients) and anxiety (total 17,214 patients), respectively. The effect estimates were pooled using random-effect meta-analysis. Depression has significant and moderately heterogeneous effect on all-cause mortality (HR = 1.57; 95%CI 1.30-1.89, p < 0.001); adjustment for confounders led to a similar effect estimate (HR = 1.40; 95%CI 1.22-1.60; p < 0.001). Larger studies and higher study prevalence of depression were associated with smaller effect size. The effect of anxiety on mortality outcome was small and not conclusive given the low number of studies (n = 6) (HR = 1.02; 95% CI 1.00-1.04, p < 0.05). This systematic review and meta-analysis suggests that depression is an important and independent predictor of all-cause mortality among HF patients, while anxiety does not appear to have a strong effect. Further research is recommended toward the detection and treatment of depression.

Oral Health as a Risk Factor for Alzheimer Disease.

In patients with Alzheimer's disease pathophysiological changes of the brain that initiate the onset of Alzheimer's disease include accumulation of amyloid-ß plaques and phosphorylation of tau-tangles. A rather recently considered risk factor for the onset of Alzheimer's disease is poor oral health. The aim of this systematic review of the literature was to assess the potential association(s) of oral health as a risk factor for the onset of Alzheimer's disease. After a systematic search of Pubmed, Embase and Web of Science. A total of 1962 studies were assessed, of which 17 studies demonstrated possible associations between oral health diseases and Alzheimer's disease. 4 theories could be distinguished that describe the possible links between oral health and the development or onset of Alzheimer's disease; 1) role of pathogens, 2) role of inflammatory mediators, 3) role of APOE alleles and 4) role of Aß peptide. The main common denominator of all the theories is the neuroinflammation due to poor oral health. Yet, there is insufficient evidence to prove a link due to the diversity of the designs used and the quality of the study design of the included studies. Therefore, further research is needed to find causal links between oral health and neuroinflammation that possibly can lead to the onset of Alzheimer's disease with the future intention to prevent cognitive decline by better dental care.

Short-term outpatient follow-up of COVID-19 patients: A multidisciplinary approach.

BACKGROUND: Short-term follow-up of COVID-19 patients reveals pulmonary dysfunction, myocardial damage and severe psychological distress. Little is known of the burden of these sequelae, and there are no clear recommendations for follow-up of COVID-19 patients.In this multi-disciplinary evaluation, cardiopulmonary function and psychological impairment after hospitalization for COVID-19 are mapped. METHODS: We evaluated patients at our outpatient clinic 6 weeks after discharge. Cardiopulmonary function was measured by echocardiography, 24-hours ECG monitoring and pulmonary function testing. Psychological adjustment was measured using questionnaires and semi-structured clinical interviews. A comparison was made between patients admitted to the general ward and Intensive care unit (ICU), and between patients with a high versus low functional status. FINDINGS: Eighty-one patients were included of whom 34 (41%) had been admitted to the ICU. New York Heart Association class II-III was present in 62% of the patients. Left ventricular function was normal in 78% of patients. ICU patients had a lower diffusion capacity (mean difference 12,5% P = 0.01), lower forced expiratory volume in one second and forced vital capacity (mean difference 14.9%; P<0.001; 15.4%; P<0.001; respectively). Risk of depression, anxiety and PTSD were 17%, 5% and 10% respectively and similar for both ICU and non-ICU patients. INTERPRETATION: Overall, most patients suffered from functional limitations. Dyspnea on exertion was most frequently reported, possibly related to decreased DLCOc. This could be caused by pulmonary fibrosis, which should be investigated in long-term follow-up. In addition, mechanical ventilation, deconditioning, or pulmonary embolism may play an important role.

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Window-based example selection in learning vector quantization.

A variety of modifications have been employed to learning vector quantization (LVQ) algorithms using either crisp or soft windows for selection of data. Although these schemes have been shown in practice to improve performance, a theoretical study on the influence of windows has so far been limited. Here we rigorously analyze the influence of windows in a controlled environment of gaussian mixtures in high dimensions. Concepts from statistical physics and the theory of online learning allow an exact description of the training dynamics, yielding typical learning curves, convergence properties, and achievable generalization abilities. We compare the performance and demonstrate the advantages of various algorithms, including LVQ 2.1, generalized LVQ (GLVQ), Learning from Mistakes (LFM) and Robust Soft LVQ (RSLVQ). We find that the selection of the window parameter highly influences the learning curves but not, surprisingly, the asymptotic performances of LVQ 2.1 and RSLVQ. Although the prototypes of LVQ 2.1 exhibit divergent behavior, the resulting decision boundary coincides with the optimal decision boundary, thus yielding optimal generalization ability.

The value of a dedicated multidisciplinary expert panel to assess treatment strategy in patients suffering from colorectal cancer liver metastases.

BACKGROUND: For patients with colorectal cancer liver metastases (CRLM), local treatment is the only treatment with curative intent. The majority of patients with CRLM are however evaluated in multidisciplinary teams of colorectal cancer specialists often lacking expertise in local treatment of liver tumors. The aim of this study was therefore to assess the value of a dedicated multidisciplinary panel consisting of hepatobiliary surgeons and interventional radiologists for patients suffering from liver-only CRLM. METHODS: Patients diagnosed with liver-only CRLM in 2016 were identified in a tertiary referral hospital, and two of the referring hospitals in the Netherlands. Diagnostic imaging was independently reviewed by a panel of four hepatobiliary surgeons and two interventional radiologists to re-evaluate treatment strategy retrospectively. If two or more panelists assessed all lesions eligible for resection and/or ablation, patients were deemed eligible for local treatment with curative intent. Interrater reliability between hepatobiliary surgeons was assessed through intraclass correlation coefficient (ICC) and weighted Cohen's kappa. RESULTS: Diagnostic imaging of 61 patients with liver-only metastases were reviewed. Local treatment strategies appeared feasible in 40/61 (65.6%) patients. Five out of 25 patients (20.0%) initially assigned to systemic therapy were deemed eligible for upfront local treatment with curative intent (p = 0.015). In this subgroup, interrater reliability between hepatobiliary surgeons was substantial (ICC: 0.704, 95% CI: 0.536-0.838, n = 25). CONCLUSION: Assessment of treatment strategy by a dedicated multidisciplinary panel including liver experts may result in an increased number of patients eligible for potentially curative treatment and reduce undertreatment of patients suffering from liver-only CRLM.

Added value of frailty and social support in predicting risk of 30-day unplanned re-admission or death for patients with heart failure: An analysis from OPERA-HF.

BACKGROUND: Models for predicting the outcome of patients hospitalized for heart failure (HF) rarely take a holistic view. We assessed the ability of measures of frailty and social support in addition to demographic, clinical, imaging and laboratory variables to predict short-term outcome for patients discharged after a hospitalization for HF. METHODS: OPERA-HF is a prospective observational cohort, enrolling patients hospitalized for HF in a single center in Hull, UK. Variables were combined in a logistic regression model after multiple imputation of missing data to predict the composite outcome of death or readmission at 30 days. Comparisons were made to a model using clinical variables alone. The discriminative performance of each model was internally validated with bootstrap re-sampling. RESULTS: 1094 patients were included (mean age 77 [interquartile range 68-83] years; 40% women; 56% with moderate to severe left ventricular systolic dysfunction) of whom 213 (19%) had an unplanned re-admission and 60 (5%) died within 30 days. For the composite outcome, a model containing clinical variables alone had an area under the receiver-operating characteristic curve (AUC) of 0.68 [95% CI 0.64-0.72]. Adding marital status, support from family and measures of physical frailty increased the AUC (p < 0.05) to 0.70 [95% CI 0.66-0.74]. CONCLUSIONS: Measures of physical frailty and social support improve prediction of 30-day outcome after an admission for HF but predicting near-term events remains imperfect. Further external validation and improvement of the model is required.

Campylobacter species isolated from extra-oro-intestinal abscesses: a report of four cases and literature review.

Campylobacter species are frequently isolated from fecal specimens of patients with diarrheal illness. Several Campylobacter species are commonly isolated from the oral cavity. In contrast, Campylobacter species are rarely isolated from extra-oro-intestinal abscesses. Reported here are four cases of extra-oro-intestinal abscesses due to polymicrobial flora, including Campylobacter species. The first case is a 35-year-old woman who was diagnosed with a brain abscess caused by C. gracilis, Streptococcus constellatus, and anaerobic Gram-positive cocci. The second case is a 65-year-old man with a history of maxillary sinus carcinoma who developed a brain abscess due to polymicrobial flora, including C. concisus. The third case is a 24-year-old male who was diagnosed with a vertebral abscess caused by C. rectus, Eubacterium brachy, and Actinomyces species. The fourth case is a 74-year-old woman who presented with an intraorbital abscess due to C. showae and Micromonas (previously Peptostreptococcus) micros. The first two patients died from a cause directly related to their abscesses. All Campylobacter species involved in the four cases were isolated anaerobically. The isolation of oral Campylobacter species, e.g., C. rectus and C. showae, from abscesses suggests an oral source. A survey of the English literature was undertaken to identify reports of Campylobacter species isolated from extra-oro-intestinal abscesses.

PCR assays for detection of human astroviruses: In silico evaluation and design, and in vitro application to samples collected from patients in the Netherlands.

BACKGROUND: Human astroviruses (HAstV) comprise three phylogenetically compact and non-adjacent groups of species including classical HAstV (HAstV-C) and the novel ones (HAstV-VA/HMO and HAstV-MLB). Of these, HAstV-C is known to be responsible for gastroenteritis while the novel HAstV are associated with cases of neurological disorders. Accurate detection of all known variants by (real-time) PCR is challenging because of the high intra- and intergroup genetic divergence of HAstV. OBJECTIVES: To evaluate published HAstV PCR assays in silico, design de novo real-time PCR assays that can detect and discriminate three groups of HAstV, and apply those to patient samples to analyse the prevalence of HAstV in stool and cerebrospinal fluid (CSF) specimens. STUDY DESIGN: In silico evaluation of published PCR assays and design of real-time PCR assays for detection of different subsets of HAstV was conducted within a common computational framework that used all astrovirus full genome sequences from GenBank. The newly designed real-time PCR assays were evaluated in vitro and applied to faecal samples (collected in January-May 2016) and cerebrospinal fluid specimens (2010-2016) from patients in the Netherlands. RESULTS: Quantitative in silico evaluation of published PCRs is provided. The newly designed real-time PCR assays can reliably assign all available HAstV genome sequences to one of the three phylogenetic groups in silico, and differentiate among HAstV-specific controls in vitro. A total of 556 samples were tested using these PCR assays. Fourteen fecal samples (2.5%) tested positive for HAstV, 3 of which could be identified as the novel HAstV-MLB variants. No novel HAstV were found in CSF specimens. CONCLUSION: Newly designed real-time PCR assays with improved detection of all known HAstV allowed the first-time identification of novel astroviruses from stool samples in the Netherlands.

Depression as an independent prognostic factor for all-cause mortality after a hospital admission for worsening heart failure.

BACKGROUND: Depression is associated with increased mortality amongst patients with chronic heart failure (HF). Whether depression is an independent predictor of outcome in patients admitted for worsening of HF is unclear. METHODS: OPERA-HF is an observational study enrolling patients hospitalized with worsening HF. Depression was assessed by the Hospital Anxiety and Depression Scale (HADS-D) questionnaire. Comorbidity was assessed by the Charlson Comorbidity Index (CCI). Kaplan-Meier and Cox regression analyses were used to estimate the association between depression and all-cause mortality. RESULTS: Of 242 patients who completed the HADS-D questionnaire, 153, 54 and 35 patients had no (score 0-7), mild (score 8-10) or moderate-to-severe (score 11-21) depression, respectively. During follow-up, 35 patients died, with a median time follow-up of 360days amongst survivors (interquartile range, IQR 217-574days). In univariable analysis, moderate-to-severe depression was associated with an increased risk of death (HR: 4.9; 95% CI: 2.3 to 10.2; P<0.001) compared to no depression. Moderate-to-severe depression also predicted all-cause mortality after controlling for age, CCI score, NYHA class IV, NT-proBNP and treatment with mineralocorticoid receptor antagonist, beta-blocker and diuretics (HR: 3.0; 95% CI: 1.3 to 7.0; P<0.05). CONCLUSIONS: Depression is strongly associated with an adverse outcome in the year following discharge after an admission to hospital for worsening HF. The association is only partly explained by the severity of HF or comorbidity. Further research is required to demonstrate whether recognition and treatment of depression improves patient outcomes.

Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C.

BACKGROUND: Niemann-Pick type C (NP-C) is a rare autosomal recessive progressive neurodegenerative disorder caused by mutations in the NP-C 1 or 2 gene. Besides visceral symptoms, presentation in adolescent and adult onset variants is often with neurological symptoms. The most frequently reported presenting symptoms of NP-C in adulthood are psychiatric symptoms (38 %), cognitive decline (23 %) and ataxia (20 %). Myoclonus can be present, but its value in early diagnosis and the evolving clinical phenotype in NP-C is unclear. In this paper we present eight Dutch cases of NP-C of whom five with myoclonus. METHODS: Eight patients with genetically confirmed NP-C were recruited from two Dutch University Medical Centers. A structured interview and neuropsychological tests (for working and verbal memory, attention and emotion recognition) were performed. Movement disorders were assessed using a standardized video protocol. Quality of life was evaluated by questionnaires (Rand-36, SIP-68, HAQ). In four of the five patients with myoclonic jerks simultaneous EEG with EMG was performed. RESULTS: A movement disorder was the initial neurological symptom in six patients: three with myoclonus and three with ataxia. Two others presented with psychosis. Four experienced cognitive deficits early in the course of the disease. Patients showed cognitive deficits in all investigated domains. Five patients showed myoclonic jerks, including negative myoclonus. In all registered patients EEG-EMG coherence analysis and/or back-averaging proved a cortical origin of myoclonus. Patients with more severe movement disorders experienced significantly more physical disabilities. CONCLUSIONS: Presenting neurological symptoms of NP-C include movement disorders, psychosis and cognitive deficits. At current neurological examination movement disorders were seen in all patients. The incidence of myoclonus in our cohort was considerably higher (63 %) than in previous publications and it was the presenting symptom in 38 %. A cortical origin of myoclonus was demonstrated. Our data suggest that myoclonus may be overlooked in patients with NP-C. All patients scored significantly lower on physical domains of HRQoL. Symptomatic treatment of movement disorders may improve physical functioning and subsequently HRQoL.

Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment.

The objective of the present study is to evaluate the efficacy and the safety of transdermal iontophoretic delivery of R-apomorphine, a potent dopamine agonist, in combination with surfactant pretreatment in patients with advanced Parkinson's disease. Iontophoresis patches were applied in 16 patients for 3.5 h, with 0.5 h of passive delivery followed by 3 h of current application at a current density of 250 microA/cm2. Eight of these patients were treated with a surfactant formulation prior to iontophoresis. The pharmacokinetics, pharmacodynamic effects, systemic and local side effects of R-apomorphine were assessed. The plasma concentration vs. time profiles upon iontophoresis of R-apomorphine were described successfully by a novel pharmacokinetic model. The model suggests that only 1.9% of the dose that has been released from the patch accumulated in the skin. The patients treated with the surfactant formulations showed a statistically significant increase of bioavailability (from 10.6+/-0.8% to 13.2+/-1.4%) and of the steady state input rate (from 75.3+/-6.6 to 98.3+/-12.1 nmol/cm2 h) compared to the control patients (iontophoresis without absorption enhancers). In five out of eight patients in the study group and in three out of eight patients in the control group, clinical improvement was observed.

Motor behaviour in the growth retarded fetus.

In ten growth retarded fetuses (IUGR) a qualitative and quantitative analysis was made of various movement patterns. The results were compared with those of ten matched appropriate-for-gestational age fetuses (AGA). The aim of the study was to see whether malnourished, growth retarded fetuses move differently to well nourished, normal fetuses. The real-time ultrasound recordings were of one hour's duration and the analysis of motility was carried out during replay of video recordings. The qualitative analysis of each separate general movement was performed with 'Gestalt perception' describing the speed, force and amplitude of each movement as well as the variability of these descriptors. Interobserver agreement was evaluated by displaying general movements of both groups to 8 observers. There was an overall interobserver agreement of 89%. The IUGR fetuses moved less, but in individual cases an overlap existed with control fetuses. There was a reduction of both number and duration of general movements in the IUGR group. Furthermore the markedly reduced incidence of startles, twitches and isolated limb movements was striking. The qualitative analysis of general movements revealed a reduction of the quicker components leading to slow and monotonous movement patterns. There was also a marked reduction of variability of speed and intensity within each movement pattern. We speculate that the reduced variability of motor patterns may find its origin in a change of central neural function, just as the reduced heart rate variability and decreased breathing irregularity found in IUGR fetuses.

[Male subfertility, modern reproduction techniques and transmission of genetic abnormalities]. / Mannelijke subfertiliteit, moderne voortplantingstechnieken en het doorgeven van genetische afwijkingen.

Somatic cells of males with azoospermia or oligozoospermia (sperm density < 20 million sperm cells/ml) were found to contain increased percentages of chromosomal abnormalities. Subfertile males with a normal somatic karyogram were found to have increased rates of aneuploidy in sperm. This creates risks for the offspring after fertilization with intracytoplasmatic sperm injection (ICSI). Certain gene mutations on the Y chromosome cause severe oligo- or azoospermia and will, in case of successful reproduction with ICSI, be transmitted to male offspring in 100% of the cases. The same holds true, irrespective of sex, of mutations responsible for cystic fibrosis. In non-random groups of ICSI pregnancies, higher proportions of de novo sex-chromosomal abnormalities have been found than expected. In addition, there are increased proportions of paternally inherited structural autosomal anomalies. Extrapolation of the findings is not yet possible, however.

Emotional sweating across the body: comparing 16 different skin conductance measurement locations.

Skin conductance (SC) is one of the most commonly used measures in psychophysiological studies involving emotional arousal and is traditionally measured at the fingers or the palms (i.e., the palmar locations) of the hand. Palmar skin conductance recording positions are, however, not always preferred for ambulatory recordings in real-life situations. This study quantifies the responsiveness and similarity with the finger of 16 different recording positions of skin conductance while watching emotional film fragments. Findings indicated foot, fingers and shoulders being most responsive, whereas arm, back, armpit, and thighbone were least responsive. The measurements at the foot were most similar with those of the finger. In contrast, arm, back, and armpit traces differed most from the finger trace. Taken together, foot and shoulders are the best alternatives to the finger for ambulatory measurement of skin conductance to reflect emotional arousal. These findings can help new applications using skin conductance, like automated emotion measurements, to come to fruition.

11C-verapamil to assess P-gp function in human brain during aging, depression and neurodegenerative disease.

P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a wide range of substrates from the brain. This is important for maintaining loco-regional homeostasis and for protecting the brain against blood-borne toxic substances. Altered P-gp function seems to be involved in the pathophysiology of neurodegenerative disease and various neurological and psychiatric disorders. Positron emission tomography (PET) with the radiotracer (11)C-verapamil (VPM-PET) is a validated technique allowing measurement of P-gp function at the human BBB. In this review, we highlight changes of P-gp function, as measured with VPM-PET, in aging and in the pathogenesis and progression of neurodegenerative disease, as well as their role in depressive disorders.

Incorporation of LpxL1, a detoxified lipopolysaccharide adjuvant, in influenza H5N1 virosomes increases vaccine immunogenicity.

The increasing number of human influenza H5N1 infections accentuates the need for the development of H5N1 vaccine candidates to prevent a potential influenza pandemic. The use of adjuvants in such vaccines can contribute significantly to antigen dose-sparing. In this study, we evaluated the capacity of the non-toxic Neisseria meningitidis lipopolysaccharide analog LpxL1 to function as an adjuvant for an influenza H5N1 virosomal vaccine. Inactivated influenza H5N1 virus (NIBRG-14) was used to construct virosomes (reconstituted virus envelopes) with LpxL1 incorporated in the virosomal membrane thus combining the influenza hemagglutinin (HA) antigen and the adjuvant in the same particle. Mice were immunized in a one- or two-dose immunization regimen with H5N1 virosomes with or without incorporated LpxL1. After a single immunization, H5N1 virosomes with incorporated LpxL1 induced significantly enhanced H5N1-specific total IgG titers as compared to non-adjuvanted virosomes but hemagglutination inhibition (HI) titers remained low. In the two-dose immunization regimen, LpxL1-modified H5N1 virosomes induced HI titers above 40 which were significantly higher than those obtained with non-adjuvanted virosomes. Incorporation of LpxL1 had little effect on virosome-induced IgG1 levels, but significantly increased IgG2a levels in both the one- and two-dose immunization regimen. Compared to non-adjuvanted virosomes, LpxL1-modified virosomes induced similar numbers of IFNgamma-producing T cells but decreased numbers of IL-4-producing T cells irrespective of the number of immunizations. We conclude that LpxL1 incorporated in H5N1 influenza virosomes has the capacity to function as a potent adjuvant particularly stimulating Th1-type immune reactions.

Awareness of congenital cytomegalovirus among doctors in the Netherlands.

BACKGROUND: Because of limited treatment options for congenital cytomegalovirus (CMV) infection, preventive strategies are important. Knowledge and awareness are essential for the success of preventive strategies. OBJECTIVES: To investigate the knowledge of congenital CMV among doctors involved in mother and child care in the Netherlands. STUDY DESIGN: A questionnaire on CMV infection was sent to doctors by snowball sampling. Knowledge concerning epidemiology, transmission, symptoms and signs of CMV infection in adults and children, and treatment options were evaluated. RESULTS: The questionnaire was completed by 246 doctors involved in mother and child care. The respondents estimated a prevalence of congenital CMV varying between 0.1 and 500 per 1000 live-born infants. The mean knowledge scores regarding transmission and postnatal symptoms increased with a more advanced career stage (i.e. older age). Gender and parenthood did not contribute to knowledge, but the field of expertise did. Respondents in the field of pediatrics had the highest mean score on postnatal symptoms and long-term effects. Respondents working in the field of gynecology and obstetrics were unaware of the precise transmission route of CMV. More than one-third of the respondents assumed that treatment was readily available for congenital CMV infection. CONCLUSIONS: The knowledge of CMV infection among doctors in the Netherlands contained several gaps. Increasing knowledge and awareness is expected to enhance the prevention of transmission, to improve recognition, and to stimulate diagnostic investigations and follow-up programs.