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2.  Four-Year Placebo-Controlled Trial of Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa (DHAX Trial) 
JAMA ophthalmology  2014;132(7):866-873.
X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100 000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome.
To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG).
A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non–X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27).
All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo.
The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence.
Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log µV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found.
Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent.
TRIAL REGISTRATION Identifier: NCT00100230
PMCID: PMC4795002  PMID: 24805262
3.  Cortical Thickness, Surface Area and Subcortical Volume Differentially Contribute to Cognitive Heterogeneity in Parkinson’s Disease 
PLoS ONE  2016;11(2):e0148852.
Parkinson’s disease (PD) is often associated with cognitive deficits, although their severity varies considerably between patients. Recently, we used voxel-based morphometry (VBM) to show that individual differences in gray matter (GM) volume relate to cognitive heterogeneity in PD. VBM does, however, not differentiate between cortical thickness (CTh) and surface area (SA), which might be independently affected in PD. We therefore re-analyzed our cohort using the surface-based method FreeSurfer, and investigated (i) CTh, SA, and (sub)cortical GM volume differences between 93 PD patients and 45 matched controls, and (ii) the relation between these structural measures and cognitive performance on six neuropsychological tasks within the PD group. We found cortical thinning in PD patients in the left pericalcarine gyrus, extending to cuneus, precuneus and lingual areas and left inferior parietal cortex, bilateral rostral middle frontal cortex, and right cuneus, and increased cortical surface area in the left pars triangularis. Within the PD group, we found negative correlations between (i) CTh of occipital areas and performance on a verbal memory task, (ii) SA and volume of the frontal cortex and visuospatial memory performance, and, (iii) volume of the right thalamus and scores on two verbal fluency tasks. Our primary findings illustrate that i) CTh and SA are differentially affected in PD, and ii) VBM and FreeSurfer yield non-overlapping results in an identical dataset. We argue that this discrepancy is due to technical differences and the subtlety of the PD-related structural changes.
PMCID: PMC4768880  PMID: 26919667
Neuro-Oncology  2014;16(Suppl 5):v144-v145.
BACKGROUND: Cognition is often affected in patients with brain tumors. Apart from language function, direct tumor effects on discrete cognitive functions have barely been studied. In this study, we quantify baseline cognitive functioning in seven cognitive domains and identify brain locations involved in these cognitive domains using tumor localization maps (TLMs), which is a new approach. METHODS: Adult patients with glioma treated at the VU University Medical Center between 2006-2011 with available preoperative neuropsychological assessment were included. Cognition was tested for verbal, visuospatial and working memory, attention, executive functioning, information processing speed, and visuoconstructive abilities. Cognitive performance was compared to matched healthy controls. Tumor volumes for TLMs were segmented on MRI fluid attenuated inversion recovery (FLAIR) hyperintense signal abnormality for low-grade gliomas, and MRI T1 contrast-enhanced abnormality for high-grade gliomas. For each cognitive domain, we applied TLMs to link cognitive performance with location throughout the brain at 1 mm resolution. Considerations for spatial dependence and multiple comparisons were taken into account. PRELIMINARY RESULTS: Seventy-four patients (50 with low-grade glioma, 22 with high-grade glioma and 2 with other histology) were included so far. Mean age of patients was 40 years. Compared to healthy controls, preoperative cognitive functioning was significantly impaired in five of seven domains. Most frequently affected were attention and working memory (30% and 21% of patients, respectively). We found no differences in cognitive domain scores between patients with low-grade and high-grade glioma. Tumor localization maps are currently being processed and statistically compared voxel-wise for each of the seven cognitive domains. Preliminary results of the TLMs demonstrate that performance in specific cognitive domains is associated with specific brain tumor locations. CONCLUSION: Empirical evidence on location of cognition can be used for optimizing brain tumor surgery and be integrated in counseling and cognitive rehabilitation for patients with newly-diagnosed glioma.
PMCID: PMC4218355
Neuro-Oncology  2014;16(Suppl 5):v145.
INTRODUCTION: Cognition is at risk in patients with brain tumors. Cognitive alterations, improvement or decline, may result from brain tumor surgery, as well as from other factors such as direct tumor effects, radiotherapy, chemotherapy, anti-epileptic drugs, and steroids. In this study, cognitive alterations after brain tumor surgery are quantified and correlated with brain location using resection probability maps, which is a new approach. METHODS: Adult patients were included, who had (1) a brain tumor, (2) resective surgery between 2006 and 2011, (3) baseline and postoperative (9-12 months) neuropsychological assessment in seven cognitive domains, and (4) pre- and postoperative MRI available. Resective surgery was performed with intraoperative stimulation mapping until functional boundaries were met. Resection probability maps quantify the likelihood of resection throughout the brain in 3D at 1 mm resolution in standard brain space. We compared resection probability maps of patients with and without cognitive alterations. Considerations for spatial dependence and multiple comparisons were taken into account. PRELIMINARY RESULTS: Seventy-four patients were so far included. The cognitive domains with most frequent and most extensive alterations after surgery were attentional function and working memory capacity. Results on the correlation between these cognitive changes and brain location are pending, but will be available in October 2014. CONCLUSION: Brain locations involved in cognitive improvement as well as decline in relation to resective surgery can be identified using resection probability maps. Brain tumors which are located in regions to be identified are associated with alterations in attention and verbal working memory.
PMCID: PMC4218359
6.  Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patients with rheumatoid arthritis 
Calprotectin, a heterodimeric complex of S100A8/9 (MRP8/14), has been proposed as an important serum biomarker that reflects disease activity and structural joint damage in rheumatoid arthritis (RA). The objective of this cross-sectional study was to test the hypothesis that calprotectin is associated with clinical and ultrasound-determined disease activity in patients with RA.
A total of 37 patients with RA (including 24 females, a mean disease duration of 20 months) underwent a clinical examination and 7-joint ultrasound score (German US-7) of the clinically dominant hand and foot to assess synovitis by grey-scale (GS) and synovial vascularity by power Doppler (PD) ultrasound using semiquantitative 0–3 grading. The levels of serum calprotectin and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at the time of the ultrasound assessment. We analysed the relationship between serum calprotectin level, traditional inflammatory markers, and ultrasound-determined synovitis.
The levels of serum calprotectin were significantly correlated with swollen joint count (r = 0.465, p < 0.005), DAS28-ESR (r = 0.430, p < 0.01), ESR (r = 0.370, p < 0.05) and, in particular, CRP (r = 0.629, p < 0.001). Calprotectin was significantly associated with GS (r = 0.359, p < 0.05) and PD synovitis scores (r = 0.497, p < 0.005). Using multivariate regression analysis, calprotectin, adjusted for age and sex, was a better predictor of PD synovitis score (R2 = 0.765, p < 0.001) than CRP (R2 = 0.496, p < 0.001).
The serum levels of calprotectin are significantly associated with clinical, laboratory and ultrasound assessments of RA disease activity. These results suggest that calprotectin might be superior to CRP for monitoring ultrasound-determined synovial inflammation in RA patients.
PMCID: PMC4572609  PMID: 26373925
7.  Epiploic appendagitis with acute appendicitis 
BMJ Case Reports  2013;2013:bcr2013010333.
A 28-year-old woman presented to accident and emergency department with a 1-day history of right-sided abdominal pain. She was afebrile, and haemodynamically stable, and the initial diagnosis was acute appendicitis. A transvaginal ultrasound scan was performed and was suggestive of appendicitis. The patient failed to improve with conservative management, and a laparosocopic appendicectomy was performed the next day to remove an inflamed, non-perforated appendix. Pelvic laparoscopy was performed, which noted normal ovaries and uterus, as well as a hard, swollen, discoloured epiploic appendage of the sigmoid colon. A decision was made not to remove the inflamed epiploic appendage. Postoperatively the patient complained of persisting pain, which settled over 2 days with analgesia and antibiotics. This case is an extremely unusual case of epiploic appendagitis and acute appendicitis. It demonstrates the importance of pelvic laparoscopy in all females with presumed appendicitis, even in the presence of an initial pathology.
PMCID: PMC3736512  PMID: 23897384
8.  Psychiatric symptoms in glioma patients: from diagnosis to management 
Patients with primary intrinsic brain tumors can experience neurological, cognitive, and psychiatric symptoms that greatly affect daily life. In this review, we focus on changes in personality and behavior, mood issues, hallucinations, and psychosis, because these are either difficult to recognize, to treat, or are understudied in scientific literature. Neurobehavioral symptoms are common, often multiple, and causation can be multifactorial. Although different symptoms sometimes require a different treatment approach, we advise a comprehensive treatment approach, including pharmacological treatment and/or psychotherapy where appropriate. Further research is needed to obtain a better estimate of the prevalence of psychiatric symptoms in glioma patients, and the extent to which these affect everyday functioning and family life.
PMCID: PMC4467748  PMID: 26089669
glioma; psychiatry; personality; mood; hallucinations; psychosis
9.  The association between cognitive functioning and health-related quality of life in low-grade glioma patients 
Neuro-Oncology Practice  2014;1(2):40-46.
Glioma patients are not only confronted with the diagnosis and treatment of a brain tumor, but also with changes in cognitive and neurological functioning that can profoundly affect their daily lives. At present, little is known about the relationship between cognitive functioning and health-related quality of life (HRQOL) during the disease trajectory. We studied this association in low-grade glioma (LGG) patients with stable disease at an average of 6 years after diagnosis.
Patients and healthy controls underwent neuropsychological testing and completed self-report measures of generic (MOS SF36) and disease-specific (EORTC BN20) HRQOL. Associations were determined with Pearson correlations, and corrections for multiple testing were made.
We analyzed data gathered from 190 LGG patients. Performance in all cognitive domains was positively associated with physical health (SF36 Physical Component Summary). Executive functioning, processing speed, working memory, and information processing were positively associated with mental health (SF36 Mental Component Summary). We found negative associations between a wide range of cognitive domains and disease-specific HRQOL scales.
In stable LGG patients, poorer cognitive functioning is related to lower generic and disease-specific HRQOL. This confirms that cognitive assessment of LGG patients should not be done in isolation from assessment of its impact on HRQOL, both in clinical and in research settings.
PMCID: PMC4371165  PMID: 26034615
brain tumor; cognitive functioning; health-related quality of life; low-grade glioma
10.  Alleviation of Brain Edema and Restoration of Functional Independence by Bevacizumab in Brain-Metastatic Breast Cancer: A Case Report 
Breast Care  2014;9(2):134-136.
Brain metastases (BM) are an increasing challenge in modern oncology, as treatment options especially after exhaustion of local treatment approaches are very limited.
Patient and Methods
A long-term surviving patient with brain-only metastatic breast cancer, who presented at our department with massive corticosteroid-refractory brain edema with serious neurological symptoms after exhaustion of all local therapy options, was started on bevacizumab.
Initiation of bevacizumab monotherapy led to rapid decrease of contrast-enhancing lesions and alleviation of brain edema, and allowed tapering and termination of corticosteroid administration. Neurological and neurocognitive function was restored and marked improvement in quality of life was observed.
Our case highlights that bevacizumab may represent a feasible and effective salvage treatment option in selected patients with BM.
PMCID: PMC4038309  PMID: 24944558
Breast cancer; Brain metastases; Neurocognitive functioning; Bevacizumab; Symptom control; Brain edema
11.  Severe necrotic oesophageal and gastric ulceration associated with dabigatran 
BMJ Case Reports  2013;2013:bcr2013009139.
A 69-year-old Caucasian man, who had been discharged 2 days previously, 5 days post-elective right total hip replacement, was re-admitted with a 16 h history of coffee-ground vomiting and epigastric pain. He had been discharged with 220 mg dabigatran, a novel oral anticoagulant. The coffee-ground vomiting started within minutes of taking the first dose. Haemodynamic compromise, agitation, decreasing conscious level and aspiration pneumonia necessitated intubation, ventilation and inotropic support in the intensive care unit. A CT on admission showed extensive intramural air seen within the lower oesophagus and a dilated stomach, duodenum and jejunum. Endoscopy of the upper gastrointestinal tract showed extensive ulceration, sloughing and multiple areas of necrosis in the distal oesophagus and stomach. The patient made a fully recovery with supportive management.
PMCID: PMC3645015  PMID: 23608859
12.  Basosquamous Carcinoma of the Head and Neck: Clinical and Histologic Characteristics and Their Impact on Disease Progression123 
Neoplasia (New York, N.Y.)  2015;17(3):301-305.
OBJECTIVES: Basosquamous carcinoma (BSC) is a rare tumor entity, and the most common onset is in the head and neck region (BSC-HN). The data on diagnosis, treatment, and especially risk assessment concerning disease course and outcome are deficient or inconsistent. This study aimed to evaluate risk factors for local relapse (LR) and lymph node metastasis (LNM) and their impact on progression-free survival (PFS). MATERIALS AND METHODS: In a retrospective monocentric study, patients with BSC-HN treated between 1999 and 2011 were analyzed regarding clinical and histologic characteristics. Prognostic parameters for LR, LNM, and PFS were evaluated. In total, 89 patients (55 male, 34 female, mean age of 71.8 years) with a mean follow-up time of 47.7 months (range 12-112) were included. RESULTS: LR occurred in four patients (4.5%), LNM occurred in five patients (5.6%). Patients with LNM had a significantly shorter PFS time (16.1 months) compared with patients without LNM (154.2 months; P < .001). Tumor depth and size (T classification), incomplete resection, localization at the ear, deep maximal vertical infiltration, muscle and vessel invasion all showed significant (P < .05) associations with LR, LNM, and shorter PFS time. BSC showed more histologic features of basal cell carcinoma (BCC), especially with regard to BerEP4 expression. CONCLUSION: While histology shows some typical characteristics of BCC, the biologic behavior and aggressiveness of BSC are similar to those of cutaneous squamous cell carcinoma. This is the first study to show that LR and, especially, LNM indicate a higher risk of an unfavorable outcome.
PMCID: PMC4372646  PMID: 25810014
13.  Scholarly Context Not Found: One in Five Articles Suffers from Reference Rot 
PLoS ONE  2014;9(12):e115253.
The emergence of the web has fundamentally affected most aspects of information communication, including scholarly communication. The immediacy that characterizes publishing information to the web, as well as accessing it, allows for a dramatic increase in the speed of dissemination of scholarly knowledge. But, the transition from a paper-based to a web-based scholarly communication system also poses challenges. In this paper, we focus on reference rot, the combination of link rot and content drift to which references to web resources included in Science, Technology, and Medicine (STM) articles are subject. We investigate the extent to which reference rot impacts the ability to revisit the web context that surrounds STM articles some time after their publication. We do so on the basis of a vast collection of articles from three corpora that span publication years 1997 to 2012. For over one million references to web resources extracted from over 3.5 million articles, we determine whether the HTTP URI is still responsive on the live web and whether web archives contain an archived snapshot representative of the state the referenced resource had at the time it was referenced. We observe that the fraction of articles containing references to web resources is growing steadily over time. We find one out of five STM articles suffering from reference rot, meaning it is impossible to revisit the web context that surrounds them some time after their publication. When only considering STM articles that contain references to web resources, this fraction increases to seven out of ten. We suggest that, in order to safeguard the long-term integrity of the web-based scholarly record, robust solutions to combat the reference rot problem are required. In conclusion, we provide a brief insight into the directions that are explored with this regard in the context of the Hiberlink project.
PMCID: PMC4277367  PMID: 25541969
14.  The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial 
Neuro-Oncology  2013;15(10):1420-1428.
Fatigue, cognitive deficits, and depression are frequently reported but often undertreated symptoms that can profoundly affect daily life in patients with primary brain tumors (PBTs). To evaluate the effects of the psychostimulant modafinil on fatigue, depression, health-related quality of life (HRQOL), and cognitive functioning in PBT patients, we performed a multicenter, double-blind placebo-controlled crossover trial.
Patients randomly received either 6 weeks of treatment with modafinil (up to 400 mg/day) or 6 weeks with placebo. After a 1-week washout period, the opposite treatment was provided. Assessments took place at baseline and immediately after the first and second condition. Patients completed self-report questionnaires on fatigue (Checklist Individual Strength [CIS]), depression (Center for Epidemiologic Studies Depression Scale [CES-D]), HRQOL (Short-Form Health Survey [SF-36]), and self-perceived cognitive functioning (Medical Outcomes Study [MOS]). They also underwent comprehensive neurocognitive testing.
In total, 37 patients participated. Relative to baseline, patients reported lower fatigue severity (CIS) and better motivation (CIS) in both the modafinil (P = .010 and P = .021, respectively) and the placebo condition (P < .001 and P = .027, respectively). The same held for physical health (SF-36 Physical Component Summary score; P = .001 and P = .008, respectively), working memory (P = .040 and P = .043), and information processing capacity (P = .036 and P = .040). No improvement in depressive symptoms was found in either condition.
Modafinil did not exceed the effects of placebo with respect to symptom management. Patient accrual was slow, and relatively many patients dropped out during the trial, due mostly to side effects. Other, preferably nonpharmacologic intervention studies should be considered to improve symptom management of PBT patients.
PMCID: PMC3779045  PMID: 23925452
brain tumor; cognitive functioning; fatigue; HRQOL; modafinil; mood
15.  Phenotypic Characterization of 3 Families With Autosomal Dominant Retinitis Pigmentosa Due to Mutations in KLHL7 
Archives of ophthalmology  2011;129(11):1475-1482.
To characterize the visual phenotype caused by mutations in the BTB-Kelch protein, KLHL7, responsible for the RP42 form of autosomal dominant retinitis pigmentosa (RP).
Comprehensive ophthalmic testing included visual acuity, static visual field, kinetic visual field, dark adaptometry, full-field electroretinography, spectral-domain optical coherence tomography, and fundus photography. Longitudinal visual function data (range, 15–27 years) were available for some of the affected individuals.
We report a phenotypic assessment of 3 unrelated families, each harboring different KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). The fundi showed classic signs of RP. Best-corrected visual acuity was 20/50 or better in at least one eye up to age 65 years Static and kinetic visual fields showed concentric constriction to central 10° to 20° by age 65 years; 2 patients with Goldmann perimetry exhibited bilateral visual field retention in the far periphery. Both rod and cone full-field electroretinographic amplitudes were substantially lower than normal, with a decline rate of 3% per year in cone 31-Hz flicker response. Rod and cone activation and inactivation variables were abnormal. Spectral-domain optical coherence tomography indicated retention of foveal inner segment-outer segment junction through age 65 years.
Mutations in KLHL7 are associated with a late-onset form of autosomal dominant retinal degeneration that preferentially affects the rod photoreceptors. Full-field electroretinographic findings, including recovery kinetics, are consistent with those observed in other forms of autosomal dominant RP.
Clinical Relevance
The phenotypes are similar among patients with 3 types of KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). Strong retention of foveal function and bilateral concentric constriction of visual fields with far periphery sparing may guide mutation screening in autosomal dominant RP.
PMCID: PMC4106140  PMID: 22084217
16.  Changes in MEG resting-state networks are related to cognitive decline in type 1 diabetes mellitus patients 
NeuroImage : Clinical  2014;5:69-76.
Integrity of resting-state functional brain networks (RSNs) is important for proper cognitive functioning. In type 1 diabetes mellitus (T1DM) cognitive decrements are commonly observed, possibly due to alterations in RSNs, which may vary according to microvascular complication status. Thus, we tested the hypothesis that functional connectivity in RSNs differs according to clinical status and correlates with cognition in T1DM patients, using an unbiased approach with high spatio-temporal resolution functional network.
Resting-state magnetoencephalographic (MEG) data for T1DM patients with (n = 42) and without (n = 41) microvascular complications and 33 healthy participants were recorded. MEG time-series at source level were reconstructed using a recently developed atlas-based beamformer. Functional connectivity within classical frequency bands, estimated by the phase lag index (PLI), was calculated within eight commonly found RSNs. Neuropsychological tests were used to assess cognitive performance, and the relation with RSNs was evaluated.
Significant differences in terms of RSN functional connectivity between the three groups were observed in the lower alpha band, in the default-mode (DMN), executive control (ECN) and sensorimotor (SMN) RSNs. T1DM patients with microvascular complications showed the weakest functional connectivity in these networks relative to the other groups. For DMN, functional connectivity was higher in patients without microangiopathy relative to controls (all p < 0.05). General cognitive performance for both patient groups was worse compared with healthy controls. Lower DMN alpha band functional connectivity correlated with poorer general cognitive ability in patients with microvascular complications.
Altered RSN functional connectivity was found in T1DM patients depending on clinical status. Lower DMN functional connectivity was related to poorer cognitive functioning. These results indicate that functional connectivity may play a key role in T1DM-related cognitive dysfunction.
•MEG RSN functional connectivity was estimated among T1DM+ and T1DM− patients and controls.•Lower alpha band in DMN, ECN and SMN significantly differed among groups.•Functional connectivity may play a key role in T1DM-related cognitive dysfunction.
PMCID: PMC4081980  PMID: 25003029
Resting-state networks; Magnetoencephalography; Functional connectivity; Phase Lag Index (PLI); Oscillations; Type 1 diabetes mellitus
17.  Internet-based guided self-help for glioma patients with depressive symptoms: design of a randomized controlled trial 
BMC Neurology  2014;14:81.
Among glioma patients, depression is estimated to be more prevalent than in both the general population and the cancer patient population. This can have negative consequences for both patients and their primary informal caregivers (e.g., a spouse, family member or close friend). At present, there is no evidence from randomized controlled trials for the effectiveness of psychological treatment for depression in glioma patients. Furthermore, the possibility of delivering mental health care through the internet has not yet been explored in this population. Therefore, a randomized controlled trial is warranted to evaluate the effects of an internet-based, guided self-help intervention for depressive symptoms in glioma patients.
The intervention is based on problem-solving therapy. An existing 5-week course is adapted for use by adult glioma patients with mild to moderate depressive symptoms (Center for Epidemiology Studies Depression Scale score ≥12). Sample size calculations yield 126 glioma patients to be included, who are randomly assigned to either the intervention group or a waiting list control group. In addition, we aim to include 63 patients with haematological cancer in a non-central nervous system malignancy control group. Assessments take place at baseline, after 6 and 12 weeks, and after 6 and 12 months. Primary outcome measure is the change in depressive symptoms. Secondary outcome measures include health-related quality of life, fatigue, costs and patient satisfaction. In addition, all patients are asked to assign a primary informal caregiver, who does not participate in the intervention but who is asked to complete similar assessments. Their mood, health-related quality of life and fatigue is evaluated as well.
This is the first study to evaluate the effects of problem-solving therapy delivered through the internet as treatment for depressive symptoms in glioma patients. If proven effective, this treatment will contribute to the mental health care of glioma patients in clinical practice.
Trial registration
Netherlands Trial Register NTR3223
PMCID: PMC3989775  PMID: 24721108
Glioma; Brain tumor; Depression; Quality of life; Internet-based treatment; Informal caregiver
18.  Differential impact of subclinical carotid artery disease on cerebral structure and functioning in type 1 diabetes patients with versus those without proliferative retinopathy 
Type 1 diabetes mellitus (T1DM) is associated with cerebral compromise, typically found in patients with microangiopathy. Associations between subclinical macroangiopathy and the brain, whether or not in the presence of microangiopathy, have not been fully explored in T1DM. We hypothesized that subclinical macroangiopathy in adult T1DM may affect the brain and interacts with microangiopathy.
In 51 asymptomatic T1DM patients with, 53 without proliferative retinopathy and 51 controls, right common carotid artery ultrasound was used to assess intima media thickness (cIMT) and distensibility (cD). Neuropsychological tests for cognitive functions, and magnetic resonance imagining for white matter integrity and functional connectivity, i.e. neuronal communication, were used.
After correction for confounders, cIMT was borderline significantly increased in all T1DM patients (P = 0.071), whereas cD was not statistically significantly altered (P = 0.45). Patients with proliferative retinopathy showed the largest increase in cIMT and decrease in cD. In all participants, after adjustment for confounders, increased cIMT was related to decreased white matter integrity (β = −0.198 P = 0.041) and decreased functional connectivity in visual areas (β = −0.195 P = 0.046). For cognition, there was a significant interaction between cIMT and the presence of proliferative retinopathy after adjustment for confounding factors (all P < 0.05). Increased cIMT was associated with lower general cognitive ability (β = −0.334; P = 0.018), information processing speed (β = −0.361; P = 0.010) and attention (β = −0.394; P = 0.005) scores in patients without, but not in patients with proliferative retinopathy.
These findings suggest that subclinical macroangiopathy may be a factor in the development of diabetes-related cognitive changes in uncomplicated T1DM, whereas in patients with advanced T1DM, proliferative retinopathy may rather be the driving force of cerebral compromise.
PMCID: PMC3995631  PMID: 24620788
Type 1 diabetes; Cognition; Subclinical macroangiopathy; Microangiopathy; Neuroimaging; Cognition
19.  Levetiracetam improves verbal memory in high-grade glioma patients 
Neuro-Oncology  2012;15(2):216-223.
Treatment of high-grade glioma (HGG) patients with anti-epileptic drugs (AEDs) has met with various side effects, such as cognitive deterioration. The cognitive effects of both older and newer AEDs in HGG patients are largely unknown. The aim of this study was to determine the effect of older and newer AEDs on cognitive performance in postoperative HGG patients.
We selected HGG patients from 3 separate cohorts for use of older, newer, or no AEDs, as they represented distinct treatment eras and provided the opportunity to compare older and newer AEDs. In all 3 cohorts, patients were included within 6 weeks following neurosurgery before the start of postoperative treatment. Cognitive functioning was evaluated by an extensive neuropsychological assessment, executed in 6 cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed).
One hundred seventeen patients met the inclusion criteria; 44 patients used no AED, 35 were on monotherapy with a newer AED (all levetiracetam), and 38 were on monotherapy with an older AED (valproic acid or phenytoin). Patients on older and newer AEDs performed equally well as patients not on an AED, and patients on levetiracetam performed even better on verbal memory tests than patients not on an AED. Post-hoc analyses revealed that within the group using older AEDs, patients on valproic acid performed better than patients on phenytoin.
Neither levetiracetam nor valproic acid was associated with additional cognitive deficits in HGG patients. Both AEDs even appeared to have a beneficial effect on verbal memory in these patients.
PMCID: PMC3548582  PMID: 23233537
high-grade glioma; cognitive functioning; anti-epileptic drugs; epilepsy; primary brain tumor
20.  Ultracold neutron detectors based on 10B converters used in the qBounce experiments☆ 
Gravity experiments with very slow, so-called ultracold neutrons connect quantum mechanics with tests of Newton's inverse square law at short distances. These experiments face a low count rate and hence need highly optimized detector concepts. In the frame of this paper, we present low-background ultracold neutron counters and track detectors with micron resolution based on a 10B converter. We discuss the optimization of 10B converter layers, detector design and concepts for read-out electronics focusing on high-efficiency and low-background. We describe modifications of the counters that allow one to detect ultracold neutrons selectively on their spin-orientation. This is required for searches of hypothetical forces with spin–mass couplings.
The mentioned experiments utilize a beam-monitoring concept which accounts for variations in the neutron flux that are typical for nuclear research facilities. The converter can also be used for detectors, which feature high efficiencies paired with high spatial resolution of 1–2μm. They allow one to resolve the quantum mechanical wave function of an ultracold neutron bound in the gravity potential above a neutron mirror.
PMCID: PMC4375608  PMID: 25843998
qBounce; Ultracold neutron detector; 10-B converter; Micron-resolution track detector; Low-background UCN counter
21.  Neurocognitive functioning in adult WHO grade II gliomas: impact of old and new treatment modalities 
Neuro-Oncology  2012;14(Suppl 4):iv17-iv24.
In the treatment of patients with low-grade glioma, there still is controversy on how surgical intervention, radiation therapy, and chemotherapy contribute to an ameliorated progression-free survival, overall survival, and treatment-related neurotoxicity. With the ongoing changes in treatment options for these patients, neurocognitive functioning is an increasingly important outcome measure, because neurocognitive impairments can have a large impact on self-care, social and professional functioning, and consequently, health-related quality of life. Many factors contribute to neurocognitive outcome, such as direct and indirect tumor effects, seizures, medication, and oncological treatment. Although the role of radiotherapy has been studied extensively, the adverse effects on neurocognitive function of other treatment-related factors remain elusive. This holds for both resective surgery, in which the use of intraoperative stimulation mapping has a high potential benefit concerning survival and patient functioning, and the use of chemotherapy that might have some interesting new applications, such as the facilitation of total resection for initially primary or recurrent diffuse low-grade glioma tumors. This article will discuss these treatment options in patients with low-grade glioma and their potential effects on neurocognitive functioning.
PMCID: PMC3480241  PMID: 23095826
chemotherapy, cognition; low-grade gliomas; radiotherapy; surgery
22.  Resting-State Brain Networks in Type 1 Diabetic Patients With and Without Microangiopathy and Their Relation to Cognitive Functions and Disease Variables 
Diabetes  2012;61(7):1814-1821.
Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA+: n = 49) and without (MA−: n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA− patients showed increased connectivity in networks involved in motor and visual processes, whereas MA+ patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy.
PMCID: PMC3379683  PMID: 22438575
23.  MEG Network Differences between Low- and High-Grade Glioma Related to Epilepsy and Cognition 
PLoS ONE  2012;7(11):e50122.
To reveal possible differences in whole brain topology of epileptic glioma patients, being low-grade glioma (LGG) and high-grade glioma (HGG) patients. We studied functional networks in these patients and compared them to those in epilepsy patients with non-glial lesions (NGL) and healthy controls. Finally, we related network characteristics to seizure frequency and cognitive performance within patient groups.
We constructed functional networks from pre-surgical resting-state magnetoencephalography (MEG) recordings of 13 LGG patients, 12 HGG patients, 10 NGL patients, and 36 healthy controls. Normalized clustering coefficient and average shortest path length as well as modular structure and network synchronizability were computed for each group. Cognitive performance was assessed in a subset of 11 LGG and 10 HGG patients.
LGG patients showed decreased network synchronizability and decreased global integration compared to healthy controls in the theta frequency range (4–8 Hz), similar to NGL patients. HGG patients’ networks did not significantly differ from those in controls. Network characteristics correlated with clinical presentation regarding seizure frequency in LGG patients, and with poorer cognitive performance in both LGG and HGG glioma patients.
Lesion histology partly determines differences in functional networks in glioma patients suffering from epilepsy. We suggest that differences between LGG and HGG patients’ networks are explained by differences in plasticity, guided by the particular lesional growth pattern. Interestingly, decreased synchronizability and decreased global integration in the theta band seem to make LGG and NGL patients more prone to the occurrence of seizures and cognitive decline.
PMCID: PMC3498183  PMID: 23166829
24.  Relationships among Multifocal Electroretinogram Amplitude, Visual Field Sensitivity, and SD-OCT Receptor Layer Thicknesses in Patients with Retinitis Pigmentosa 
In patients with retinitis pigmentosa, preserved cone photoreceptor function measured by multifocal electroretinogram amplitude and visual field sensitivity correlate well with the remaining thickness of the photoreceptor layer.
To compare local functional measures, the multifocal electroretinogram (mfERG) and visual field sensitivity, with a local structural measure, spectral domain (SD) optical coherence tomography (OCT), of receptor damage in patients with retinitis pigmentosa (RP).
MfERGs, visual fields, and SD-OCT scans were obtained from 10 patients with RP, ranging in age from 23 to 59 years. Average amplitudes, average linear sensitivities, and average layer thicknesses were measured from within the central 3° and from three concentric annuli located between 3° and 8°, 8° and 15°, and 15° and 24°. A computer program aided manual segmentation and calculated OCT thickness in the scans.
Within each patient with RP, mfERG amplitude for each circle/annulus was highly correlated with corresponding layer thicknesses in the outer retina (r = 0.88 to 0.99), but not at all correlated with thickness of the inner nuclear layer or total retina. Across all ring eccentricities, relative mfERG amplitude and relative visual field sensitivity were correlated with relative SD-OCT outer retinal thickness.
In patients with RP, preserved cone photoreceptor function measured by mfERG amplitude and visual field sensitivity correlate well with the remaining thickness of the photoreceptor layer. All three measures show comparable relative loss beyond 3° eccentricity. In the fovea, SD-OCT outer retina thickness showed less relative loss than either mfERG or visual field sensitivity.
PMCID: PMC3317422  PMID: 22247460
25.  Resistin in idiopathic inflammatory myopathies 
Arthritis Research & Therapy  2012;14(3):R111.
The purpose of this study was to evaluate and compare the serum levels and local expression of resistin in patients with idiopathic inflammatory myopathies to controls, and to determine the relationship between resistin levels, inflammation and disease activity.
Serum resistin levels were determined in 42 patients with inflammatory myopathies and 27 healthy controls. The association among resistin levels, inflammation, global disease activity and muscle strength was examined. The expression of resistin in muscle tissues from patients with inflammatory myopathies and healthy controls was evaluated. Gene expression and protein release from resistin-stimulated muscle and mononuclear cells were assessed.
In patients with inflammatory myopathies, the serum levels of resistin were significantly higher than those observed in controls (8.53 ± 6.84 vs. 4.54 ± 1.08 ng/ml, P < 0.0001) and correlated with C-reactive protein (CRP) levels (r = 0.328, P = 0.044) and myositis disease activity assessment visual analogue scales (MYOACT) (r = 0.382, P = 0.026). Stronger association was observed between the levels of serum resistin and CRP levels (r = 0.717, P = 0.037) as well as MYOACT (r = 0.798, P = 0.007), and there was a trend towards correlation between serum resistin and myoglobin levels (r = 0.650, P = 0.067) in anti-Jo-1 positive patients. Furthermore, in patients with dermatomyositis, serum resistin levels significantly correlated with MYOACT (r = 0.667, P = 0.001), creatine kinase (r = 0.739, P = 0.001) and myoglobin levels (r = 0.791, P = 0.0003) and showed a trend towards correlation with CRP levels (r = 0.447, P = 0.067). Resistin expression in muscle tissue was significantly higher in patients with inflammatory myopathies compared to controls, and resistin induced the expression of interleukins (IL)-1β and IL-6 and monocyte chemoattractant protein (MCP)-1 in mononuclear cells but not in myocytes.
The results of this study indicate that higher levels of serum resistin are associated with inflammation, higher global disease activity index and muscle injury in patients with myositis-specific anti-Jo-1 antibody and patients with dermatomyositis. Furthermore, up-regulation of resistin in muscle tissue and resistin-induced synthesis of pro-inflammatory cytokines in mononuclear cells suggest a potential role for resistin in the pathogenesis of inflammatory myopathies.
PMCID: PMC3446487  PMID: 22577940

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