Deoxynivalenol triggers the expression of IL-8-related signaling cascades and decreases protein biosynthesis in primary monocyte-derived cells.

Humans and their immune system are confronted with mold-contaminated food and/or mold-contaminated air in daily life and indoor activities. This results in metabolic stress and unspecific disease symptoms. Other studies provided evidence that exposure to mold is associated with the etiology of allergies. Deoxynivalenol (DON) is of great concern due to its frequent occurrence in toxically relevant concentrations. The exposure to this toxin is a permanent health risk for both humans and farm animals because DON cannot be significantly removed during standard milling and processing procedures. However, the direct effect on immunity or hematology is poorly defined because most investigations could not separate the effect of DON-contaminated feed intake. Due to the widespread distribution of DON after rapid absorption, it is not surprising that DON is known to affect the immune system. The immune system of the organism has one important function, to defend against the invasion of unknown substances/organisms. This study shows for the first time a synergistic effect of both-low physiological DON-doses in combination with low LPS-doses with the focus on the IL-8 expression on protein and RNA level. Both doses were found in vivo. IL-8 together with other anorectic cytokines like IL-1ß can affect the food intake and anorexia. We could also show that a calcium-response is not involved in the increased IL-8 production after acute DON stimulation with high or low concentrations.

The study of the pseudo-polyrotaxane architecture as a route for mild surface functionalization by click chemistry of poly(ε-caprolactone)-based electrospun fibers.

Polycaprolactone (PCL) electrospun fibers are widely developed for biomedical applications. However, their hydrophobicity and passivity towards cell growth is an important limitation. An original method to functionalize PCL nanofibers, making them reactive for bioconjugation of proteins or other molecules of interest in water under mild conditions, is reported here. This method involves the preparation of pseudo-polyrotaxanes (pPRs) of cyclodextrin (CD) and PCL. Core:shell PCL:pPR fibers were then prepared by coaxial electrospinning in order to bring available reactive hydroxyl groups from the CD to the fiber surface. Different pPR architectures (star, miktoarm and block-copolymer-like) were synthesized to study the effect of the pPR structure on fiber morphology and surface reactivity by grafting fluorescein isothiocyanate (FITC). Finally, bicyclononyne groups were grafted onto the star-pPR based fibers allowing the conjugation of a fluorescent dye by click chemistry in water without any copper catalyst proving the potential of the method for the biofunctionalization of PCL-based fibers.

Methylating micronutrient supplementation during pregnancy influences foetal hepatic gene expression and IGF signalling and increases foetal weight.

PURPOSE: Maternal diet during pregnancy impacts foetal growth and development. In particular, dietary levels of methylating micronutrients (methionine, folate, choline, vitamins B6, and B12) interfere with the availability and allocation of methyl groups for methylation reactions, thereby influencing normal transcription. However, the currently recommended methylating micronutrient supplementation regimen is haphazard and arbitrary at best. METHODS: To investigate the effects of a methylating micronutrient-rich maternal diet, pregnant Pietrain sows were fed either a standard diet (CON) or a diet supplemented with methionine, folate, choline, B6, B12, and zinc (MET). Foetal liver and muscle (M. longissimus dorsi) tissues were collected at 35, 63, and 91 days post-conception. Transcriptional responses to diet were assessed in foetal liver. Altered insulin-like growth factor (IGF) signalling in transcriptome analyses prompted investigation of IGF-2 and insulin-like growth factor binding proteins (IGFBPs) levels in muscle and liver. RESULTS: Maternal diet enriched with methylating micronutrients was associated with increased foetal weight in late gestation. Hepatic transcriptional patterns also revealed differences in vitamin B6 and folate metabolism between the two diets, suggesting that supplementation was effective. Additionally, shifts in growth-supporting metabolic routes of the lipid and energy metabolism, including IGF signalling, and of cell cycle-related pathways were found to occur in liver tissue in supplemented individuals. Weight differences and modulated IGF pathways were also reflected in the muscle content of IGF-2 (increased in MET) and IGFBP-2 (decreased in MET). CONCLUSIONS: Maternal dietary challenges provoke stage-dependent and tissue-specific transcriptomic modulations in the liver pointing to molecular routes contributing to the organismal adaptation. Subtle effects on late foetal growth are associated with changes in the IGF signalling mainly in skeletal muscle tissue that is less resilient to dietary stimuli than liver.

Pregnancy affects morphology of induced endometriotic lesions in a mouse model through alteration of proliferation and angiogenesis.

OBJECTIVE: Pregnancy is known to alleviate the symptoms of endometriosis and is also known to be a pro-angiogenic condition affecting blood and lymphatic vessels. However, angiogenesis actively participates in the development of endometriosis. The objective of our study was to study the impact of pregnancy on endometriotic tissue. Study design We performed a cross-sectional, control versus treatment study in a mouse model of endometriosis. Thirty-one female C57Bl6 mice were mated and became pregnant and 31 females were not mated and served as control. Intraperitoneal endometriotic lesions were surgically induced in C57Bl6 mice which were subsequently mated or not (group P: pregnant, group NP: non-pregnant). P and NP mice were sacrificed on day E15.5 of the pregnancy of P mice and lesions were harvested. Lesions were weighed and analyzed by histology, immunohistology, flow cytometry and real-time quantitative RT-PCR (qRT-PCR). RESULTS: Pregnancy reduced lesion weight, decreased the proportion of cystic component (0.02 vs. 0.4; p<0.001) and modified the architecture of peritoneal endometriotic lesions. Pregnancy also increased cell proliferation in both stromal and glandular tissue as shown by the increase in Ki 67-positive cells in the P group (glandular: 19 vs. 3.9%, p<0.001; stromal: 8.7 vs. 3.3%, p<0.01). Finally, pregnancy increased angiogenesis in endometriotic lesions as indicated by an increased microvessel density (CD-31 and LYVE-1 stainings: respectively 2.2 vs. 5.1%, p<0.01 and 0.4 vs. 0.9%, p<0.001), an increased number of LYVE1 positive cells evaluated by flow cytometry (18.9 vs. 4.6%, p<0.05) and a rise in VEGF-A, -R2 and -R3 RNA expression shown by qRT-PCR (p<0.001; p<0.01; p<0.05). CONCLUSION: These challenging results provide insight in understanding the pathophysiology of endometriosis and evoke a correlation between lesion architecture and symptomatology.

Hepatic expression patterns in psychosocially high-stressed pigs suggest mechanisms following allostatic principles.

Psychosocial challenges are known to introduce cellular and humoral adaptations in various tissues and organs, including parts of the sympatho-adrenal-medullary system and hypothalamic-pituitary-adrenal axis as well as other peripheral tissue being responsive to cortisol and catecholamines. The liver is of particular interest given its vital roles in maintaining homeostasis and health as well as regulating nutrient utilization and overall metabolism. We aimed to evaluate whether and how response to psychosocial stress is reflected by physiological molecular pathways in liver tissue. A pig mixing experiment was conducted to induce psychosocial stress culminating in skin lesions which reflect the involvement in aggressive behavior and fighting. At 27 weeks of age, animals prone to psychosocially low- and high-stress were assigned to mixing groups. Skin lesions were counted before mixing and after slaughter on the carcass. Individual liver samples (n=12) were taken. The isolated RNA was hybridized on Affymetrix GeneChip porcine Genome Arrays. Relative changes of mRNA abundances were estimated via variance analyses. Molecular routes related to tRNA charging, urea cycle, acute phase response, galactose utilization, and steroid receptor signaling were found to be increased in psychosocially high-stressed animals, whereas catecholamine degradation and cholesterol biosynthesis were found to be decreased. In particular, psychosocially high-stressed animals show decreased expression of catechol-O-methyltransferase (COMT) which has been linked to molecular mechanisms regulating aggressiveness and stress response. The expression patterns of high-stressed animals revealed metabolic alterations of key genes related to energy-mobilizing processes at the expense of energy consuming processes. Thus, the coping following psychosocial challenges involves transcriptional alterations in liver tissue which may be summarized with reference to the concept of allostasis, a strategy which is critical for survival.

High- and low-protein gestation diets do not provoke common transcriptional responses representing universal target-pathways in muscle and liver of porcine progeny.

AIM: Maternal diets introduce transcriptional changes in the offspring, highlighting the concept of genetic and physiological plasticity. Our previous analyses investigated stage-dependent transcriptional responses to either maternal high or low protein/carbohydrate ratios in either muscle or liver. Foetal programming is proposed to be mediated by a small number of gatekeeper processes, such as cytoskeleton remodelling and cell-cycle regulation. Here, we conducted an overall analysis of a three-dimensional data set aiming to elucidate, whether there are universally targeted pathways of adaptive transcriptional response to different protein/carbohydrate ratios. METHODS: Microarray analyses were performed on liver and skeletal muscle tissue sampled at 94 days post-conception and 1, 28 and 188 days post-natum from offspring (n = 253) of German Landrace gilts that were fed isoenergetic diets containing low, high or adequate protein. RESULTS: Cluster analyses revealed a hierarchical influence of tissue, ontogenetic stage and diet on transcript levels. Considering results cumulatively over stages, liver showed only marginal transcriptional differences between the dietary groups, whereas considerable differences appeared in muscle. Considering results cumulatively over tissues, nutrition-responsive transcriptions were observed along ontogenesis. Pathway analyses revealed transcript differences in genes related to tissue remodelling, cell-cycle regulation and mitochondrial function. CONCLUSION: The factors tissue, stage and diet impact gene expression in a hierarchical order. Porcine liver appeared to be a tissue that was more resilient to nutritional modulation compared with skeletal muscle tissue. Differential modulation between tissues and dietary groups reveal that there are no universal target-pathways of adaptive transcriptional response to different protein diets.

Thermal signature analysis as a novel method for evaluating inflammatory arthritis activity.

OBJECTIVE: To examine the potential usefulness of a novel thermal imaging technique to evaluate and monitor inflammatory arthritis activity in small joints using rat models, and to determine whether thermal changes can be used to detect preclinical stages of synovitis. METHODS: Three different rat strains were studied in a model of inflammatory arthritis of the ankle induced by an intra-articular (IA) injection of complete Freund's adjuvant (CFA), compared with the contralateral ankle injected with normal saline. Arthritis activity and severity scores, ankle diameters, pain related posture scores, and thermal images were obtained at 10 different times between 0 h (before induction) and day 7. The pristane induced arthritis (PIA) model was used to study preclinical synovitis. Thermal images were obtained at each time point using the TSA ImagIR system and were digitally analysed. RESULTS: Rats developed similar ankle arthritis detected six hours after the IA injection of CFA, which persisted for seven days. All ankle clinical indices, including arthritis activity and severity scores, correlated significantly with ankle thermal imaging changes in the monoarthritis model (p<0.003). No thermal imaging changes were detected in preclinical stages of PIA. However, PIA onset coincided with increased ankle thermal signature. CONCLUSIONS: Thermal measurements correlated significantly with arthritis activity and severity indices. The technique was highly sensitive and could measure directly two cardinal signs of inflammation (warmth and oedema, based on ankle diameter) in an area (ankle) that is less than half the size of a human interphalangeal joint, suggesting a potential use in drug trials or clinical practice.

[Cognitive functions and cerebral oxygenation of older patients after general and regional anaesthesia]. / Kognitive Funktion und zerebrale Oxygenierung älterer Patienten nach Allgemeinund Regionalanästhesie.

OBJECTIVE: The aim of the present study was to show the influence of cerebral oxygenation (regional cerebral oxygen saturation rSO(2) by near infrared spectroscopy) and of the nocturnal arterial oxygen saturation (SatO(2) by pulse oximetry) on the restitution of cognitive functions in patients aged between 40 and 85 years scheduled for elective hip arthroplasty. METHODS: A total of 40 patients (ASA II) were randomized to be operated either in general anaesthesia or regional anaesthesia. The patients were additionally classified by age (40-64 years and 65-85 years). Cognitive functions were tested 14-16 h pre-operatively (t0), 1.5 h post-operatively (t1) and at the first and third postoperative days (t2 and t3). During testing, as well as during surgery and postoperatively until t1, rSO(2) was continuously measured. SatO(2) was measured in the night before surgery (N0) and for 3 nights after surgery (N1, N2, N3) between 22.00 p.m. and 5.00 a.m. These measurements were divided into interval groups (80-83%, 84-87%, 88-91%, 92-95%, 96-100%). RESULTS: Almost all cognitive functions were significantly reduced at t1 in all groups compared to t0, but recovered up to the third postoperative day (t3). RSO(2) in contrast was significantly reduced in all groups compared to t0 at the third postoperative day (t3). The relative proportion of the intervals compared to the total measurement time for SatO(2) shifted in both anaesthesia procedures: before surgery (N0) the most frequented interval was 96-100%, after surgery (N1, N2) it was 88-91%. There was no correlation between rSO(2), the restitution of the tested cognitive functions and SatO(2). CONCLUSIONS: Cognitive functions recovered completely during the first 3 postoperative days in patients scheduled for elective hip surgery under general or regional anaesthesia regardless of age and type of anaesthesia. This restitution of cognition occurred despite a significant decrease of cerebral oxygenation (rSO(2)) and despite an increase of nocturnal hypoxaemic intervals. Changes of the rsO(2) up to 3% below the baseline values (measured by NIRS) do not predict cognitive restitution. A minimal limiting value of the rSO(2) could not be defined.

Amantadine increases gait steadiness in frontal gait disorder due to subcortical vascular encephalopathy: a double-blind randomized placebo-controlled trial based on quantitative gait analysis.

In a randomized, double-blind placebo-controlled trial, 40 patients diagnosed as subcortical vascular encephalopathy (SVE) were given a daily dose of 500 ml i.v. amantadine vs. placebo for 5 days. Both groups were treated with physiotherapy on a daily basis. Quantitative gait analyses were performed at days 1 and 6 to evaluate gait steadiness from cadence, length of heel-to-toe movements, variability of centre of gravity (COG) and double support time. Both placebo- and amantadine-receiving patient groups showed mild improvement in gait parameters after study, which failed to show the superiority of amantadine, when comparing drug-induced changes between both groups. However, analysing the treatment effects from day 0 to day 6 in both groups separately, statistically significant changes could be found in the amantadine group for cadence, length of heel-to-toe movements in single support phase as well as for variability in double support phase and double support time (two-tailed paired t-test, p < 0.05), whereas in the placebo group, a statistically significant effect could only be seen for double support time (p < 0.05). In this small pilot study, amantadine tends to improve gait steadiness as evaluated by cadence, length of heel-to-toe movements in single support phase, variability in double support phase and double support time, in patients with moderate frontal gait disorder due to SVE. Improvements in the placebo group can be interpreted as physiotherapy effect, which improved gait steadiness slightly, however, this was statistically significant only for double support time.

Elevated levels of fragmented DNA nucleosomes in native and activated lymphocytes indicate an enhanced sensitivity to apoptosis in sporadic Alzheimer's disease. Specific differences to vascular dementia.

Apoptotic cell death is thought to be the most likely mechanism of cell death contributing to neurodegeneration in Alzheimer's disease (AD). Here, we provide evidence that in sporadic AD cases the vulnerability of peripheral cells to undergo apoptosis is increased compared to non-demented elderly controls and, very importantly, to patients with subcortical vascular encephalopathy (SVE) as another, but demented control group. Quiescent 'native' and 'activated' lymphocytes from AD patients that were predisposed to commit apoptotic cell death by priming the cells with interleukin-2, are shown to accumulate apoptosing cells to a significantly higher extent in spontaneous and in oxidative stress-induced in vitro apoptosis. Our results demonstrate robust differences in cell death sensitivity between AD and vascular dementia. In none of the conditions investigated, lymphocytes from SVE patients were significantly different from non-demented controls. The comparable findings of a higher extent of apoptotic features in neurons and in peripheral blood cells of AD patients are remarkable and may suggest a rather general modulation of apoptotic mechanisms by the disease, which even can be picked up at the level of peripheral lymphocytes under specific in vitro conditions.

Gemcitabine for relapsed or resistant lymphoma.

BACKGROUND: Gemcitabine therapy has not been widely assessed in the treatment of hematological malignancies. We have examined the efficacy and safety of gemcitabine in patients with relapsed or resistant lymphoma. PATIENTS AND METHODS: Gemcitabine (1 g/m2) was given weekly for 7 consecutive weeks, followed by a week off treatment. The drug was then given for 3 consecutive weeks, followed by a week off treatment; this regimen was continued until disease progression or drug intolerance. Fifteen patients have enrolled. Most have been extensively pre-treated for advanced diffuse large-cell or mantle-cell lymphoma. RESULTS: The drug was well tolerated; no patient suffered treatment-related sepsis, hemorrhage or death. Non-hematopoietic toxicity led to discontinuation of gemcitabine therapy in two patients. Dose reductions or delays were required for about two-thirds of treatments. Of 13 evaluable patients, one had a complete response, 3 a partial response, 3 stable disease, and 6 disease progression. After 6 infusions of gemcitabine, a patient with advanced Hodgkin's disease has had a complete remission lasting 21 months. CONCLUSIONS: Gemcitabine has substantial activity and acceptable toxicity in heavily pre-treated patients with advanced lymphoma. Further study is warranted.

Assessment of gait in subcortical vascular encephalopathy by computerized analysis: a cross-sectional and longitudinal study.

In subcortical vascular encephalopathy (SVE) gait disturbance is a common and early clinical sign which might be used to monitor disease progression. In the absence of reliable scales and with regard to the equivocal results of highly complex gait imaging devices we assessed the natural course of SVE in a prospective study, using a new straight forward technique to quantify and compare sequential gait studies. We report the results of 300 computerized gait analyses in 119 patients with SVE and 63 age-matched controls. Thirty-nine SVE patients were re-evaluated to monitor the natural course of the disease and to study the correlation of gait disturbances with MRI changes and neuropsychological findings. The system consists of a set of shoes containing 16 load sensors and a measuring-unit reading each sensor at 20-ms intervals. By off-line analysis we graded each recording on a Gait Disorder Score (GDS) with six variables indicating gait steadiness: step frequency, length of gait lines (which represent the movement of the centre of gravity during heel to toe movement), length of single support lines, variability of single and of double support lines, and double support time. In cross-sectional analysis, patients with SVE showed cadence (steps/min) to be reduced at 87.3 +/- 19.5 (96.4 +/- 7.8 in controls, P < 0.05). Length of gait lines was significantly less: 0.70 +/- 0.13 vs. 0.80 +/- 0.05 in controls, with length of single support gait lines reduced at 0.42 +/- 0.14 in SVE (0.58 +/- 0.06 in controls, P < 0.05). Variability of both single support lines (5.69 +/- 1.90%; 4.24 +/- 1.07% in controls, P < 0.05) and double support lines was elevated (3.59 +/- 1.62% vs. 2.54 +/- 0.59%), while duration of double support phases was increased (0.19 +/- 0.10 s vs. 0.13 +/- 0.02 s in controls, P < 0.05). The progressive character of the disease was demonstrated by increasing GDS values in 39 SVE patients with a frontal gait disorder who were re-investigated after a mean interval of 26 months (5.4 +/- 4.5 vs. 8.4 +/- 5.5, P < 0.05). This study shows the value of a new and practicable gait analysis system for the evaluation of gait disorders and it quantifies the deterioration of gait in SVE patients.

Contemporary methods in hypnotic preparation for childbirth.

Hypnosis is a viable adjunct to any medical procedure and is not intended to replace conventional medical techniques. In recent years, many of us who practice hypnosis have seen a re-emergence of interest in mind-body approaches to health care. Hypnotic methods for preparation for childbirth are a logical contribution to that mind-body perspective.

Bilateral facial nerve palsy secondary to the administration of high-dose paclitaxel.

Bilateral facial nerve palsy is an uncommon occurrence. We describe a case of bilateral facial nerve palsy secondary to a single cycle of high-dose paclitaxel therapy (825 mg/m2), in a woman with breast cancer. Prior to her high-dose therapy, she had a residual grade 2 peripheral neuropathy following treatment with ten cycles of standard-dose paclitaxel (total dose 3200 mg). The features of the peripheral neuropathy due to standard-dose paclitaxel, which can be both motor and sensory, are well described. Cumulative paclitaxel dose is considered a risk factor for development of the neuropathy. Although facial nerve palsy secondary to paclitaxel is not previously reported, other cranial nerve toxicity has been described. Consistent with reports of the reversibility of paclitaxel-induced peripheral neuropathy, the facial nerve palsies in our patient resolved over 23 months. Ongoing studies of high-dose paclitaxel warrant close attention to its cumulative neurotoxic effects, particularly in patients previously treated with neurotoxic chemotherapy.

Invasive squamous cell carcinoma with sporotrichoid metastasis in a patient with cutaneous T cell lymphoma treated with chronic extracorporeal photopheresis.

An 83-year-old Caucasian man with cutaneous T-cell lymphoma developed an aggressive squamous cell carcinoma of the left forearm, which recurred and metastasized after Mohs micrographic surgery and systemic chemotherapy with cis-platin and 5-fluorouracil. He was treated with extracorporeal photopheresis, radiation therapy, PUVA photochemotherapy, and interferon therapy for cutaneous T-cell lymphoma. Aggressive squamous cell carcinoma can occur in the setting of extracorporeal photopheresis.

In the best of families: understanding hypnosis complications in graduate and post-graduate training experiences.

Unexpected, unwanted complications co-incident with the use of hypnosis can occur even to mental health professionals and in advanced hypnosis training. This article reports three such incidents, which occurred in the practice of a trained, licensed mental health professional, and university faculty member. Suggestions are provided for preventive practice, which may have reduced the risk of untoward aftereffects.

[Anesthesia in geriatric patients. The determination of physiological variables for cognitive function in geriatric patients after regional or general anesthesia]. / Anästhesie bei geriatrischen Patienten. Die Bedeutung physiologischer Variablen für die kognitive Leistungsfähigkeit geriatrischer Patienten nach Regionaloder Allgemeinanästhesie.

OBJECTIVE: The aim of the present study was to show the influence of the parameters of gas exchange (arterial oxygen pressure paO2, arterial oxygen saturation SatO2) and haemodynamics (arterial systolic and mean blood pressure RRs and MAP) on the restitution of cognitive functions in geriatric patients scheduled for elective hip arthroplasty. METHODS: A total of 30 patients (70 years, ASA II) were randomized to be operated either in regional anaesthesia (n = 15) or general anaesthesia (n = 15). PaO2 (by capillary blood gas analysis), RRs and MAP (by oscillometry) were measured 15 and 90 minutes after arrival in the recovery unit (t1 and t2), 24 and 72 hours postoperatively (t3 and t4), and cognitive functions were tested. Intraoperatively, throughout the day and the first night after surgery we measured satO2 by continuous pulse oximetry. We recorded MAP and RRs by oscillometry every 3 minutes during the operation and every 15 minutes for the rest of that day and night. RESULTS: The parameters of gas exchange and haemodynamics did not differ among the groups. PaO2 was significantly reduced in both groups compared to baseline 24 hours postoperatively (t3) and remained low until 72 hours postoperatively (t4). Nearly all cognitive functions were significantly reduced in both groups compared to baseline 15 and 90 minutes after arrival in the recovery unit (t1 and t2), but recovered on the first postoperative day (t3). Both groups kept deficits in verbal memory and reading capacity up to the third postoperative day (t4). There was no correlation between the physiological parameters and the restitution of the tested cognitive functions. CONCLUSION: The restitution of cognitive functions during the first three postoperative days in geriatric patients scheduled for elective hip surgery does not depend on the anaesthetic technique. According to our results regional anaesthesia does not show any advantage for geriatric patients undergoing elective hip arthroplasty.

Changes of intracellular calcium regulation in Alzheimer's disease and vascular dementia.

Free intracellular calcium ([Ca2+]i) represents probably the most important intracellular messenger for many signal transduction pathways. Due to this crucial role of [Ca2+]i, it has been assumed that alterations of [Ca2+]i are critically involved in brain aging and in the pathophysiology of Alzheimer's disease (AD). This hypothesis is corroborated by several studies demonstrating changes of [Ca2+]i in peripheral cells from AD patients. However, the findings are still controversial. Using blood lymphocytes and neutrophils as two different peripheral model systems, we evaluated several parameters of intracellular Ca2+ regulation in a very large group of AD patients and non-demented controls. We found no major difference in Ca2+ homeostasis, since neither the basal [Ca2+]i, nor the activation-induced Ca2+ responses differed among neutrophils or lymphocytes from aged controls and AD patients. However, we observed a delayed Ca2+ response of AD lymphocytes after phytohemagglutinin (PHA) stimulation indicating an impaired function of Ca2+ influx-controlling mechanisms. Furthermore, we studied whether differences exist in Ca2+ regulation between lymphocytes from patients with vascular dementia and AD patients, to define AD-specific alterations and to distinguish between the two dementia groups and non-demented control subjects respectively. First evidences indicate that Ca2+ mobilization in lymphocytes is specifically impaired in lymphocytes from patients with vascular dementia.