Detection of HHV-6 Virus in specimen of a ductal pancreatic adenocarcinoma with comparison in tumor and normal tissue.

AIMS: The association of human herpesvirus 6 (HHV-6) species with pancreatic cancer is controversially discussed. The aim of this study was to further investigate the postulated association and to identify the basis of HHV-6 DNA positivity reported for pancreatic cancer tissue. METHODS: All samples of patients with pancreatic cancer (cancer and surrounding tissue) were analyzed for presence of HHV-6 DNA by PCR and then selected cases by immunohistochemistry. RESULTS: Sixty eight per cent (68% = 52/77) of all patients were HHV-6 DNA positive in any of the samples, 49% (38/77) were positive in tumor tissue. Specimens of just one patient were HHV-6A DNA positive, all other patients were positive for HHV-6B. Immunohistochemical analysis of HHV-6 DNA positive samples did not reveal any specific HHV-6B protein positive tumor cell. In contrast, supposed immune cells presented intra- and peritumorally expressed HHV-6B-protein. The cause of presence of these cells in the tumor stroma is unknown, as of yet. CONCLUSIONS: HHV-6 DNA-positivity of pancreatic cancer tissue described by us and others is probably not due to the infection of pancreatic cells by HHV-6, but rather due to the migration of HHV-6 positive immune cells into the pancreas. Based on our data, we suppose that there is no direct evidence for HHV-6 as a causative agent of pancreatic cancer, but further in-depth studies (including investigation of immune status of patients) are necessary to make definitive conclusions.

The effect of sugar-sweetened beverages at 4 years of age on appetitive behaviours of 7-year-olds from the Generation XXI birth cohort.

The consumption of energy-dense sugar-sweetened beverages (SSB) and its low satiating effects may influence the development of child eating behaviours. We aimed to investigate the association of SSB consumption at 4 years on appetitive behaviours at age 7 years. Children from the Generation XXI birth cohort were included (n 3880). SSB consumption was evaluated through a FFQ and appetitive behaviours were evaluated through the Children's Eating Behaviour Questionnaire, which includes eight subscales. Two composite factors, derived by principal component analysis (Appetite Restraint - related to Food Fussiness, Enjoyment of Food, Slowness in Eating and Satiety Responsiveness - and Appetite Disinhibition - related to Food Responsiveness, Emotional Under- and Overeating and Desire to Drink), were also investigated. The dose-response relationship between SSB consumption and appetitive behaviours was examined using multivariable linear regression (continuous eating behaviour scores) and multinomial logistic regression (tertile categories of eating behaviour scores). Child SSB consumption at 4 years was associated with higher Appetite Disinhibition and Desire to Drink and lower Food Fussiness and Slowness in Eating at 7 years. Consuming SSB ≥1 times/d (compared with a lower intake) was associated with 29 % increase in the odds of Desire to Drink (3rd v. 1st tertile). Pre-schoolers' SSB consumption was associated with higher food approach and less food avoidant behaviours later in childhood. Family characteristics, particularly maternal SSB consumption, explained part of these associations. It is essential to promote the intake of water, instead of sugary drinks, and make parents and caregivers aware of the importance of this exposure, since they have a pivotal role in shaping children's eating behaviours.

Caloric compensation in preschool children: Relationships with body mass and differences by food category.

Maintaining a healthy weight may involve compensating for previously consumed calories at subsequent meals. To test whether heavier children demonstrated poorer caloric compensation across a range of conditions, and to explore whether compensation failure was the result of inadequate adjustment of overall intake or specific over-consumption of highly palatable, high energy-density 'junk' foods, we administered two compensation tests to a sample of 4-5 y olds. For Test A, preloads varied only in carbohydrate content and were organoleptically indistinguishable (200 ml orange-flavored beverage [0 kcal vs. 200 kcal]). For Test B, the preloads varied substantially in both macronutrient composition and learned gustatory cues to caloric content (200 ml water [0 kcal] vs. 200 ml strawberry milkshake [200 kcal]). Each preload was followed 30 min later by a multi-item ad-libitum meal containing junk foods (chocolate cookies, cheese-flavored crackers) and core foods (fruits and vegetables, bread rolls, protein foods). Testing took place at the children's own school under normal lunch-time conditions. Children were weighed and measured. Caloric compensation occurred in both tests, in terms of total, junk and core food intake (RMANOVA, all p < 0.01). Higher BMI z scores were associated with greater average caloric compensation (r = -0.26; p < 0.05), such that overweight/obese children showed least compensation (41%), children over the 50th centile the next least (59%), and children under the 50th centile (80%) the most. For Test A only, obese/overweight children compensated less well than normal-weight children in terms of junk food intake (RMANOVA preload-by-weight group interaction p < 0.05), with no significant effect for core foods. Our results suggest that caloric compensation is consistently poorer in heavier children, and that overweight/obese children's preferences for junk foods may overwhelm intake regulation mechanisms within meals containing those foods.

Lunch-time food choices in preschoolers: Relationships between absolute and relative intakes of different food categories, and appetitive characteristics and weight.

Children's appetitive characteristics measured by parent-report questionnaires are reliably associated with body weight, as well as behavioral tests of appetite, but relatively little is known about relationships with food choice. As part of a larger preloading study, we served 4-5year olds from primary school classes five school lunches at which they were presented with the same standardized multi-item meal. Parents completed Child Eating Behavior Questionnaire (CEBQ) sub-scales assessing satiety responsiveness (CEBQ-SR), food responsiveness (CEBQ-FR) and enjoyment of food (CEBQ-EF), and children were weighed and measured. Despite differing preload conditions, children showed remarkable consistency of intake patterns across all five meals with day-to-day intra-class correlations in absolute and percentage intake of each food category ranging from 0.78 to 0.91. Higher CEBQ-SR was associated with lower mean intake of all food categories across all five meals, with the weakest association apparent for snack foods. Higher CEBQ-FR was associated with higher intake of white bread and fruits and vegetables, and higher CEBQ-EF was associated with greater intake of all categories, with the strongest association apparent for white bread. Analyses of intake of each food group as a percentage of total intake, treated here as an index of the child's choice to consume relatively more or relatively less of each different food category when composing their total lunch-time meal, further suggested that children who were higher in CEBQ-SR ate relatively more snack foods and relatively less fruits and vegetables, while children with higher CEBQ-EF ate relatively less snack foods and relatively more white bread. Higher absolute intakes of white bread and snack foods were associated with higher BMI z score. CEBQ sub-scale associations with food intake variables were largely unchanged by controlling for daily metabolic needs. However, descriptive comparisons of lunch intakes with expected amounts based on metabolic needs suggested that overweight/obese boys were at particularly high risk of overeating. Parents' reports of children's appetitive characteristics on the CEBQ are associated with differential patterns of food choice as indexed by absolute and relative intake of various food categories assessed on multiple occasions in a naturalistic, school-based setting, without parents present.

A link between sICAM-1, ACE and parietal blood flow in the aging brain.

A connection between Alzheimer's disease (AD) and endothelium pathology has been inferred from measured decreases in both blood flow and metabolism in the parietal and temporal cortex. However, it is not known whether these alterations are seen in normal aging. We performed regional cerebral blood flow (rCBF) measurements in 22 AD patients and in 44 non-demented subjects during a simple test of information processing speed. Cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble form of intercellular adhesion molecule-1 (sICAM-1) were analyzed in non-demented subjects. We found correlations between sICAM-1 and ACE (p=0.004), and sICAM (but not ACE) and CSF/plasma albumin ratio (p<0.0001). Higher concentrations of sICAM-1 (>893ng/L) and ACE (>5.22microg/L) were exclusively associated with lower parietal blood flow (p<0.001). The rCBF patterns in the AD and non-demented subjects with biomarker levels above median showed similar reductions in the temporoparietal areas. Our findings provide evidence that elevated CSF sICAM-1 and ACE are associated with lower perfusion levels in the parietal cortex of cognitively intact elderly.

TNF-alpha-induced self expression in human lung endothelial cells is inhibited by native and oxidized alpha1-antitrypsin.

Endothelial cells are among the main physiological targets of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In endothelial cells TNF-alpha elicits a broad spectrum of biological effects including differentiation, proliferation and apoptosis. alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteases plays a vital role in protecting host tissue from proteolytic injury at sites of inflammation. Recently, it has been shown that AAT can be internalized by pulmonary endothelial cells, raising speculation that it may modulate endothelial cell function in addition to suppressing protease activity. Using Affymetrix microarray technology, real time PCR and ELISA methods we have investigated the effects of AAT on un-stimulated and TNF-alpha stimulated human primary lung microvascular endothelial cell gene expression and protein secretion. We find that AAT and TNF-alpha generally induced expression of distinct gene families with AAT exhibiting little activity in terms of inflammatory gene expression. Approximately 25% of genes up regulated by TNF-alpha were inhibited by co-administration of AAT including TNF-alpha-induced self expression. Surprisingly, the effects of AAT on TNF-alpha-induced self expression was inhibited equally well by oxidized AAT, a modified form of AAT, which lacks serine protease inhibitor activity. Overall, the pattern of gene expression regulated by native and oxidized AAT was similar with neither inducing pro-inflammatory gene expression. These findings suggest that inhibitory effects of native and oxidized forms of AAT on TNF-alpha stimulated gene expression may play an important role in limiting the uncontrolled endothelial cell activation and vascular injury in inflammatory disease.

rCBF pathology in Alzheimer's disease is associated with slow processing speed.

Decreased information processing speed (mental slowing) is a known sequelae of many brain disorders, and can be assessed by continuous naming tasks. Functional imaging studies have shown that pause and articulation times in continuous speech are normally associated with different brain regions, but knowledge about such association in dementia is lacking. We therefore tested the hypothesis that perfusion deficits in Alzheimer's disease (AD) are not only associated with slower processing, but also with these speech measures. Using regional cerebral blood flow (rCBF) measurements during the performance of a continuous colour and form-naming task, we found that naming speed was substantially slower in AD patients than in controls. This slower naming was exclusively determined by an increase in mean pause time, and only to a limited extent by articulation time. The increased pause time was uniquely associated with temporo-parietal rCBF reductions of the patients, while articulation was not. By contrast, the rCBF of healthy elderly control subjects was consistently accompanied by substantially shorter articulation and pause times, although the naming measures were not statistically associated with rCBF. These findings suggest that pause time (in contrast to articulation time) may serve as a sensitive measure in the assessment of information processing speed deficits in dementia, by virtue of its close association with brain pathology.

Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease.

It has been suggested that a number of molecules associated with inflammation are involved in the pathogenesis of Alzheimer's disease (AD). We measured the levels of alpha(1)-antichymotrypsin (ACT), alpha(1)-antitrypsin (AAT), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and oxidised low-density lipoprotein (oxLDL) in matched cerebrospinal fluid (CSF) and plasma of 141 patients with probable AD. We found a significant relationship between CSF and plasma levels of ACT (r = 0.4, p < 0.001), IL-6 (r = 0.74, p < 0.001), MCP-1 (r = 0.71, p < 0.001), and a borderline relationship between CSF and plasma oxLDL (r = 0.22, p < 0.05). In addition, linear regression analysis revealed a positive correlation between levels of CSF-ACT and oxLDL (p < 0.001), but an inverse relation between levels of CSF ACT, CSF AAT and MCP-1 (p < 0.001). A significant correlation was also found between levels of CSF ACT, oxLDL and the ratio of CSF to serum albumin, which is used as a measure of the blood-brain barrier function. Our data extend previous reports regarding the inflammatory markers in the plasma and CSF of patients with AD and provide good evidence that levels of ACT, IL-6, MCP-1 and oxLDL in plasma and CSF might be candidates as biomarkers for monitoring the inflammatory process in AD.

Frontal lobe dysfunction in long-term cannabis users.

This study examined the neurophysiological effects of cannabis. Cerebral blood flow (CBF) was measured in 12 long-term cannabis users shortly after cessation of cannabis use (mean 1.6 days). The findings showed significantly lower mean hemispheric blood flow values and significantly lower frontal values in the cannabis subjects compared to normal controls. The results suggest that the functional level of the frontal lobes is affected by long-term cannabis use.

Treatment of cobalamin deficiency in dementia, evaluated clinically and with cerebral blood flow measurements.

We investigated the relation between cobalamin deficiency, clinical changes and brain function in dementia patients. On admittance to the clinic, 24 patients had cobalamin deficiency, and dementia with additional symptoms of delirium. During cobalamin supplementation, the patients underwent repeated regional cerebral blood flow (rCBF) studies, psychiatric evaluations, and in some cases assessment with MMSE and the Organic Brain Syndrome scale. Fifteen patients who showed mild to moderate dementia improved clinically, and also showed a concomitant increase in their general CBF after treatment. In contrast, 9 patients who were severely demented showed no obvious clinical improvement, and no general blood flow change, although some regional flow increases were seen in sensory motor areas. We conclude that symptoms which probably indicated superimposed delirium such as clouding of consciousness, disorientation and clinical fluctuation, responded to the vitamin B12 supplementation, while the underlying dementia condition remained basically unchanged. The clinical improvement was also mirrored in general and focal rCBF changes.

Synapse density related to cerebral blood flow and symptomatology in frontal lobe degeneration and Alzheimer's disease.

In order to evaluate the functional significance of synaptic pathology, synaptic density was quantitated and related to clinical symptomatology and regional cerebral blood flow (rCBF) in 8 patients with frontal lobe degeneration of non-Alzheimer type (FLD) and 19 patients with Alzheimer's disease (AD). Synaptic density was measured in all layers of prefrontal and parietal cortex. The clinical picture of FLD was dominated by a frontal lobe syndrome with changes in personality and behavior, while AD was dominated by temporoparietal symptoms. This parallels the finding of frontal rCBF reductions in FLD patients and temporoparietal reductions in AD patients. Synaptic density was significantly decreased in both FLD and AD, with a regional severity which closely correlated with that of the degeneration, symptomatology and rCBF deficit. The results suggest that synaptic pathology is a likely cause of clinical symptoms and regional metabolic decrement in dementia.

Brain function in spider phobia.

Measurements of regional cerebral blood flow (rCBF) were performed in 16 women suffering from spider phobia. The non-invasive 133Xe inhalation method, giving information about the blood flow of superficial areas, was used. The subjects were studied under three conditions: during resting, when exposed to a videotape showing nature scenery, and finally when watching a video with living spiders. During the rCBF measurements the subjects' behaviour was registered systematically and respiration, blood pressure, Pco2, and heart rate were monitored. Eight subjects who showed and reported severe panic during the spider exposure had marked rCBF decreases in frontal areas, especially in the right hemisphere. The remaining eight subjects displayed a more efficient control of their emotions and became frightened, but not panic-stricken, during the spider exposure. These showed a consistent rCBF increase in the right frontal area compared to neutral stimulation. Thus, results revealed significant functional changes in the frontal cortex in subjects with spider phobia during phobogenic exposure. It seems likely that these frontal changes are related to the experience and control of phobic anxiety.

Functional imaging of the frontal lobes in organic dementia. Regional cerebral blood flow findings in normals, in patients with frontotemporal dementia and in patients with Alzheimer's disease, performing a word fluency test.

Patterns of functional cortical activation were studied by means of regional cerebral blood flow measurements, performed during rest and during a word fluency task in normal subjects (n = 22), in patients with Alzheimer's disease (n = 17), and in patients with frontotemporal dementia (n = 15). Although all groups showed a significant activation of the Broca's area during word production, the activation of the dorsolateral prefrontal cortex was clearly subnormal in both dementia groups. The frontal dysfunction was not explained by number of words produced, illness duration, or age. Thus, the results demonstrate that the word fluency task is a sensitive measure of frontal lobe function, and its incorporation in imaging studies may facilitate the detection of subtle functional impairment of the frontal lobes in organic dementia.

Orthostatic hypotension and low blood pressure in organic dementia: a study of prevalence and related clinical characteristics.

OBJECTIVE: To determine the prevalence of orthostatic hypotension (OH), low blood pressure and dizziness, falls and fractures in patients with organic dementia. DESIGN: We prospectively studied 151 patients, assessing the prevalence of OH, hypertension, heart disorders, diabetes mellitus and the use of medication possibly associated with OH. SETTING: The patients were admitted to our psychogeriatric clinic as part of routine clinical investigation of their dementia. PATIENTS: Forty-six patients with Alzheimer's disease (AD), 28 patients with frontotemporal dementia (FTD) and 77 patients with vascular dementia (VaD) were investigated. MAIN OUTCOME MEASURE: Due to the paucity of information about the prevalence of OH in organic dementia, this study is mainly explorative in nature, thus preventing explicit hypothesis formulation. However, clinical impressions indicated a higher prevalence of OH in organic dementia than normally seen in healthy elderly. RESULTS: OH/low blood pressure was present in 39-52% of the patients. The majority reached their maximum systolic decrease within 5 minutes of standing, but in 20-30% the maximum blood pressure drop occurred after 5 minutes or later. In 38%, the systolic blood pressure drop was more than 40 mm Hg. Hypertension and heart disease was found only in AD and VaD, with no difference between those with and without OH/low blood pressure. Falls and fractures were common in orthostatic and hypotensive patients, with an incidence of more than 50% in AD and VaD. CONCLUSIONS: The results support our clinical impressions that OH and low blood pressure is common and an important factor in organic dementia.

Orthostatic hypotension in organic dementia: relationship between blood pressure, cortical blood flow and symptoms.

Regional cerebral blood flow was measured in 35 patients with organic dementia (Alzheimer's disease, n = 13, vascular dementia, n = 17, frontotemporal dementia, n = 5) and orthostatic hypotension. Measurements were performed during supine rest and during head-up tilt (60 degrees). Despite marked blood pressure falls, few patients had symptoms of orthostatic hypotension. All three dementia groups had a decrease in regional cerebral blood flow in the frontal lobes during head-up tilt, but no change in mean hemispheric flow. All patients had a consistent drop in their systolic blood pressure upon head-up tilt, with a wide variation over time. The findings suggest that orthostatic hypotension needs to be considered, and actively sought for, in organic dementia as many patients may lack the typical symptoms of orthostatic hypotension, despite a marked fall in blood pressure.

Neuropsychological assessment of schizophrenic patients during a psychotic episode: persistent cognitive deficit?

Neuropsychological test performance and clinical symptoms were assessed in 14 schizophrenic patients at admission to and discharge from an acute inpatient psychiatric service. Despite significant clinical improvement at discharge, no major change in cognitive performance was observed. Furthermore, patients at discharge were significantly impaired compared with normal control subjects case-matched for gender, age, handedness and level of education. The results suggest that some degree of cognitive impairment may be relatively independent from schizophrenic symptoms and that such impairment may represent part of a residual enduring "trait" vulnerability.

Cortical blood flow during head-up postural change in subjects with orthostatic hypotension.

Regional cerebral blood flow was measured with the 133-Xenon inhalation method in seven healthy subjects with orthostatic hypotension not due to autonomic failure (i.e. non-neurogenic clinical disorder). Measurements were performed during supine rest and during head-up tilt (70 degrees). All subjects had a consistent drop in systolic blood pressure and the typical symptomatology of orthostatic hypotension. The results showed lower mean hemispheric blood flow during head-up tilt than during supine rest. In addition, a consistent and significant redistribution of the regional flow values was seen, with a reduction in frontal and an increase in postcentral areas. The frontal flow decrease during tilt was more marked than in subjects without orthostatic hypotension and was not related to variations in the level of PCO2 or to respiration. In contrast to the clinical symptoms of orthostatic hypotension (dizziness, nausea, visual disturbances, and in some cases syncope), the cortical blood flow reduction was, however, relatively moderate.

Regional cerebral blood flow in frontal lobe dementia of non-Alzheimer type.

Twenty-five out of 26 cases of autopsy-verified frontal lobe degeneration of non-Alzheimer type (FLD) were found to have focal frontal or frontotemporal blood flow reductions involving both hemispheres. The deviant case had an asymmetric frontal pathology only apparent on the right side. Focal reduction of blood flow in the frontal lobes is, however, a common and unspecific flow abnormality found in e.g. Pick's disease. Creutzfeldt-Jakob's disease, and in some cases of Alzheimer's disease. Low frontal flow has also been reported in schizophrenia and in toxic encephalopathy. Since a characteristic feature of FLD is a steady progress of the pathology, serial flow measurements extending over several years are especially informative.

Functional activation of the frontal lobes. Regional cerebral blood flow findings in normals and in patients with frontal lobe dementia performing a word fluency test.

The present study examined the utility of the Word Fluency Test (WFT) as a frontal-lobe-activating test in brain imaging. Regional cerebral blood flow (rCBF) was measured during rest and during the WFT in 49 healthy volunteers and in 15 patients with frontal lobe dementia (FLD). The results showed a highly significant frontal lobe activation in 85% of the normal subjects. This finding was not related to age or to the level of performance on the WFT. A significant frontal activation was seen in 13 of the 15 FLD patients. The frontal flow increase did not reach normal levels, and was not related to age, illness duration or severity of clinical symptoms. The results suggest that the WFT is an ideal test to use in conjunction with functional imaging in normals as well as in patients with organic dementia.