A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans.

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (approximately 63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.

Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment.

BACKGROUND: Natalizumab is the first monoclonal antibody therapy approved for multiple sclerosis (MS). Its therapeutic mechanism is the blockade of the α4-integrin subunit of the adhesion molecule (AM) very late activation antigen-4 (VLA-4), which leads to an inhibition of immune cell extravasation into the central nervous system (CNS). METHODS: We investigated changes in the expression levels of unblocked α4-integrin and further AM (intercellular adhesion molecule-1, -2, -3 (cICAM-1, -2, -3), leukocyte function associated antigen-1 (LFA-1)) on peripheral blood mononuclear cells (PBMC) determined by flow cytometry from 25 patients with MS before the first natalizumab infusion and before the fourth infusion. In 15 MS patients AM expression was evaluated every 3 months over 1 year. RESULTS: We found a significant decrease (p < 0.0001) of unblocked α4-integrin cell surface expression on all investigated PBMC subsets (T cells -61.7%, B cells -69.1%, monocytes/macrophages -46.4%) in the blood of MS patients after 3 months of natalizumab treatment. Moreover, a continuous decrease (p < 0.05) of unblocked α4-integrin expression levels was seen after 3, 6, 9, and 12 months. As a secondary effect, expression levels of the other investigated AM were differentially affected. CONCLUSIONS: Results show a sustained decrease of unblocked α4-integrin expression not only in all patients but also in all investigated PBMC subsets. This probably results in a continuously decreasing transmigration of PBMC into the CNS and may explain the improved clinical efficacy in the second treatment year and also the increasing risk of progressive multifocal leukoencephalopathy during long-term natalizumab therapy. We conclude that AM expression profiles are promising candidates for the development of a biomarker system to determine both natalizumab treatment response and patients at risk for opportunistic CNS infections.

Patient-reported quality of life in multiple sclerosis differs between cultures and countries: a cross-sectional Austrian-German-Polish study.

BACKGROUND: Patient-reported quality of life (QOL) is an outcome measure in clinical trials in multiple sclerosis (MS), but translated QOL instruments may affect the actual comparability of data. OBJECTIVES: We aimed to investigate possible differences in QOL in MS between cultures and countries. We employed the Functional Assessment of Multiple Sclerosis (FAMS) Version 4 questionnaire, which is a state-of-the-art QOL instrument. METHODS: Some 484 MS patients from Austria (145), Germany (144), and Poland (195) aged 20-60 years, and stratified for sex and disease severity as measured by the Expanded Disability Status Scale (EDSS) score completed the respective FAMS translation and a socio-demographic questionnaire. RESULTS: Analysis of variance and post-hoc Scheffé-test showed that 64% of the FAMS items were answered significantly differently (p < 0.001) between the three countries. A multivariate regression analysis including all the available disease-related and socio-demographic variables revealed the factors age, EDSS score, employment, social contacts, MS course, and country to be significant predictors of both the total FAMS score and the score for items answered differently between the three countries. CONCLUSIONS: Differences exist in the QOL of MS patients from Austria, Germany, and Poland which seem to lie beyond the impact of disease severity. They appear to be related to culture or other country-specific factors, as country was an independent predictor of differently answered items of the FAMS and thus also of the whole FAMS. QOL instruments should consider this aspect to faithfully reflect subjective information such as patient-reported benefit of treatment in multinational clinical trials.

Decision-making for and impact of early immunomodulatory treatment: the Austrian Clinically Isolated Syndrome Study (ACISS).

BACKGROUND AND PURPOSE: When to start disease-modifying treatment (DMT) in patients with a clinically isolated syndrome (CIS) requires individual weighing of benefits versus possible burden of side effects and costs. How this occurs in a routine setting is barely known. The aim of the study was to investigate the decision-making process regarding immediate or later DMT and the ensuing impact on CIS patients in Austria. METHODS: Demographic and (para) clinical characteristics of 296 CIS patients were recorded in 29 multiple sclerosis (MS) centres, and the patients' overall condition was rated on a visual analogue scale (VAS). Clinical follow-up and VAS ratings were repeated at 6-month intervals over 2 years. The decision for initiation of DMT was at the physician's and patient's discretion. RESULTS: In 29% of patients, DMT was started within 3 months and this decision was independently associated with a T2-lesion number >or=9 on MRI and a worse VAS rating by the physician. DMT initiation in the subsequent 6 months was additionally associated with the presence of oligoclonal bands and rarely occurred thereafter. Adapted to the clinical course, later treatment was associated with the highest rate of conversion to clinically definite MS and greatest disability after 2 years whilst never treated patients fared best. Patient VAS ratings significantly improved during follow-up independently of treatment decisions. CONCLUSION: The management of Austrian CIS patients relies strongly on MRI findings and the physicians' interpretation of the patients' overall situation which, after 2 years, depends primarily on the course of the disease.

Classification of non-aneurysmal subarachnoid haemorrhage: CT correlation to the clinical outcome.

AIM: To propose a new computed tomography (CT)-based classification system for non-aneurysmal subarachnoid haemorrhage (SAH), which predicts patients' discharge clinical outcome and helps to prioritize appropriate patient management. METHODS AND MATERIALS: A 5-year, retrospective, two-centre study was carried out involving 1486 patients presenting with SAH. One hundred and ninety patients with non-aneurysmal SAH were included in the study. Initial cranial CT findings at admission were correlated with the patients' discharge outcomes measured using the Modified Rankin Scale (MRS). A CT-based classification system (type 1-4) was devised based on the topography of the initial haemorrhage pattern. RESULTS: Seventy-five percent of the patients had type 1 haemorrhage and all these patients had a good clinical outcome with a discharge MRS of

Relationship between thrombin generation and carotid intima-media thickness.

UNLABELLED: Increasing evidence indicates that thrombin plays a role not only in thrombosis but also in the progression of atherosclerosis. AIM: The relationship between thrombin generation and intima-media thickness (IMT) as an index of subclinical atherosclerosis was investigated. Participants, material, methods: We examined 163 asymptomatic middle-aged persons free of overt clinical atherosclerotic disease. They underwent ultrasonography of the common carotid arteries. In addition, thrombin generation was measured by means of CAT (calibrated automated thrombography). For our study we divided the healthy study participants into three age groups (<45, 45-60 and >60 years). RESULTS: A significant positive correlation was seen between endogenous thrombin potential (ETP) (p = 0.012), time to peak (TTP) (p = 0.033) start tail (p = 0.007) and carotid IMT in the group of healthy volunteers younger than 45 years. CONCLUSION: We demonstrated that in adults younger than 45 years without clinically overt atherosclerotic disease ETP was significantly associated with carotid IMT. It is tempting to speculate that ETP may serve as an index for subclinical atherosclerosis in persons below 45 years.

[Consensus statement "Dementia 2010" of the Austrian Alzheimer Society]. / Konsensusstatement "Demenz 2010" der Osterreichischen Alzheimer Gesellschaft.

The Austrian Alzheimer Society developed evidence-based guidelines based on a systematic literature search and criteria-guided assessment with subsequent transparent determination of grades of clinical recommendation. The authors evaluated currently available therapeutic approaches for the most common forms of dementia and focused on diagnosis and pharmacological intervention, taking into consideration the situation in Austria. The purpose of these guidelines is the rational and cost-effective use of diagnostic and therapeutic measures in dementing illnesses. Users are physicians and all other providers of care for patients with dementia in Austria.

Cerebral perfusion (HMPAO-SPECT) in patients with depression with cognitive impairment versus those with mild cognitive impairment and dementia of Alzheimer's type: a semiquantitative and automated evaluation.

PURPOSE: Comparative evaluation of regional brain perfusion measured by HMPAO-SPECT of patients with mild cognitive impairment (MCI), dementia of Alzheimer's type (DAT) and depression with cognitive impairment (DCI). METHODS: A total of 736 patients were investigated because of suspected cognitive dysfunction. After exclusion of patients with other forms of dementia than DAT or relevant accompanying disorders, SPECT data from 149 MCI, 131 DAT and 127 DCI patients, and 123 controls without any cognitive impairment, were analysed. Relative cerebral blood flow of 34 anatomical regions was assessed with automated analysis software (BRASS). RESULTS: Calculation of global forebrain perfusion discriminated demented from nondemented patients. Compared to controls DCI patients showed hypoperfusion of the thalamus, lentiform nucleus and medial temporal cortex. MCI patients differed significantly from controls concerning perfusion in both hemispheric temporal and parietal areas, and in the (right hemispheric) posterior part of the cingulate gyrus. MCI and DCI patients differed in the parietal, temporal superior and right hemispheric cingulate gyrus posterior cortices. Global forebrain and regional perfusion was more extensively reduced in DAT patients and discriminated them from controls, and MCI and DCI patients. Frontal perfusion disturbance was only present in DAT patients. CONCLUSION: Automated analysis of HMPAO-SPECT data from MCI patients showed significant perfusion deficits in regions also involved in DAT patients, but ROC analysis demonstrated only moderate sensitivity and specificity for differentiating DAT patients from controls and DCI patients. Frontal hypoperfusion seems to correspond with conversion from MCI to DAT. Finally, the results in DCI patients again raise the question of depression as an early symptom of neurodegeneration.

Ferritin and FasL (CD95L) mediate density dependent apoptosis in primary rat hepatocytes.

Based on a recent description of an apoptosis stimulating property for hepatocyte derived isoferritins, this investigation demonstrates that ferritin, released in vitro from hepatocytes substantially contributes to density dependent apoptosis in primary hepatocytes and is significantly (P < or = 0.05) inhibited by anti-H-ferritin antibody rH02. Furthermore, total protein release and albumin secretion rapidly decline in a time and density dependent mode under serum-free conditions, whereas ferritin secretion, which is upregulated at initial stages of primary culture is not affected by cell density. Supplementation with dexamethasone (DEX) or proliferative stimulation by epidermal growth factor (EGF) and insulin strongly suppresses density dependent apoptosis. Both regimens have previously been shown to inhibit isoferritin mediated apoptosis in hepatocytes, most likely by interrupting proapotitc mitochondrial signalling. Finally, FasL/Fas also participates in density dependent apoptosis, since apoptosis is significantly (P < or = 0.005) reduced in high density cultures supplemented with an anti-FasL antibody. This antibody has also been shown to neutralise ferritin mediated apoptosis in primary hepatocytes, suggesting a linkage of ferritin and Fas in density dependent apoptosis. In conclusion, ferritin contributes to apoptosis in primary hepatocytes in an autocrine, density dependent mode, involving Fas stimulation and proapoptotic mitochondrial signalling. With respect to liver physiology, these findings may indicate that ferritin plays a yet unrecognised role as an acute phase signalling molecule in early stages of tissue repair and liver regeneration, and may also be responsible for the limited ability to propagate human hepatocytes in culture and the limited expansion of donor cells in the recipient liver upon cell transplantation.

MMP-9 haplotypes and carotid artery atherosclerosis: an association study introducing a novel multicolour multiplex RealTime PCR protocol.

BACKGROUND: Among other matrix metalloproteinases (MMPs), gelatinase B (MMP-9) is discussed to be associated with the pathogenesis of vascular diseases. Two single nucleotide polymorphisms (SNPs) of the MMP-9 gene, C-1562T in the promoter region and a G/A transition in exon 6 (R + 279Q), have been addressed in previous association studies which, however, produced conflicting results. MATERIAL AND METHODS: A novel multiplex RealTime PCR protocol for the fast and simultaneous detection of both polymorphisms is presented, which was used for genotyping 1737 participants of a prospective study investigating genetic factors influencing the progression of atherosclerosis. RESULTS: Haplotype analysis revealed -1562C/+279Q as the major haplotype in this population. Allelic distribution of the C-1562T polymorphism was consistent with data published for similar cohorts; however, we found that R + 279Q allelic distribution appears to vary significantly among Caucasian populations. Considering clinical data available from 1487 participants, we found significant associations between the presence of atherosclerotic plaque and the CA-haplotype in men (P = 0.028, phi = 0.08), and between the AG variant of exon 6 and common carotid artery intima-media thickness (CIMT) in women (P = 0.004, Eta(2) = 0.019). CONCLUSIONS: In summary, our results demonstrate associations of MMP-9 genotypes with different stages of carotid atherosclerosis.

Diffuse Lewy body disease as substrate of primary lateral sclerosis.

We describe the case of a 40-year-old male patient who had presented clinically as primary lateral sclerosis for the past 10 years and neuropathologically as diffuse Lewy body disease (DLBD). Neuropathology demonstrated DLBD as an almost ubiquitous disorder of the neuronal cytoskeleton.

Polyneuropathy associated with chronic hypoxaemia: prevalence in patients with chronic obstructive pulmonary disease.

The prevalence of clinical and electrophysiological signs of peripheral nerve disease was evaluated in 151 patients with chronic obstructive pulmonary disease. Patients with concomitant disorders affecting the peripheral nervous system were excluded. Thirty patients had clinical signs of a mild sensorimotor and distal neuropathy and 13 additional patients had only electrophysiological abnormalities. The rate and the severity of the neuropathy correlated with the severity of chronic hypoxaemia. Three out of 20 patients with mild hypoxaemia (PaO2 less than 15 mm Hg below normal) had polyneuropathy as compared with 15 out of 36 with severe hypoxaemia (PaO2 more than 30 mm Hg below normal (rates different at the 10% level)). PaO2 and age were the only variables discriminating between patients with and without peripheral neuropathy.

Comparison of second lumbrical and interosseus latencies with standard measures of median nerve function across the carpal tunnel: a prospective study of 450 hands.

The second lumbrical-interosseus distal motor latency (2LI-DML) was compared prospectively in 450 hands. Median nerve function was assessed by standard motor and sensory electrophysiological tests. In a control group of 100 hands the upper limit of normal for the 2LI-DML was 0.5 ms. In all hands studied the correlation coefficients of 2LI-DML were higher with sensory nerve tests than with motor studies. Carpal tunnel syndrome (CTS) was diagnosed clinically in 276 hands, and 174 showed no clinical signs of CTS. The 2LI-DML was prolonged in 269 of the 276 hands, with clinical signs of CTS and normal in 170 of 174 non-CTS hands. Thus the 2LI-DML resulted in a sensitivity of 97.5%. On the other hand, combining the standard tests yielded a sensitivity of 98.5 %. In 31 of 36 additional hands a lumbrical response was recorded, although motor and sensory responses form standard median nerve conduction studies were absent, and the 2LI-DML was substantially prolonged. The 2LI-DML therefore represents a highly sensitive, fast, easy-to-perform, and cost-efficient method to study median nerve function across the wrist and may help to localize the lesion in cases in which standard electrophysiological methods fail.

Diagnosis and treatment of middle fossa arachnoid cysts and subdural hematomas.

Nine cases with temporal fossa arachnoid cysts were diagnosed by computerized tomography (CT). Five patients also had subdural hematomas, three of them following head trauma. When the hematoma was chronic and of equal hypodensity with the cyst, a clear-cut differentiation was not possible from the CT scan. The presence of a subdural hematoma could only be suggested by thickened arachnoid structures crossing the hypodense area, indicating the wall between cyst and hematoma. The cyst could often be diagnosed by bulging of the skull bone and a temporal lobe defect. Differences in density between cyst and hematoma, such as in subacute subdural hematoma, delineated both entities. Typical examples are demonstrated. Treatment consisted of evacuation of the hematoma and excision of the cyst in all cases.

Cholesteryl ester transfer protein TaqIB polymorphism and its relation to parameters of the insulin resistance syndrome in an Austrian cohort.

The cholesteryl ester transfer protein (CETP) is responsible for the exchange of triglycerides and cholesteryl esters between lipoprotein particles leading to an increased hepatic clearance of HDL-cholesteryl esters. A high CETP activity reduces serum HDL levels, whereas persons without CETP activity have high HDL levels. We investigated the association of the TaqIB CETP polymorphism and various parameters of the insulin resistance syndrome in a cross sectional population based study. We included 1029 persons without known cardiovascular disease or diabetes mellitus consecutively enrolled in our SAPHIR program (Salzburg Atherosclerosis Prevention program in persons with a High Infarction Risk). Numerous clinical and laboratory data were accomplished. Insulin sensitivity was measured by a short insulin tolerance test. The TaqIB CETP polymorphism was determined by PCR, TaqI restriction and electrophoresis. 35.2% were homozygous for the prevalence (B1B1), 46.7% were heterozygous (B1B2), and 18.1% homozygous for the absence (B2B2) of the restriction site. HDL cholesterol and apolipoprotein A1 were lower and small dense low-density lipoproteins (sdLDL) higher in B1B1 compared to B2B1 and B2B2 persons. In women, we found a significant interaction effect between CETP genotype and adiposity for HDL cholesterol. B1B1 women with a BMI and a waist circumference above the median had 9.7 mg/dl lower HDL than B1B2 and 9.1 mg/dl lower HDL than B2B2 women (P < 0.001). In men, no interaction effect but a marked genotype to HDL correlation was found. There was a high CETP effect on sdLDL detected in men (P = 0.001). B1B1 men had sdLDL in 36%, B1B2 in 24.6%, and B2B2 in only 14.5%. Men with adiposity and insulin resistance had twice as many sdLDL as insulin sensitive men. We found a significant sex specific effect of the TaqIB CETP polymorphism on the insulin resistance parameters HDL-cholesterol and sdLDL in an Austrian population based study.

Imaging the basilar artery by contrast-enhanced color-coded ultrasound.

Conventional transcranial color-coded real-time sonography of the vertebrobasilar system is limited by imaging problems of the distal segment of the basilar artery. Lung-stable contrast-enhancing agents may overcome this problem by enhancing the quality of Doppler signals by as much as 20%. Fourty-two patients underwent sonographic evaluation of the vertebrobasilar system before and after receiving intravenously administered galactose-based contrast-enhancing agent Levovist by transforaminal and transtemporal routes. Imaging quality was classified into five categories depending on the length of visible color-flow by transforaminal approach: 1--no signal, 2--1-9.9 mm, 3--10-19.9 mm, 4--20-29.9 mm, 5--> or = 30 mm. For transtemporal insonation, imaging quality was classified either as no color flow or sufficient color flow of the basilar tip. By unenhanced investigation, average signal length of color flow was 16 +/- 8 mm for transforaminal investigation; application of Levovist improved this value to 26.6 +/- 6 mm. For unenhanced transforminal approach, 4.8% were assigned to category 1, 11.9% to category 2, 54.8% to category 3, 23.8% to category 4 and 4.8% to category 5. After signal enhancement with Levovist, category 1 covered 0%, category 2 2.4%, category 3 7.14%, category 4 59.5% and category 5 30.9% (p < 0.001). Unenhanced transtemporal approach allowed identification of the basilar tip in 78.6% with an average length of 6.3 +/- 2 mm; contrast enhancement improved this values to 92.9% and 8.3 +/- 3.3 mm respectively (p < 0.05). The application of transpulmonary contrast-enhancing agents improves the reliability of transcranial color-coded duplex sonography of the basilar artery.

Clinical and diagnostic findings in a patient with Creutzfeldt-Jakob disease (type Heidenhain).

A 61-year-old woman had Creutzfeldt-Jakob disease, type Heidenhain, that progressed for 4 months until death, 3 of which she spent in a hospital. The diagnosis was verified by autopsy. Consecutive brain computed tomography, magnetic resonance imaging, blood flow measurements, electroencephalography (EEG), and routine laboratory tests were performed. All imaging techniques showed nonspecific pathological changes, whereas EEG revealed alterations indicative for Creutzfeldt-Jakob disease.

Computer subtraction in regional cerebral blood-volume measurements using the EMI-Scanner.

A computerized subtraction technique has been described to measure regional cerebral blood volume (rCBV) using the EMI-Scanner in a group of 13 patients. Sodium iothalamte was injected intravenously (1-75 ml./kg) to increase the absorption of X rays in the cerebral circulation. Significant regional differences in CBV were shown, values in the frontal and temporal regions being lower than the mean hemisphere value (4-9 +/- 0-7) and higher in the occipital region. The left hemisphere showed a significantly higher CBV when compared with the right. Measurements of CBV in the cortex showed no regional variation, but the mean cortical value of 6-0 +/- 1-8 was significantly higher than the hemisphere mean.

Measurement of regional cerebral blood volume using the EMI 1010 scanner.

Regional cerebral blood volume (rCBV) was measured in 14 patients with normal CT scans. An EMI CT 1010 scanner was used in combination with a computer subtraction technique. The mean CBV in the cortex was 5.0 ml/100 ml of tissue and 2.2 in the white matter. Regional differences were not significant and no difference was found between the right and left hemispheres.

[Classification and course of cerebral infarcts on computer tomography (author's transl)]. / Klassifikation und Verlauf des Hirninfarktes im Computertomogramm.

The typical computer tomographic signs of ischaemic cerebral infarct are discussed on the basis of 631 cases. Infarcts have three typical stages. Stage I, one week, fresh infarct with signs of oedema (space-occupying lesion with an unsharp margin, slightly reduced density, lack of contrast uptake). Stage II, second to fourth week, reduction in the oedema. Frequently very marked contrast enhancement of the cortex and basal nuclei. Stage III, later than four weeks. Development of malacic cysts, with further reduction in density and size. Development of homolateral atrophy. The computer tomographic diagnosis of cerebral infarcts during Stage I is often very difficult. Distinction from infiltrating tumour is often possible only after further observation. The diagnosis of cerebral infarcts in stages II and III is possible in most cases. Haemorrhagic cerebral infarcts do not follow a temporal pattern as accurately as anaemic infarcts. They show circular increase in contrast of slowly diminishing size. The increased contrast persists considerably longer and is clearly distinguished from that in an anaemic cerebral infarct.