Selective enhancement of spatial learning under chronic psychosocial stress

The hippocampus has long been proved to be implicated in several learning and memory processes. Being integrated into the limbic-hypothalamus-pituitary-adrenal axis, the hippocampus also plays an active role in the regulation of the stress response. Long lasting elevated levels of glucocorticoids resulting from a prolonged stress exposure affect hippocampal functions and structure, inducing learning and memory alterations and suppressing cell proliferation in the adult dentate gyrus. Here, adult male tree shrews (Tupaia belangeri) exposed to chronic psychosocial stress were tested repeatedly on a holeboard apparatus using two different learning tasks devised to evaluate hippocampal-dependent and hippocampal-independent cognitive function. We show that chronic stress enhanced learning in animals performing the hippocampal-dependent task, whereas no stress-induced effect was found in the hippocampal-independent task. Additionally, after five weeks of stress, cell proliferation was reduced in the hippocampal dentate gyrus. These results indicate that specific memory processes not only may remain intact, but indeed are facilitated by chronic stress, despite elevated cortisol levels and suppressed hippocampal cell proliferation.     

Decreased redox state in red blood cells from patients with sarcoidosis

BACKGROUND AND AIM OF THE WORK: The glutathione system has a key role in the defence against oxidative stress. To function properly, this system needs NADPH to maintain glutathione (GSH) in its reduced form. We hypothesized that the clinical problems associated with sarcoidosis might be related to a decreased anti-oxidant defence and we therefore measured the activity of the NADPH-generating enzyme glucose-6-phosphate dehydrogenase (G6PD), the GSH-regenerating enzyme glutathione reductase (GR) and indirectly the level of NADPH in red blood cells from patients with sarcoidosis. METHODS: In a population of sarcoidosis (n = 88) patients, G6PD, GR and GR activity after incubation with chromate (GR-Cr) were measured in erythrocytes. A decreased concentration of NADPH was revealed by an increased GR-Cr (> 0.6 IU/g Hb). To exclude a mutation in the G6PD gene, sequencing was performed in cases with an abnormal GR-Cr. Sarcoidosis pulmonary disease severity was evaluated by means of laboratory data, radiographic staging, HRCT scoring, pulmonary function and exercise capacity testing. RESULTS: Fourteen (29.2%) females and one (2.5%) male demonstrated an increased GR-Cr test, indicative of a decreased NADPH level. Patients with an abnormal test result demonstrated also significantly increased ACE and GR values (p < 0.05). Only one female case (of 6 tested) appeared to have a mutation in the G6PD gene. CONCLUSION: In a considerable percentage of female patients with sarcoidosis, a decreased level of NADPH in the erythrocytes was found.     

Eradication of glioblastoma,and breast and colon carcinoma xenografts by Hsp70 depletion

Heat shock protein 70 (Hsp70) is an antiapoptotic chaperone protein highly expressed in human tumors. Here we demonstrate that locoregional application of adenovirus expressing antisense Hsp70 cDNA (Ad.asHsp70) eradicates orthotopic xenografts of glioblastoma and breast carcinoma, as well as s.c. xenografts of colon carcinoma in immunodeficient mice. Ad.asHsp70-treated tumors showed massive apoptosis-like cell death and recruitment of macrophages. Human monocyte-derived macrophages effectively removed the corpses of Ad.asHsp70-treated tumor cells in vitro. Interestingly, both tumor cell death and phagocytosis were caspase-independent. Thus, Hsp70 appears as a promising target for the treatment of cancers resistant to classic caspase-mediated apoptosis.     

The impact of a self-help pamphlet on reducing risk drinking among 30- to 49-year-old men in Helsinki, Finland

This study evaluates the impact of a self-help pamphlet designed to support self-control of drinking. It was conducted in Helsinki, Finland, in 2001 and 2002 and focused on men between 30 and 49 years of age. The respondents were randomly selected in an intervention and a control area and compared with each other before and after the intervention using independent samples (N = 4418) The results support previous findings showing that interventions like this serve as a supplement to other prevention and early treatment measures. Although the results were encouraging, there is a need for more in-depth studies in the field.     

Carotid stenosis degree in CT angiography: assessment based on luminal area versus luminal diameter measurements

The aim of this study was to investigate CT angiography (CTA) luminal area measurements in the assessment of carotid artery stenosis compared with the current clinically used criteria based on lumen diameter measurements. Seventy-two vessels in 36 patients were evaluated by CTA and digital subtraction angiography (DSA). Two observers measured area and diameter stenosis degrees using automated 3D CTA analysis software. The ratio of the largest/smallest luminal diameter at the level of maximal stenosis (L/S ratio) was used to describe lumen morphology. Diagnostic agreement between CTA and DSA was calculated. For the assessment of area stenosis, interobserver and intraobserver correlation coefficients were 0.898 and 0.906 (p<0.001). The correlation coefficient between the diameter stenosis and area stenosis was lower in stenoses with extremely noncircular lumen (L/S ratio 1.5) (r=0.797, p<0.001) compared with stenoses with circular lumen (LS ratio <1.2) (r=0.978, p<0.001). Only satisfactory agreement ( 0.54-0.77, p<0.001) was obtained between area stenosis on CTA and diameter stenosis on DSA. Assessment of stenosis degree with area measurements on 3D CTA proved to be reproducible. Area stenosis provides a less-severe estimate of the degree of carotid stenosis but might theoretically express the real hemodynamic significance of the lesion better than diameter stenosis, especially in stenoses with noncircular lumen.     

Impairment of lung function in asbestos-exposed workers in relation to high-resolution computed tomography

OBJECTIVES: The aim of the study was to determine the causes of impairment of ventilatory function and diffusing capacity in smoking asbestos-exposed workers (N=590) showing radiological pleural thickenings or pulmonary fibrosis. METHODS: High-resolution computed tomography (HRCT) and spirometry were performed, and diffusing capacity was measured. The workers were divided into five groups based on the HRCT scoring: pleural disease (N=190), pulmonary fibrosis (N=68), emphysema (N=148), combined fibrosis and emphysema (N=74), and marked adhesions (N=110). The graded lung function impairment was compared between the groups. RESULTS: Moderate impairment of forced expiratory volume in 1 second [odds ratio (OR) 2.72, 95% confidence interval (95% CI) 1.31-5.57] and forced vital capacity (OR 2.81, 95% CI 1.05-6.89) was associated with the persons with combined fibrosis and emphysema. Marked impairment of diffusing capacity was associated with the combined fibrosis and emphysema (OR 4.94, 95% CI 2.48-9.77) but not with pleural disease (OR 0.21, 95% CI 0.09-0.45) or pulmonary fibrosis (OR 0.36, 95% CI 0.08-1.05). For the persons with combined fibrosis and emphysema, the mean fibrosis score did not differ between normal, slightly reduced, or markedly reduced diffusing capacity, but the emphysema score was significantly higher for the patients with marked impairment than for those with normal diffusing capacity (P < 0.01). CONCLUSIONS: Different profiles of asbestos- and smoking-induced pulmonary or pleural disease were found. The results indicate that the most important factor determining the degree of functional impairment in smoking asbestos-exposed workers is the presence of pulmonary emphysema.     

Regeneration of human auditory nerve. In vitro/in video demonstration of neural progenitor cells in adult human and guinea pig spiral ganglion

Time lapse video recordings of cultured adult human and guinea pig spiral ganglion (hSG and gpSG) show that mitogen responsive progenitor/stem cells develop in the form of spheres that proliferate and differentiate into mature neurons and glia cells. Neurospheres, cultured with EGF and bFGF showed expression of nestin and incorporation of 5'-Bromo-2-deoxyuridine (BrdU). Newly formed BrdU labelled cells were positive for beta-tubulin, and also for GFAP demonstrating that neuronal cells were derived from a dividing population of progenitor cells. Dissociated spheres cultured either with glia cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), induced differentiation of the progenitor cells. Video microscopy showed that neurons develop from subcultured spheres maintained for up to four weeks. Neurons showed fasciculation and migration with a speed of 10-30 microm/h, and some cells had up to 6 mm long neurites coexpressing TrkB and TrkC receptors. Precise dissection suggests that the neurons formed are cochlea-specific. The results suggest that the mammalian auditory nerve has the capability for self-renewal and replacement. Transplantation of progenitor cells together with established means to induce neural differentiation and fiber growth may facilitate strategies for better repair and treatment of auditory neuronal damage.     

Distinct molecular portraits of human failing hearts identified by dedicated cDNA microarrays

Aims: This study aimed to investigate whether a molecular profiling approach should be pursued for the classification of heart failure patients. Methods and results: Applying a subtraction strategy we created a cDNA library consisting of cardiac- and heart failure-relevant clones that were used to construct dedicated cDNA microarrays. We measured relative expression levels of the corresponding genes in left ventricle tissue from 17 patients (15 failing hearts and 2 nonfailing hearts). Significance analysis of microarrays was used to select 159 genes that distinguished between all patients. Two-way hierarchical clustering of the 17 patients and the 159 selected genes led to the identification of three major subgroups of patients, each with a specific molecular portrait. The two nonfailing hearts clustered closely together. Interestingly, our classification of patients based on their molecular portraits did not correspond to an identified etiological classification. Remarkably, patients with the highest medical urgency status (United Network for Organ Sharing, Status 1A) clustered together. Conclusion: With this pilot feasibility study we demonstrated a novel classification of end-stage heart failure patients, which encourages further development of this approach in prospective studies on heart failure patients at earlier stages of the disease.     

Evaluation of the MDHAQ in Finnish patients with RA [corrected

OBJECTIVE: To study the characteristics of the Multidimensional Health Assessment Questionnaire (MDHAQ) in Finnish patients with rheumatoid arthritis. METHODS: The reliability of the questionnaire was tested by test-retest procedure. Construct validity was studied by factor analysis and convergent validity by calculating correlations between the Finnish MDHAQ (Finn-MDHAQ) scales and the Finnish Health Assessment Questionnaire (HAQ) and the Finnish Arthritis Impact Measurement Scales (Finn-AIMS2). Correlations between Finn-MDHAQ and measures of clinical characteristics, disease activity, and functional class were also measured. An item analysis was made of the Finn-MDHAQ scales Function (FN) and Psychological (PS). RESULTS: Internal consistency on the FN scale was 0.92 (95% lower limit 0.89) and 0.66 (0.56) on the PS scale. Reproducibility (95% CI) on FN was 0.93 (0.82 to 0.97) and on PS 0.84 (0.70 to 0.92). Factor analysis identified 2 factors, mobility of upper extremities and trunk, and mobility of lower extremities. Strong correlations were found between the FN scale and HAQ and physical subscales of Finn-AIMS2 and between PS and the psychological subscales of Finn-AIMS2. In item analysis corrected item correlation was high on the Finn-MDHAQ scales, except in one item on the PS scale. CONCLUSION: The Finn-MDHAQ is an applicable, reliable, and valid instrument for the part of the FN scale measuring functional ability in Finnish rheumatic patients. The incongruity in the PS scale structure that produced moderate internal consistency can be overcome with minor modifications.     

Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain

PURPOSE: Breast cancer resistance protein (BCRP) is a half adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed on cellular membranes and included in the group of multidrug resistant (MDR)-related proteins. Recently, upregulation of different MDR proteins has been shown in human epilepsy-associated conditions. This study investigated the expression and cellular distribution of BCRP in human control and epileptic brain, including a large number of both neoplastic and nonneoplastic specimens from patients with chronic pharmacoresistant epilepsy. METHODS: Several epileptogenic pathologies, such as hippocampal sclerosis (HS), focal cortical dysplasia (FCD), dysembryoplastic neuroepithelial tumor, oligodendroglioma astrocytoma, and glioblastoma multiforme were studied by using Western blot and immunocytochemistry. RESULTS: With Western blot, we could demonstrate the presence of BCRP in both normal and epileptic human brain tissue. In contrast to P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2, BCRP expression levels did not change in tissue from patients with HS, compared with control hippocampus. No BCRP immunoreactivity was observed in glial or neuronal cells, including reactive astrocytes and dysplastic neurons in FCD. BCRP expression was, however, increased in tumor brain tissue. Immunocytochemistry demonstrated that BCRP was exclusively located in blood vessels and was highly expressed at the luminal cell surface and in newly formed tumor capillaries. This localization closely resembles that of P-gp. The higher expression observed in astrocytomas by Western blot analysis was related to the higher vascular density within the tumor tissue. CONCLUSIONS: These results indicate a constitutive expression of BCRP in human endothelial cells, representing an important barrier against drug access to the brain. In particular, the strong BCRP expression in the microvasculature of epileptogenic brain tumors could critically influence the bioavailability of drugs within the tumor and contribute to pharmacoresistance.