Ageing and diabetes: implications for brain function

Polymorphisms of the renin-angiotensin system are associated with cardiovascular disorders, possibly as a consequence of increased brain angiotensin II activity. Within the brain, angiotensin controls blood pressure, fluid balance and hormone secretion; it also influences behaviour: reduction of central angiotensin function has both antidepressant-like and axiolytic-like actions. Evidence concerning the role of the renin-angiotensin system in learning and memory is contradictory, although more studies support the proposal that angiotensin reduces cognitive function. Studies of renin-angiotensin system genotype and psychological status have suggested an association between the angiotensin-converting enzyme deletion allele and age related cognitive decline, but a greater prevalence of the insertion allele in Alzheimer's disease. The deletion allele has also been associated with depressive illness, as has the M allele of the angiotensinogen gene although other studies have failed to replicate these findings. The role of the brain renin-angiotensin system in human psychopathology remains to be fully explored.     

Alterations of slow and fast rod ERG signals in patients with molecularly confirmed Stargardt disease type 1

PURPOSE: To investigate the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients with molecularly confirmed Stargardt disease type I (STGD1). There is evidence that these slow and the fast rod ERG signals can be attributed to the rod bipolar-AII cell pathway and the rod-cone coupling pathway, respectively. METHODS: Twenty-seven patients with STGD1 with mutations in both alleles of the ABCA4 gene were included. Scotopic ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic troland x sec (log scot td x sec) were measured at a flicker frequency of 15 Hz. In addition, scotopic standard ERGs were obtained. Twenty-two normal subjects served as controls. RESULTS: The amplitudes of both the slow and fast rod ERG signals were significantly reduced in the STGD1 group. The phases of the slow rod signals lagged significantly, whereas those of the fast rod signals did not. The standard scotopic ERG did not reveal significant alterations. CONCLUSIONS: The results provide evidence that a defective ABCA4 transporter can functionally affect both the rod bipolar-AII cell pathway and the rod-cone coupling pathway. In STGD1, the scotopic 15-Hz flicker ERG may reveal subtle abnormalities at different sites within the rod system that remain undetected by standard ERG techniques.     

Clinical relevance of protein-tyrosine (De-)phosphorylation in head and neck cancer

Previous studies have shown that protein tyrosine (de)phosphorylation plays an important role in head and neck cancer. Protein-tyrosine kinases (PTK) and protein-tyrosine phosphatases (PTPase) activities in the cytosol of tumor tissue were significantly increased compared to normal tissue of cancer patients as well as controls. Additionally, the enzyme activities in normal tissue of tumor patients were significantly higher than enzyme activities in normal tissue of the control group. In this paper, we have correlated the cytosolic and membranous PTK and PTPase activity of tumor and nontumor tissue with several clinical and histological parameters known to influence the clinical outcome. Furthermore, we have analyzed the value of the enzyme activities as an independent predictor of clinical behavior and occurrence of second primary tumors. We confirmed our earlier observations that cytosolic and membranous PTK activities and cytosolic PTPase activities in tumor tissues are increased compared to activities in nontumor tissues and controls. Moreover, we also confirmed the findings of increased enzyme activities in nontumor tissues compared to findings in control tissues. This finding in histologically proven healthy mucosa is highly interesting because it indicates that these biochemical changes are obviously not (yet) translated into morphological changes. Significant differences were found in membranous PTK activity when the patients were grouped by sex, tumor localization, lymph node metastasis, and previous radiotherapy. During the follow-up period, no relation could be found between enzyme activities in tumor and/or nontumor tissues and disease-free interval or occurrence of second primary tumors.     

Dual pathway for angiotensin II formation in human internal mammary arteries

1. Angiotensin converting enzyme (ACE) is thought to be the main enzyme to convert antiotensin I to the vasoactive angiotensin II. Recently, in the human heart, it was found that the majority of angiotensin II formation was due to another enzyme, identified as human heart chymase. In the human vasculature however, the predominance of either ACE or non-ACE conversion of angiotensin I remains unclear.
2. To study the effects of ACE- and chymase-inhibition on angiotensin II formation in human arteries, segments of internal mammary arteries were obtained from 37 patients who underwent coronary bypass surgery.
3. Organ bath experiments showed that 100 μM captopril inhibited slightly the response to angiotensin I (pD₂ from 7.09±0.11–6.79±0.10, P<0.001), while 100 μM captopril nearly abolished the response to [pro¹⁰] angiotensin I, a selective substrate for ACE, and the maximum contraction was reduced from 83±19%–23±17% of the control response (P=0.01). A significant decrease of the pD₂ of angiotensin I similar to captopril was observed in the presence of 50 μM chymostatin (pD₂ from 7.36±0.13–6.99±0.15, P<0.039), without influencing the maximum response. In the presence of both inhibitors, effects were much more pronounced than either inhibitor alone, and a 300 times higher dose was needed to yield a significant contraction response to angiotensin I.
4. These results indicate the presence of an ACE and a non-ACE angiontensin II forming pathway in human internal mammary arteries.

     

Haematological pathology of shell lesions in the New Zealand abalone,<Emphasis Type="Italic"> Haliotis iris</Emphasis> (Mollusca: Gastropoda)

The aim of this study was to establish normal values of haemocyte counts, serum levels of total protein, glucose, LDH, ALT, AST, amylase, Ca²⁺ and Fe²⁺ and muscle glycogen content of clinically healthy abalone, and to evaluate the effect of a pathological shell condition on these analytes. Haematology and serum chemistry values are presented from 70 clinically healthy abalone, 56 mildly affected abalone and 31 severely affected abalone housed under laboratory conditions. The total number of circulating haemocytes (13.1×10⁶ cells/ml) and proportion of circulating hyalinocytes (53%) increased significantly (P<0.05) in abalone with severe shell lesions. The proportion of haemocyte stem cells of severely affected abalone (12%) was below the calculated reference ranges (19%–25%, P>0.05). Severely affected abalone had significantly (P<0.05) elevated levels of haemolymph glucose (>20 g/l), and their adductor muscles contained least glycogen (0.95 mg/g). Based on our findings, comprehensive reference values are provided, but we were unable to validate the diagnostic value of the serum chemistry analytes.Abbreviations Tot HC total number of circulating haemocytes - Diff HC differential haemocyte count - LDH lactate dehydrogenase - ALT alanine amino transferase - AST aspartate amino transferase - ALP alkaline phosphatase - GGT gamma glutamyltranspeptidase - CK creatinine kinase - Ca²⁺ calcium - Fe²⁺ iron - Na⁺ sodium - K⁺ potassium     

Expression of cytokeratins and vimentin in epithelial cells of normal and pathologic thyroid tissue

Summary The presence of intermediate filament proteins of the cytokeratin and vimentin type was evaluated in normal and pathologically changed thyroid tissue specimens. Using the indirect immunoperoxidase technique with 4 different cytokeratin monoclonal antibodies: RCK114 (broad spectred), K2080 (broad spectred), RGE53 (directed against component 18, present in simple epithelium) and RKSE60 (directed against component 10, associated with keratinization). Co-expression of cytokeratin and vimentin was evaluated with a double immunoenzyme staining technique.The results indicate that normal and transformed cells express cytokeratins of the non-epidermal type. Cytokeratins of the epidermal type are sometimes present in carcinomas. They do not differentiate in tumour type (i.e. papillary, follicular, anaplastic or medullary carcinoma).The co-expression of cytokeratins and vimentin is not restricted to carcinomas: in a small percentage of cases it is also present in normal epithelial cells of the thyroid gland. Moreover, the distribution pattern of cytokeratins and vimentin within the cell is changed in malignant transformed epithelial cells of the gland and seems to be inversely related to the degree of differentiation of these cells. The implications of our findings for the possible use of cytokeratins and vimentin in diagnostic pathology are discussed.     

Coping mechanisms, perception of health and cardiovascular dysfunction in Africans.

The purpose of this study was to compare active and passive coping strategies of Africans with perception of own health and cardiovascular data. The subjects included 236 apparently healthy Africans (men=109; women=127). The COPE questionnaire was adapted, translated and validated for Africans. Scores on reliable sub-scales were used to classify men and women into more active coping (AC) and more passive coping (PC) subgroups. The General Health Questionnaire measured subjective perception of health. Blood pressure was recorded before and during application of the handgrip test, using the Finapres, a continuous non-invasive blood pressure monitor. Plasma renin activity (PRA) values, measured with radio immuno assay, were compared to blood pressure variables. Analyses of co-variance, adjusted for resting values and age, indicated that PC men responded with a larger increase in total peripheral resistance (TPR) (p=0.006), larger decrease in stroke volume (p=0.07), smaller increase in cardiac output (p=0.09) and larger increases in PRA resting (p=0.04) and reactivity (p< or =0.05) values. PC subjects reported a more negative perception of health than AC subjects. Young PC women presented greater hypertension prevalence rates (p< or =0.01) than AC women. In conclusion, all AC and PC subjects reacted with increased vascular reactivity on the handgrip test. PC men presented enhanced vascular reactivity, PRA and perception of poorer health values.     

Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells

Two different types of CpG motif-containing oligonucleotides (CpG ODN) have been described: CpG-A with high induction of IFN-alpha in plasmacytoid dendritic cells; and CpG-B with little induction of IFN-alpha, but potent activation of B cells. In this study, we demonstrate that CpG-A fail to activate B cells unless plasmacytoid dendritic cells are present. We identified a new set of CpG ODN sequences which induces high levels of IFN-alpha in plasmacytoid dendritic cells but remains capable of directly activating B cells. These new CpG ODN (termed CpG-C) are more potent stimulants of B cells than CpG-B due to their ability of directly and indirectly (via plasmacytoid dendritic cells) activating B cells. The sequence of CpG-C combines structural elements of both CpG-A and CpG-B. The most potent sequence, M362, contains a 5'-end 'TCGTCG-motif' and a 'GTCGTT-motif', both of which are present in CpG-B (ODN 2006); a palindromic sequence characteristic for CpG-A (ODN 2216); but no poly G motif required for CpG-A. In conclusion, we defined the first CpG-containing sequences that potently activate both TLR9-expressing immune cell subsets in humans, the plasmacytoid dendritic cell and the B cell. CpG-C may allow for improved therapeutic immuno-modulation in vivo.