In the last 10 years most people in the western world have become fully aware of the medical and social dimensions of Alzheimer's disease. One might conclude, therefore, that the life of Aloys Alzheimer (1864-1915) would be an object of intensive study. However, compared to other scientists from the turn of the century, our knowledge of Alzheimer is still limited. One of the most decisive factors in his life was Emil Kraepelin, the real "inventor" of the Alzheimer dementia. A critical-historical attitude should be especially maintained if one looks at Alzheimer's dementia, Alzheimer's famous "discovery". Many of today's psychiatrists would assume that the description of Alzheimer's disease was the scientific climax of Alzheimer's professional life and the ultimate aim of his research. However, this view is the result of our modern knowledge. Kraepelin's creation of Alzheimer's disease in 1909 was not based on a large number of "objective" findings, but on his idea of "nosological entities". Alzheimer's disease is a striking example of the fact that a new medical idea must comprise conceptual prerequisites, clinical observations and innovative technologies.

Alzheimer Disease↗

PubMedDate not supplied

Clinical predictors of malaria in Gambian children with fever or a history of fever.

Diagnosis of malaria in children is difficult without laboratory support because the symptoms and signs of malaria overlap with those of other febrile illnesses such as pneumonia. Nevertheless, in many parts of Africa diagnosis of malaria must be made without laboratory investigation. Therefore, a scoring system has been developed to assist peripheral health care workers in making this diagnosis. Four hundred and seven Gambian children aged 6 months to 9 years who presented to a rural clinic with fever or a recent history of fever were investigated. A diagnosis of malaria was made in 159 children who had a fever of 38 degrees C or more and malaria parasitaemia of 5000 parasites/microL or more. Symptoms and signs in children with malaria were compared with those in children with other febrile illnesses to identify features which predicted malaria. Symptoms and signs were incorporated into various logistic regression models to test which were best independent predictors of malaria and these regression models were used to construct simple scoring systems which predicted malaria. A nine terms model predicted clinical malaria with a sensitivity of 89% and a specificity of 61%, values comparable to those obtained by an experienced paediatrician without laboratory support. The ability of peripheral health care workers to diagnose malaria using this approach is now being investigated in a prospective study.

Antimalarials↗

PubMedDate not supplied

Increased activity of catalase in tumor cells overexpressing IGFBP-2.

Elevated levels of IGFBP-2 are found in serum and tissues under various stressful conditions and in many malignancies. In previous studies, we have shown that overexpression of IGFBP-2 results in increased tumorigenic potential in Y-1 mouse adrenocortical tumor cells, and that these effects are presumably mediated through IGF-independent mechanisms. Here, we show that highly proliferative IGFBP-2-overexpressing Y-1 cells, but not control Y-1 cells, grow to very high cell densities. In order to evaluate whether the increased cell densities in IGFBP-2-transfected Y-1 cells were accompanied by alterations in the oxidative stress system, we analyzed the effect of IGFBP-2 overexpression on the activity of various antioxidative enzymes in two malignant cell lines. Among the tested antioxidative enzymes (catalase, superoxide-dismutase, glutathione peroxidase, glutathione S-transferase), only catalase enzyme activity was significantly higher in IGFBP-2-transfected Y-1 mouse adrenocortical tumor cells and in IGFBP-2-transfected human colon tumor cells (Caco-2) compared to control-transfected Y-1 and Caco-2 cells and non-tumor 293 human epithelial cells. However, overexpression of catalase in malignant cells did not result in increased resistance to oxidative stress as measured by cell viability and protein oxidation after treatment of the cells with hydrogen peroxide. This might be due to an upregulation of the GST enzyme activity after treatment with H (2)O (2) that we observed selectively in the control-transfected Y-1 cells and which might compensate for the higher catalase activity in the IGFBP-2 overexpressing cells. In summary, we found a strong and selective upregulation of the catalase activity in IGFBP-2 overexpressing malignant Y-1 and Caco-2 cell lines that might contribute to the highly malignant phenotype of IGFBP-2 overexpressing tumors through as yet unknown mechanisms.

Adrenal Cortex Neoplasms↗

PubMedDate not supplied

Characterization of insulin-like growth factor binding proteins (IGFBPs) secreted by bovine adrenocortical cells in primary culture: regulation by insulin-like growth factors (IGFs) and adrenocorticotropin (ACTH).

In previous studies, we have shown that insulin-like growth factor II (IGF-II) stimulates basal as well as ACTH-induced cortisol secretion from bovine adrenocortical cells more potently than IGF-I [1]. The steroidogenic effect of both IGFs is mediated through interaction with the IGF-I receptor, and modified by locally produced IGF-binding proteins (IGFBPs). In the present study, we therefore characterized the IGFBPs secreted by bovine adrenocortical cells in primary culture, and investigated the effect of corticotropin (ACTH) and recombinant human IGF-I and IGF-II on the regulation of IGFBP synthesis. By Western ligand blotting, four different molecular forms of IGF-binding proteins were identified in conditioned medium of bovine adrenocortical cells with apparent molecular weights of 39-44 kDa, 34 kDA, 29-31 kDa, and 24 kDa. In accordance to their electrophoretic mobility, glycosylation status and binding affinity, these bands were identified by immunoprecipitation and immunoblotting as IGFBP-3, IGFBP-2, IGFBP-1, and deglycosilated IGFBP-4, respectively. Quantification of the specific bands by gamma counting revealed that, in unstimulated cells, IGFBP-3 accounts for approximately half of the detected IGFBP activity, followed by IGFBP-1, IGFBP-2 and IGFBP-4. ACTH treatment predominantly increased the abundance of IGFBP-1 and to a lesser extent IGFBP-3 in a time and dose-dependent fashion. In contrast, IGF-I or IGF-II (6.5 nM) preferentially induced the accumulation of IGFBP-3 (1.9-fold) and to a lesser extent of IGFBP-4, but did not show any effect on IGFBP-1. When ACTH and IGFs were combined, an additive stimulatory effect on the accumulation of IGFBP-3 and IGFBP-4 was observed. In contrast to their different steroidogenic potency, no significant difference in the stimulatory effect of IGF-I and IGF-II on IGFBP secretion was found. In conclusion, bovine adrenocortical cells synthesize IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4, and their secretion is regulated differentially by ACTH and IGFs. These results, together with earlier findings, suggest that IGF-binding proteins play a modulatory role in the regulation of differentiated adrenocortical functions. Therefore, bovine adult adrenocortical cells provide a useful tissue culture model in which the complex interactions between two IGF-ligands, at least four IGF binding proteins and two IGF-receptors can be evaluated.

Adrenal Cortex↗

PubMedDate not supplied

Beneficial effects of human serum albumin on stability and functionality of alginate microcapsules fabricated in different ways.

A key engineering challenge in designing microcapsules made from biocompatible alginate is maintaining adequate exchange of nutrients and oxygen between the entrapped cells and the environment, while simultaneously avoiding swelling and subsequent failure of the microcapsule. Approval for the use of alginate in pharmaceutical and/or biomedical applications also strictly requires that the components of the microcapsule material must meet the safety criteria of the ASTM and FDA. Incorporation of foetal calf serum (FCS) into the microcapsules for stabilization is not in accordance with the guidelines affirmed by these organizations. FCS should be substituted by microcapsule-stabilizing additives that are medically approved. In this communication, it is shown that 10% FCS can be replaced by 1% human serum albumin (i.e. by an agent for which medical approval is granted) without compromising effects on long-term in vitro stability. Furthermore, it is demonstrated that human serum albumin (HSA) significantly enhances cell survival and, particularly, insulin secretion of encapsulated rat islets over a time period of 3 weeks when incubated in culture medium. Thus, HSA-stabilized microcapsules made from UHV(Lam) alginate are apparently a promising system for immunoisolation of cells, particularly when alginate is cross-linked by injection of BaCl(2) crystals into the alginate droplets. Slight adjustments of the alginate concentration can tailor the microcapsule permeability to the released therapeutic factor.

Alginates↗

PubMedDate not supplied

Growth hormone has no direct effect on human adrenal steroid and insulin-like growth factor-binding protein secretion.

Although it is known that growth hormone (GH) exerts its growth-promoting effects mainly via Insulin-like growth factor-I (IGF-I), an increasing number of direct effects of GH has been described in many tissues. In vivo, mice transgenic for human growth hormone (hGH) show significantly elevated levels of corticosterone, enlarged adrenal glands, and altered levels of insulin-like growth factor binding proteins (IGF-BPs). Recently, we have shown that IGF's induce the secretion of cortisol and IGF-BP's in adult human adrenocortical cells. However, since human adrenal glands express the intact GH-receptor, the objective of this study was to investigate whether GH exerts a direct effect on the steroidogenesis and IGF-BP synthesis in adult human adrenocortical cells. Primary cell cultures in monolayer were incubated under serum-free conditions with human growth hormone and/or ACTH for up to 72 hours. Cortisol was measured by specific RIA and the secretion of insulin-like growth factor binding proteins was analyzed by Western ligand blotting. hGH alone was unable to stimulate basal or ACTH-induced cortisol secretion. Additionally, neither hGH alone or in combination with ACTH did significantly alter the secretion of IGF-BP's. Therefore we conclude that hGH is unable to directly stimulate cortisol secretion and IGF-BP secretion in cultured human adrenocortical cells.

Adrenal Cortex↗