Do aluminium and/or glutamate induce Alzheimer PHF-like formation? An electron microscopic study

Paired helical filaments (PHFs) constitute the majority of filaments in neurofibrillary tangles (NFTs), an Alzheimer's disease (AD) characteristic. PHFs consists of two filaments helically twisted around one another in a regular pattern. The effects of possible PHF-inducing candidates, namely aluminium and glutamate, were observed at the ultrastructural level in this investigation. Rat cerebral explants were exposed to aluminium, citric acid and glutamate singly or combined from 7–12 days in vitro (DIV), while control explants remained in basal medium. On 12 DIV, explants were processed for EM. Three–four EM explants were serially sectioned per condition. Ten 60 nm sections from five systematically sampled areas per explant were collected. One section was randomly chosen per sampled area and all neurons within it observed at 81 200– to record the presence of accumulations of curved filaments (CFs), straight filaments (SFs) or PHFs. Using stereological methods, absolute numbers and the percentage incidence of CFs and SFs were calculated. A significant increase in the frequency of neurons containing CF aggregations in aluminium explants compared to glutamate explants was found. There were no significant differences between conditions for neurons containing SF accumulations. Possible PHFs were observed in one aluminium/glutamate-treated explant. These results suggest that aluminium alone can cause significant formation of accumulations of C- or S-shaped CFs, some of which are double-stranded and twisted around one another regularly. However, structures that were possibly PHF-like were only observed in one aluminium-treated explant, thus making it premature to draw an association between aluminium and the induction of AD-like pathology.     

The Future Detection and Prevention of Institutional Abuse: Giving Children a Chance to Participate in Research

The involvement of children in research studies is historically fraught with difficulties. Experiments on children without their consent or knowledge have been carried out in the past and thus the need for stringent ethical control is undoubtedly necessary. However this paper argues that the need to protect children from unethical research has somehow become entwined in the web of secrecy that surrounds the very nature of child abuse. In the name of 'protection' are children in danger of not having their voice heard?

In the foreword to 'Listening to Children' (Alderson, 1995) Roger Singleton writes, 'much research is carried out on and about children, but seldom with children. Children themselves are often strangely silent'. This paper draws on recent literature on the institutional abuse of young people in residential care and the lack of voice that those abused in residential care have traditionally had, suggesting that their silence is not 'strange' but perhaps contrived.

This paper does not repeat the work of Alderson (1995) and make suggestions as to how research with children may best be carried out, but seeks to address the issues in relation to research with children who are in institutions.     

Proteinase inhibitors reduce basement membrane degradation by human breast cancer cell lines.

The relative importance of different proteinases, and their inhibition, in the breakdown of human endothelial basement membrane (BM) by MDA-MB-231 and MCF7ADR human breast cancer cell lines has been studied using 35S-labelled BM-coated 96-well culture plates. Basement membrane degradation (BMD) was independent of cell proliferation above the seeding density. Inhibitors of aspartic (pepstatin and PD 134678-0073) and cysteine proteinases (E64) had little effect on BMD under normal culture conditions, suggesting that cathepsins D, B and L have only a minor role. In contrast, inhibitors of urokinase-type plasminogen activator (uPA) and/or plasminogen activation to plasmin (aprotinin, amiloride, EACA, tranexamic acid, anti-uPA antibody) all reduced BMD by MDA-MB-231 cells by approximately 30-40%, but only in the presence of serum or plasminogen. BB94, an inhibitor of matrix metalloproteinases (MMPs), also reduced BMD by about 30% under these conditions but was similarly effective in serum-free medium. Combinations of BB94 with any of the uPA/plasminogen activation inhibitors in serum-containing medium had additive effects, while BB94 with pepstatin and E64 under serum-free conditions reduced BMD to 16% of control. Serum-containing conditioned medium exhibited appreciable BMD, largely due to aprotinin-inhibitable activity. Although small reductions in cell proliferation were seen with some inhibitors, the combination of BB94 with E64 or E64d reduced the cell population by about 60% under serum-containing conditions. These in vitro observations suggest that combinations of proteinase inhibitors, particularly of uPA/plasminogen activation and MMPs, may merit clinical evaluation as potential antimetastatic therapy for breast cancer.     

A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish national birth cohort

As a prerequisite to the use of the Finnish National Hospital Discharge Register in psychiatric epidemiological research, we studied the diagnostic reliability of the register in terms of the psychiatric morbidity experienced by a national birth cohort. We investigated all entries to the register for a sample based upon the Northern Finland 1966 birth cohort at the age of 16 years (n=11017). Until the end of 1993 (age 27 years), a total of 563 subjects had a register diagnosis indicating a psychiatric illness, 37 of them being schizophrenia. When operational criteria (DSM-III-R) were applied to clinical information in the available original hospital records for cases of psychosis, personality disorder and substance abuse (n=249), 71 fulfilled criteria for schizophrenia, including all of the 37 cases in the register and an additional 34 (48% false-negatives), most frequently diagnosed in the register as schizophreniform or other psychosis. Despite the official use of DSM-III-R nomenclature, it appears that the clinical concept of schizophrenia in Finland, manifest within the register, remains very restrictive. The application of operational criteria is a necessary prerequisite for scientific research on schizophrenia.     

Relationship of "bleeding on probing" and "gingival index bleeding" as clinical parameters of gingival inflammation

Abstract Bleeding on probing (BOP) and the gingival index have been used to clinically characterize the degree of gingival inflammation. It is, however, unclear to what extent these parameters correlate to each other and to probing pocket depth (PD). The purpose of this clinical study was to evaluate the association between BOP and GI bleeding (scores of 2 and 3), as well as the relationship of these variables to PD, in a group of patients presenting with naturally-occurring gingivitis. Based on screening examinations of 125 subjects with at least 20 teeth, no more than 4 sites with PD over 6 mm, a BOP frequency of 30% or greater, and no systemic condition that would influence the inflammatory response, were selected. 2 weeks after screening they were examined at 6 sites per tooth for plaque index, GI, PD and BOP. A standardized pressure sensitive probe (Florida Probe) with 20 g probing force was used for BOP and PD measurements. In this population, means of 40.9% (S.E.= 1.36) BOP sites and 35.3% (S.E, = 1.81) GI bleeding sites per patient were found. A total of 20,008 sites ranging in PD up to 5.9 mm were evaluated; however, the majority of sites (19,723, 98.6%) presented with <4 mm PD. When sites were evaluated, BOP demonstrated a positive correlation with PD, whereas GI bleeding correlated with PH. For sites characterized by the absence of BOP as well as the absence of GI bleeding (scores 0 and 1), the highest % of agreement between the 2 indices (77.7%) was found in shallow sites (0.1–2 mm). In contrast, when sites presenting with both BOP and GI bleeding were analyzed, the highest % of agreement (85,4%) was found for sites with PD >4.0 mm. In this gingivitis population group, it appears that BOP and GI bleeding evaluate distinct inflammatory1 conditions of the gingival tissues, and the relationship between the 2 clinical parameters may vary according to PD at the individual site examined.     

Relation between toxicity and carcinogenesis in the kidney: an heuristic hypothesis

Cellular toxicity and cellular carcinogenesis are closely linked. In the kidney, this relationship has been emphasized by the recent discovery of a number of putatively non-mutagenic chemicals that result in acute and chronic toxicity and ultimately in carcinogenesis, especially in the male rat. Many, but not all such compounds, result in renal PTE phagolysosomal overload. At the same time, known metabolites of other carcinogens, e.g., HCBD and FBPA, result in acute renal injury and/or necrosis, followed by chronic tubular disease, interstitial nephritis, and ultimately carcinogenesis. A series of cell mechanisms have been suggested that lead from acute cell injury to altered control of cell division. These mechanisms appear to involve ion deregulation, (especially [Ca2+]i) resulting from a variety of continued injuries, (e.g., oxidative stress from inflammatory cells) and ultimately leading to altered gene expression.