Investigations of the site and mechanisms of drug-induced reductions in the reabsorption of divalent cations by the kidney

Disturbances in electrolyte homeostasis are a frequent adverse side-effect of the administration of aminoglycoside antibiotics such as gentamicin, and the antineoplastic agent cis-platinum. The aims of this work were to further elucidate the site(s) and mechanism(s) by which these drugs may produce disturbances in the renal reabsorption of calcium and magnesium. These investigations were undertaken using a range of in vivo and in vitro techniques and models. Initially, a series of in vivo studies was conducted to delineate aspects of the acute and chronic effects of both drugs on renal electrolyte handling and to select and evaluate an appropriate animal model: subsequent investigations were focused on gentamicin. In a study of the acute and chronic effects of cis-platinum administration, there were pronounced acute changes in a variety of indices of nephrotoxic injury, including electrolyte excretion. Most effects resolved but there were chronic increases in the urinary excretion of calcium and magnesium. The renal response of three strains of rat (Fischer 344, Sprague-Dawley (SD), and Wistar) to a ranges of doses of gentamicin was also investigated. Drug administration produced substantially different responses between strains, in particular marked differences in calcium and magnesium excretion. The results suggested that the SD rat was an appropriately sensitive strain for use in further investigations. Acute infusion of gentamicin in the anaesthetised SD rat produced rapid, substantial increases in the fractional excretion of calcium and magnesium, while sodium and potassium output were unaffected, confirming previous results of similar experiments using F344 rats. Studies using lithium clearance measurements in the anaesthetised SD rat were undertaken to investigate the effects of gentamicin on proximal tubular calcium reabsorption. Lithium clearance was unaffected by acute gentamicin infusion, suggesting that the site of acute gentamicin-induced hypercalciuria may not be located in the proximal tubule. Inhibition of Ca2+ ATPase activity was investigated as a potential mechanism by which calcium reabsorption could be affected after aminoglycoside administration. In vitro, both Ca2+ ATPase and Na+/K+ ATPase activity could be similarly inhibited by the presence of aminoglycosides, in a dose-related manner. Whilst inhibition of Na+/K+ ATPase could be demonstrated biochemically after in vivo administration of gentamicin, there were no concurrent effects on Ca2+ ATPase activity, suggesting that inhibition of Ca2+ ATPase activity is unlikely to be a primary mechanism of aminoglycoside-induced reductions of calcium reabsorption. Histochemical studies could not discern inhibition of either Na+/K+ ATPase or Ca2+ ATPase activity after in vivo administration of gentamicin. Selection of renal cell lines for further investigative in vitro studies on the mechanisms of altered cation reabsorption was considered using MTT (3-(4,5,-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and Neutral Red cytotoxicity assays. The ability of LLC-PK1 and LLC-RK1 cell lines to correctly rank a series of nephrotoxic compounds with their known nephrotoxic potency in vivo was studied. Using these cell lines grown on semi-permeable inserts, alterations in the paracellular transport of 45Ca was investigated as a possible mechanism by which gentamicin could alter calcium reabsorption in vivo. Short term exposure (I h) of LLC-RK1 cells to gentamicin, via both cell surfaces, resulted in a reduction in paracellular permeability to both transepithelial 3H-mannitol and 45Ca fluxes. When LLC-RK1 cells were exposed via the apical surface only, similar dose-related reductions were seen to those observed when cells were exposed to the drug from both sides. Short-term basal exposure to gentamicin appeared to contribute less to the observed reductions in 3H-mannitol and 45Ca fluxes. Experiments investigating transepithelial movement of 45Ca and 3H-mannitol on LLC-PK1 cells after acute gentamicin exposure were inconclusive. Longer exposure (48 h) to gentamicin caused an increase in the permeability of the monolayer and a consequent increase in transepithelial 45Ca flux in the LLC-RK1 cell line; increases in permeability of LLC-PK1 cells to 45Ca and 3H-mannitol were not apparent under the same conditions. The site and mechanism at which gentamicin, in particular, alters calcium reabsorption cannot be definitively described from these studies. However, indirect evidence from lithium clearance studies suggests that the site of the lesion is unlikely to be located in the proximal tubule. The mechanism by which gentamicin exposure alters calcium reabsorption may be by reducing paracellular permeability to calcium rather than by altering active calcium transport processes.

Investigative framework for research into the design of manufacturing processes

This paper is based a major research project run by a team from the Innovation, Design and Operations Management Research Unit at the Aston Business School under SERC funding. International Computers Limited (!CL), the UK's largest indigenous manufacturer of mainframe computer products, was the main industrial collaborator in the research. During the period 1985-89 an integrated production system termed the "Modular Assembly Cascade'' was introduced to the Company's mainframe assembly plant at Ashton-under-Lyne near Manchester. Using a methodology primarily based upon 'participative observation', the researchers developed a model for analysing this manufacturing system design called "DRAMA". Following a critique of the existing literature on Manufacturing Strategy, this paper will describe the basic DRAMA model and its development from an industry specific design methodology to DRAMA II, a generic model for studying organizational decision processes in the design and implementation of production systems. From this, the potential contribution of the DRAMA model to the existing knowledge on the process of manufacturing system design will be apparent.

The question of question types in police interviews:a review of the literature from a psychological and linguistic perspective

The past two decades has seen a plethora of papers and academic research conducted on investigative interviews with victims, witnesses and suspected offenders, with a particular focus on questioning techniques and typologies. However, despite this research, there still remain significant discrepancies amongst academic researchers and practitioners over how best to describe types of questions. This article considers the available literature relating to interviews with children and adults from both a psychological and linguistic perspective. In particular, we examine how different types of questions are described, and explore the discrepancies between competing definitions. © 2010, equinox publishing.

The psychosocial impact of food allergy and food hypersensitivity in children, adolescents and their families:a review

Food allergy affects 6% of children but there is no cure, and strict avoidance of index allergens along with immediate access to rescue medication is the current best management. With specialist care, morbidity from food allergy in children is generally low, and mortality is very rare. However, there is strong evidence that food allergy and food hypersensitivity has an impact on psychological distress and on the quality of life (QoL) of children and adolescents, as well as their families. Until recently, the measurement of QoL in allergic children has proved difficult because of the lack of investigative tools available. New instruments for assessing QoL in food allergic children have recently been developed and validated, which should provide further insights into the problems these children encounter and will enable us to measure the effects of interventions in patients. This review examines the published impact of food allergy on affected children, adolescents and their families. It considers influences such as gender, age, disease severity, co-existing allergies and external influences, and examines how these may impact on allergy-related QoL and psychological distress including anxiety and depression. Implications of the impact are considered alongside avenues for future research.

Warfarin toxicity: do discharge ICD-10 codes and yellow cards accurately identify serious adverse drug reactions?

Focal points: ICD-10 codings and spontaneous yellow card reports for warfarin toxicity were compared retrospectively over a one-year period Eighteen cases of ICD-10 coded warfarin toxicity were identified from a total of 55,811 coded episodes More than three times as many ADRs to warfarin were found by screening ICD-10 codes as were reported spontaneously using the yellow card scheme Valuable information is being lost to regulatory authorities and as recognised reporters to the yellow card scheme, pharmacists are well placed to report these ADRs, enhancing their role in the safe and appropriate prescribing of warfarin

Exploring types and functions of questions in police interviews

There is a proliferation of categorization schemes in the scientific literature that have mostly been developed from psychologists’ understanding of the nature of linguistic interactions. This has a led to problems in defining question types used by interviewers. Based on the principle that the overarching purpose of an interview is to elicit information and that questions can function both as actions in their own right and as vehicles for other actions, a Conversational Analysis approach was used to analyse a small number of police interviews. The analysis produced a different categorization of question types and, in particular, the conversational turns fell into two functional types: (i) Topic Initiation Questions and (ii) Topic Facilitation Questions. We argue that forensic interviewing requires a switch of focus from the ‘words’ used by interviewers in question types to the ‘function’ of conversational turns within interviews.

Recall, verbatim memory and remembered narratives

Memory is central to investigative interviews with witnesses and suspects, yet decades of research have shown that remembering is subject to constructive and reconstructive processes that can adversely impact the reliability of accounts that are elicited at interview. In this chapter we first outline research concerning our memory for events (‘episodic memory’) before moving on to discuss the ways in which our attempts to validate and communicate those memories can bias what is eventually reported. We then focus on some of the implications this can have for investigative interviews, specifically the problem of ‘skill fade’ in interviewing, the impact of implicit beliefs about memory and issues surrounding the reliability of recollections of direct speech. We conclude that appropriately structuring the retrieval context is the key to achieving best memory evidence.

Communication in forensic contexts:future directions and conclusions

This chapter reviews the important areas that psychology, linguistics and law enforcement have impacted upon in terms of rigorous and collaborative scientific endeavours. Important areas that will be of interest to both researchers and practitioners for research relating to communication in forensic contexts are discussed in detail, including vulnerability, the use of intermediaries and interpreters in forensic interviews and questioning techniques.