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Biomedical subjects

J Savory

Publications and source records attributed to J Savory.

At least 37 records · Page 2Linked to original sources
PubMed1996

Prevention and treatment of aluminum toxicity including chelation therapy: status and research needs.

The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.

Aluminum↗
PubMed1996

Quantitative image analysis of temporal changes in tau and neurofilament proteins during the course of acute experimental neurofibrillary degeneration; non-phosphorylated epitopes precede phosphorylation.

Perturbation of the neuronal cytoskeleton represents an integral feature of neurofibrillary tangles which are characteristic neuropathological findings seen in Alzheimer's disease. Microtubule associated protein tau (tau) is considered to be the major component of these lesions although neurofilament proteins also are present. The present study explores the formation of intraneuronal tau and neurofilament protein aggregates using intracisternal administration of aluminum maltolate to rabbits. The time course of the formation of these aggregates and subsequent phosphorylation have been investigated by immunohistochemical methods using a panel of monoclonal antibodies, with quantitation of the staining by image analysis. Neurofilament proteins begin to aggregate by day 1 following aluminum maltolate injection on day 0. Increases in non-phosphorylated neurofilament proteins are observed first, with phosphorylated epitopes being recognized by day 3. Tau follows a similar pattern in that non-phosphorylated epitopes appear to precede phosphorylation. The monoclonal antibody Alz-50 which recognizes a phosphorylation-independent epitope of tau in Alzheimer's disease paired helical filaments, demonstrates positivity in the aluminum maltolate-treated rabbits by day 3. Other tau monoclonal antibodies which recognize phosphorylated tau in paired helical filaments (AT8 and PHF-1) show positive immunostaining on days 6-8. These results indicate that intraneuronal aggregation of cytoskeletal proteins can be initiated by factors other than phosphorylation. However, phosphorylation occurring as a secondary event probably contributes to stabilization of the aggregates.

Animals↗
PubMed1996

Robotics and the changing face of the clinical laboratory.

Rapid changes in healthcare coupled with parallel advances in technology have stimulated the evolution of new approaches for laboratory automation. In particular, the emergence of commercially available laboratory robotic systems offers promise for streamlining the clinical laboratory. Increasing cost-containment pressures make the application of this technology extremely attractive, and several organizations have begun to systematically integrate robotic devices into their laboratory automation schemes. Integration of these technologies, however, presents many challenges for software developers, instrument manufacturers, and laboratory workers. Differing needs across laboratories require flexibility and intelligence in robots, instruments, and control systems. Standardization of mechanical and electronic interfaces will be key to making these systems easy to integrate. Systems engineering, aided by simulation modeling and artificial intelligence schemes, will be important to assist in the design of optimal configurations. Software for the overall control of integrated automation will be needed that can be tailored by the laboratorian to fit the requirements of the individual laboratory. Thus, laboratory workers will need to be actively involved in implementing this new wave of laboratory automation, becoming well-versed in computers, electronics, and systems engineering.

Autoanalysis↗
PubMed1995

Tau immunoreactivity associated with aluminum maltolate-induced neurofibrillary degeneration in rabbits.

Intracisternal administration of aluminum maltolate to rabbits produces a marked argyrophilic neurofibrillary degeneration (NFD) which is also immunoreactive for both phosphorylated and non-phosphorylated microtubule associated protein tau. Using tissue fixation in PBF, the monoclonal antibodies Tau-2 and AT8 stain the NFD. Dephosphorylation markedly reduces the positivity of AT8. Using PLP-fixed tissue, monoclonal antibody Tau-1 also immunostains aluminum-induced NFD.

Aluminum↗
PubMed1995

The absence of extracellular calcium potentiates the killing of cultured hepatocytes by aluminum maltolate.

Dose- and time-dependent killing of cultured rat hepatocytes was produced by aluminum maltolate (AlM), a neutral, water-soluble complex of aluminum 3-hydroxy-2-methyl-4H-pyran-4-one. Treatment with 10 mM AlM for 1 h killed 50% or more of the cells within 3 h. Removal of calcium from the culture medium or treatment with calcium channel blockers (verapamil, nifedipine, diltiazem) potentiated the cell killing. By contrast, inhibition by thapsigargin of the sequestration of intracellular calcium by the endoplasmic reticulum reduced the toxicity of AlM. In turn, activation of protein kinase C with 12-O-tetradecanoylphorbol 13-acetate or activation of protein kinase A with 8-[4-chlorophenyl-thio]adenosine 3',5'-cyclic monophosphate also reduced the toxicity of AlM. By contrast, inhibition of protein kinase activity by staurosporine potentiated the cell killing. Staurosporine, however, did not reverse the protection afforded by thapsigargin. Hepatocytes treated with AlM for 1 h were rescued by adding deferoxamine as late as 90 min following the removal of AlM, whereas pretreatment for 1 h with deferoxamine did not prevent the toxicity of AlM. ATP depletion did not precede loss of viability. Pharmacologic probes excluded oxidative stress as a mechanism of lethal injury by AlM, and inhibition of protein synthesis by cycloheximide did not protect the hepatocytes, thereby excluding activation of a cell death program. These data define a new model in which aluminum kills liver cells by a mechanisms distinct from previously recognized pathways of lethal cell injury. It is hypothesized that aluminum binds to cytoskeletal proteins intimately associated with the plasma membrane. This interaction eventually disrupts the permeability barrier function of the cell membrane, an event that heralds the death of the hepatocyte. The intracellular calcium ion concentration and protein phosphorylation may modify the interaction of aluminum with its critical targets. Alternatively, aluminum may inhibit the phosphorylation of cytoskeletal elements, thereby interfering with their function.

Aluminum↗
PubMed1995

Development of a robotic near patient testing laboratory.

Many laboratories have centralized critical care services to conserve resources, but centralization has often been at the expense of providing optimized patient care. We have created a remotely controlled clinical laboratory that provides whole blood analysis of blood gases (PCO2, PO2), pH, electrolytes (Na+, K+, Cl-), glucose, and hemoglobin near the patient's beside, while maintaining the distinct advantage of central laboratory control. The automated remote laboratory provides extremely rapid turnaround times, eliminates the cost of labor for specimen processing, reduces the risk from contaminated specimens, reduces staff training, and results in improved patient care.

Centralized Hospital Services↗
PubMed1995

Quantitative evaluation of Al maltolate-induced neurodegeneration with subsequent Al removal by desferrioxamine treatment.

The intracisternal administration of aluminum maltolate to New Zealand white rabbits produces a reproducible neurofibrillary degeneration which is significantly reversed by desferrioxamine treatment. Quantitative analysis of brain and spinal cord tissue demonstrates that the aluminum deposition is higher close to the injection site than at locations further removed from the point of administration. Most importantly, treatment with desferrioxamine removes most of the aluminum from the brain and spinal cord, even from the sites of highest concentration. The ability to manipulate this system in the formation and degradation of NFD and in removal of aluminum may shed light on mechanisms of NFD formation and have implications for therapeutic advances in the treatment of certain human neurodegenerative diseases.

Aluminum↗
PubMed1995

Hyperaluminemia associated with liver transplantation and acute renal failure.

Iatrogenic aluminium toxicity is reported in a patient who underwent an orthotopic liver transplant and who had concomitant renal failure requiring hemodialysis. Following transplantation the patient developed a metabolic encephalopathy with only mildly elevated blood ammonia concentrations. During the period following transplantation the patient received massive infusions of albumin and was on oral feeding (vivonexten), both of which contained aluminium, as did the dialysis fluid. Hyperaluminemia and profoundly elevated liver tissue aluminium concentrations were observed. Treatment with desferrioxamine, a trivalent ion chelator, decreased the plasma aluminium concentrations with an improvement in the patient's mental status.

Acute Kidney Injury↗
PubMed1994

Partial reversal of aluminium-induced neurofibrillary degeneration by desferrioxamine in adult male rabbits.

Desferrioxamine, a chelating agent with a high affinity for aluminium, has been reported to slow the clinical progression of dementia associated with Alzheimer's disease [4]. We report here the effects of desferrioxamine treatment on aluminium-induced neurofibrillary degeneration in rabbits. Adult male New Zealand white rabbits received a single injection of aluminium-maltolate into the lateral cerebral ventricle. Three days later, one group of rabbits was treated with intramuscular injections of desferrioxamine twice daily; a second group received saline instead of desferrioxamine. Both groups were sacrificed 4 or 5 days following initiation of desferrioxamine or saline treatment. Minimal neurofibrillary degeneration was found in two of six desferrioxamine-treated rabbits, while all six rabbits treated with saline showed extensive neurofibrillary degeneration, particularly in the ventral horn of the lower spinal cord. Quantitation of the neurofibrillary degeneration in ventral horn neurons of lumbar cord revealed 30% to be affected in saline-treated animals compared to zero-affected neurons following desferrioxamine treatment. When sacrificed just 3 days after aluminium treatment, 50% of the rabbits already revealed neurofibrillary degeneration, corresponding to the time-point when desferrioxamine treatment was begun in the above animals; on quantitation, 7.5% of ventral lumbar cord neurons were involved. These findings indicate a partial reversal of aluminium-induced neurodegeneration by desferrioxamine. Delaying desferrioxamine treatment to 6 days after aluminium administration prevented any reversal of the aluminium effect; all animals had abundant neurofibrillary degeneration as well as a striking basophilic spicular deposit of calcium and argyrophilic material in the leptomeninges, lateral ventricles and brain parenchyma adjacent to these areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum Compounds↗
PubMed1994

Clinical complaints: a means of improving quality of care.

OBJECTIVES: To establish the reasons for clinical complaints, complainants' feelings about the original incident, and their motivation in complaining. DESIGN: Postal questionnaire survey. SETTING: 24 hospitals in North West Thames region. SUBJECTS: 1007 complainants who had written to 20 hospitals between 1 January 1992 and 30 June 1993 about a complaint involving a clinical incident. MAIN MEASURES: Personal details, the nature of the complaint, the complainant's reaction to the original incident, the quality of the explanation at the time of the incident, the reasons for making a complaint, and what would have prevented the incident. RESULTS: 491 completed questionnaires were received (response rate 49%). Complaints arose from serious incidents, generally a clinical problem combined with staff insensitivity and poor communication. Clinical complaints were seldom about a clinical incident alone (54; 11%); most (353; 72%) included a clinical component and dissatisfaction with personal treatment of the patient or care. In all, 242(49%) complainants reported a need for additional medical treatment, 206(42%) reported that the patient's condition had worsened as a result of treatment, and 175(36%) that side effects had been experienced. In 26(5%) cases the patient had died. Complainants' primary motive was to prevent recurrence of a similar incident. Lack of detailed information and staff attitude were identified as important criticisms. CONCLUSIONS: The emphasis must be on obtaining a better response to complaints at the clinical level by the staff involved in the original incident, not simply on adjusting the complaints procedure. Staff training in responding to distressed and dissatisfied patients is essential, and monitoring complaints must form part of a more general risk management programme.

Attitude of Health Personnel↗
PubMed1994

In vitro evaluation of papaverine hydrochloride incompatibilities: a simulation of intraarterial infusion for cerebral vasospasm.

PURPOSE: To elucidate, in light of reports of complications associated with intraarterial infusion of papaverine hydrochloride, the known propensity of papaverine hydrochloride to form precipitate in combination with other solutions or pharmaceuticals. METHODS: Initially simulating a situation experienced during an intraarterial papaverine infusion for cerebral vasospasm, we mixed various concentrations of papaverine with serum, nonheparinized and heparinized saline, and nonionic contrast material. RESULTS: Papaverine in concentrations of 0.3% (300 mg/100 mL of normal saline) or greater formed a precipitate when mixed with human serum (blood). The precipitate crystals were 50 to 100 microns in size and could be returned to solution simply by the addition of more serum. CONCLUSION: Crystal emboli are a possible transient cause of complications experienced during treatment of vasospasm with its attendant altered flow dynamics.

Cerebral Angiography↗
PubMed1993

Incidence of lead poisoning in young children from inner-city, suburban, and rural communities.

The Centers for Disease Control (CDC) have recently lowered the acceptable blood lead concentration in young children from < or = 25 to < or = 10 micrograms/dl (< or = 1.21 to < or = 0.48 mumol/L). The incidence of lead toxicity with respect to geographical areas and socioeconomic status has not yet been defined. We evaluated the incidence of increased lead concentration in inner-city, suburban, and rural children aged 9 months to 3 years. Seven hundred eighty of the 4,196 studied inner-city samples (18.6%) had lead concentrations > or = 10 micrograms/dl (0.48 mumol/L), of which only 71 (1.6%) had lead values > or = 25 micrograms/dl (1.21 mumol/L). Only 5 of the 212 studied children (2.4%) from suburbia and 7 of the 120 children (5.8%) from rural communities had blood lead concentrations > or = 10 micrograms/dl (0.48 mumol/L). None of these children, however, had a lead concentration > or = 15 micrograms/dl (0.73 mumol/L). In contrast, 276 inner-city subjects (6.6%) had lead values > or = 15 micrograms/dl (0.73 mumol/L). Our data indicate that a correlation exists between geographical location and blood lead concentration in young children. Government health agencies at all levels should prioritize their limited resources for those areas that are most at risk for lead poisoning.

Centers for Disease Control and Prevention, U.S.↗
PubMed1993

Aluminum neurotoxicity in experimental animals.

Neurotoxic effects of aluminum (Al) were recognized > 100 years ago, but have only recently been studied in detail. By far, the most dramatic effect of Al is that of producing intraneuronal perikaryal neurofilamentous aggregates, which consist of phosphorylated neurofilaments. Several species have been used to demonstrate this effect, rabbit being most common; the effect also is seen in in vitro systems. Besides its role in producing neurofibrillary pathology, Al appears to modify the blood-brain barrier and exert cholinergic and noradrenergic effects. Possible mechanisms of Al neurotoxicity could be related to cell damage via free radical production, impairment of glucose metabolism, and effects on signal transduction.

Aluminum↗
PubMed1993

Quantitative studies on aluminum deposition and its effects on neurofilament protein expression and phosphorylation, following the intraventricular administration of aluminum maltolate to adult rabbits.

The deposition of aluminum (Al) in the brain and spinal cord of adult male New Zealand white rabbits was monitored following the intraventricular administration of Al maltolate. Although decreasing concentrations of Al were observed from the injection site (approximately 10 micrograms/g dry tissue) to the lumbar cord (2.1 micrograms/g), argyrophilic tangles were present in the perikarya and proximal neurites of neurons as far distal as the lumbar and sacral cord areas. Quantitative immunoblot studies of the three neurofilament protein isoforms failed to detect changes resulting from Al maltolate treatment. Similarly no significant alterations in the total phosphate content of these cytoskeletal proteins were observed. Lastly, on Northern blots, the expression of genes encoding for the 200 kDa and 68 kDa neurofilament proteins also was unaffected by Al maltolate treatment.

Aluminum↗
PubMed1992

Trace metals: essential nutrients or toxins.

Trace metals play important roles in biological processes, both as essential components and toxins. Monitoring body status of trace metals thus has become an important function of many clinical, industrial, and government laboratories. Deficiencies of some essential trace metals are seen occasionally, but of most importance is the area of metal toxicity resulting from environmental, occupational, accidental, or iatrogenic exposure. Major questions persist about which specimen best reflects body status, and in this regard each metal has different requirements. Blood is used most widely, urine has a few applications, and hair can be used, although external contamination is an ever-present problem. Tissue is by far the best specimen but is not easily obtained. Contamination of specimens during collection and processing must be controlled. Of the instrumental techniques available, atomic absorption spectrometry has been used most widely, particularly with electrothermal and atomization approaches.

Chemistry, Clinical↗
PubMed1991

Aluminium maltol-induced neurocytoskeletal changes in fetal rabbit midbrain in matrix culture.

We have developed a neuronal culture system to evaluate the neurotoxic effects of aluminium maltol on fetal rabbit midbrain sections containing the oculomotor nucleus. Cultures were treated with 5, 7, 9, 11, 13 and 15 mumol/l aluminium maltol or 39 and 45 mumol/l maltol (molal equivalents to 13 and 15 mumol/l aluminium maltol). Control cultures were maintained in nutrient medium alone. Silver-positive neuritic swellings and occasional perikaryal neurofibrillary tangles were observed in cultures treated with 11, 13 and 15 mumol/l aluminium maltol. The number of tangles (involved neurons) produced in aluminium maltol treated cultures were counted and compared to (untreated) controls. We observed a total of 3, 7 and 7% of involved neurons following treatment with 11, 13 and 15 mumol/l aluminium maltol respectively, and none in the control group. By immunohistochemistry, neurofibrillary tangles were immunoreactive with MAbs to phosphorylated (SMI-31), non-phosphorylated, phosphorylation dependent (SMI-32) and phosphorylation independent (SMI-33) epitopes of the high (-H) and middle (-M) molecular weight neurofilament subunits (NF-H/M). By contrast these lesions were nonreactive with MAbs recognizing tau, MAP2 or different beta-tubulin isotypes. The perikaryal tangles consisted of focal accumulations of 10 nm straight filaments by electron microscopy. These findings are in agreement with previous data from rabbit in vivo studies after the administration of aluminium maltol intravenously (Bertholf et al., 1989) or intraventricularly (Katsetos et al., 1990). Using this in vitro system, aluminium-induced neurofibrillary tangles can be consistently produced, and changes in the distribution of neurofilament proteins evaluated. These studies may aid in the assessment of the possible role of aluminium in the aetiology of human neurodegenerative disorders.

Aluminum↗