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J Savory

Publications and source records attributed to J Savory.

At least 19 recordsLinked to original sources
PubMed2006

Experiments with thermalized rare isotope beams from projectile fragmentation: a precision mass measurement of the superallowed beta emitter 38Ca.

The mass of the short-lived radio nuclide 38Ca (T(1/2) = 440 ms) has been measured with the 9.4-T Penning trap mass spectrometer of the Low-Energy Beam and Ion Trap Facility. A mass uncertainty of deltam = 280 eV has been achieved, corresponding to deltam/m = 8 x 10(-9). The result makes 38Ca, a superallowed beta emitter, a new candidate to test the conserved-vector-current hypothesis. The experiment is also the first demonstration that short-lived radioactive isotopes produced by projectile fragmentation of relativistic heavy-ion beams can be slowed down and prepared such that precision experiments of this kind are possible.

Journal Article↗
PubMed2001

Abeta(1-42) and aluminum induce stress in the endoplasmic reticulum in rabbit hippocampus, involving nuclear translocation of gadd 153 and NF-kappaB.

Apoptosis may represent a prominent form of neuronal death in chronic neurodegenerative disorders, such as Alzheimer's disease. Although apoptosis under mitochondrial control has received considerable attention, mechanisms used within the endoplasmic reticulum (ER) and nucleus in mediating apoptotic signals are not well understood. A growing body of evidence is emerging from different studies which suggests an active role for the ER in regulating apoptosis. Disturbances of ER function have been shown to trigger two different apoptotic pathways; one involves cross-talk with mitochondria and is regulated by the antiapoptotic Bcl-2, and the second is characterized by the activation of caspase-12. Also, stress in the ER has been suggested to result in the activation of a number of proteins, such as gadd 153 and NF-kappa, and in the downregulation of the antiapoptotic protein, Bcl-2. In the present study, the intracisternal injection in aged rabbits of either the neurotoxin aluminum maltolate or of Abeta(1-42), has been found to induce nuclear translocation of gadd 153 and the inducible transcription factor, NF-kappaB. Translocation of these two proteins is accompanied by decreased levels of Bcl-2 in both the ER and the nucleus. Aluminum maltolate, but not Abeta, induces caspase-12 activation which is a mediator of ER-specific apoptosis; this is the first report of the in vivo activation of caspase-12. These findings indicate that the ER may play a role in regulating apoptosis in vivo, and could be of significance in the pathology of neurodegeneration and related disorders.

Active Transport, Cell Nucleus↗
PubMed2001

Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits.

Neurodegenerative diseases, including Alzheimer's disease, are characterized by a progressive and selective loss of neurons. Apoptosis under mitochondrial control has been implicated in this neuronal death process, involving the release of cytochrome c into the cytoplasm and initiation of the apoptosis cascade. However, a growing body of evidence suggests an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondrial, or in concert with mitochondrial-initiated pathways. Members of the Bcl-2 family of proteins have been shown to either inhibit apoptosis, as is the case with Bcl-2, or to promote it, in the case of Bax. Investigations in our laboratory have focused on neuronal injury resulting from the intracisternal administration of aluminum maltolate to New Zealand white rabbits, an animal system relevant to a study of human disease in that it reflects many of the histological and biochemical changes associated with Alzheimer's disease. Here we report that treatment of young adult rabbits with aluminum maltolate induces both cytochrome c translocation into brain cytosol, and caspase-3 activation. Furthermore, as assessed by Western blot analysis, these effects are accompanied by a decrease in Bcl-2 and an increase in Bax reactivity in the endoplasmic reticulum.

Aluminum↗
PubMed2001

GDNF protects against aluminum-induced apoptosis in rabbits by upregulating Bcl-2 and Bcl-XL and inhibiting mitochondrial Bax translocation.

Direct (intracisternal) injection of aluminum complexes into rabbit brain results in a number of similarities with the neuropathological and biochemical changes observed in Alzheimer's disease and provides the opportunity to assess early events in neurodegeneration. This mode of administration induces cytochrome c release from mitochondria, a decrease in Bcl-2 in both mitochondria and endoplasmic reticulum, Bax translocation into mitochondria, activation of caspase-3, and DNA fragmentation. Coadministration of glial cell neuronal-derived factor (GDNF) inhibits these Bcl-2 and Bax changes, upregulates Bcl-XL, and abolishes the caspase-3 activity. Furthermore, treatment with GDNF dramatically inhibits apoptosis, as assessed by the TUNEL technique for detecting DNA damage. Treatment with GDNF may represent a therapeutic strategy to reverse the neuronal death associated with Alzheimer's disease and may exert its effect on apoptosis-regulatory proteins.

Alzheimer Disease↗
PubMed2001

Genetic algorithm for scheduling of laboratory personnel.

BACKGROUND: Staffing core laboratories with appropriate skilled workers requires a process to schedule these individuals so that all workstations are appropriately filled and all the skills of each worker are exercised periodically to maintain competence. METHODS: We applied a genetic algorithm to scheduling laboratory personnel. Our program, developed in Visual Basic 4.0, maximizes the value of a fitness function that measures how well a given scheduling of individuals and their skills matches a set of work tasks for a given work shift. The user provides in an Excel spreadsheet the work tasks, individuals available to work on any given date, and skills each individual possesses. The user also specifies the work shift to be scheduled, the range of dates to be scheduled, the number of days that an individual stays on a given workstation before rotating, and various parameters for the genetic algorithm if they differ from the default values. RESULTS: For >22 months, the program matched individuals to those tasks for which they were qualified and maintained personnel skills by rotating job duties. The schedules generated by the program allowed supervisory personnel to anticipate dates far in advance of when worker availability would be limited, so staffing could be adjusted. In addition, the program helped to identify skills for which too few individuals had been trained. This program has been well accepted by the staff in the clinical laboratories of a 670-bed university medical center, saving 37 h of labor per month, or approximately $11,000 per year, in time that supervisory personnel have spent developing work schedules. CONCLUSIONS: The genetic algorithm approach appears to be useful for scheduling in highly technical work environments that employ multiskilled workers.

Algorithms↗
PubMed2001

Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Part 2.

BACKGROUND: C-Reactive protein (CRP) can provide prognostic information about risk of future coronary events in apparently healthy subjects. This application requires higher sensitivity assays than have traditionally been available in the clinical laboratory. METHODS: Nine high-sensitivity CRP (hs-CRP) methods from Dade Behring, Daiichi, Denka Seiken, Diagnostic Products Corporation, Iatron, Kamiya, Olympus, Roche, and Wako were evaluated for limit of detection, linearity, precision, prozone effect, and comparability with samples from 388 apparently healthy individuals. RESULTS: All methods had limits of detection that were lower than the manufacturers' claimed limit of quantification except for the Kamiya, Roche, and Wako methods. All methods were linear at 0.3-10 mg/L. The Diagnostic Products Corporation, Kamiya, Olympus, and Wako methods had imprecision (CVs) >10% at 0.15 mg/L. The Iatron, Olympus, and Wako methods demonstrated prozone effects at hs-CRP concentrations of 12, 206, and 117 mg/L, respectively. hs-CRP concentrations demarcating each quartile in a healthy population were method-dependent. Ninety-two to 95% of subjects were classified into the same quartile of hs-CRP established by the Dade Behring method by the Denka Seiken, Diagnostic Products Corporation, Iatron, and Wako methods. In contrast, 68-77% of subjects were classified into the same quartile by the Daiichi, Kamiya, Olympus, and Roche methods. No subject varied by more than one quartile by any method. CONCLUSIONS: Four of the nine examined hs-CRP methods classified apparently healthy subjects into quartiles of hs-CRP similar to the classifications assigned by the comparison method. Additional standardization efforts are required because an individual patient's results will be interpreted using population-based cutpoints.

Adolescent↗
PubMed1999

Age-related hippocampal changes in Bcl-2:Bax ratio, oxidative stress, redox-active iron and apoptosis associated with aluminum-induced neurodegeneration: increased susceptibility with aging.

We propose that aging is an important factor in the susceptibility of neurons to oxidative stress and to subsequent apoptosis. In the present report we demonstrate that aged rabbits treated intracisternally with aluminum maltolate exhibit intense intraneuronal silver positivity indicative of the formation of neurofilamentous aggregates, together with oxidative stress. These changes occur in the CA1 region of the hippocampus as well as in cerebral cortical areas. Apoptosis, measured by the TUNEL in situ technique, colocalizes with oxidative stress. Young animals treated with aluminum show few of these alterations, while age-matched controls are essentially negative. Further studies on the time course of these and related changes demonstrate that oxidative stress and redox-active iron accumulation in hippocampal neurons occur very rapidly, within a period of 3 hours, and increased in intensity at 72 hours. Changes suggestive of apoptosis are seen by 24 hours and are pronounced at 72 hours. In aged animals there is an initially intense immunopositivity at 3 hours for Bcl-2, with negative staining for Bax. By 72 hours, when apoptosis is strongly evident, Bcl-2 is negative and Bax strongly positive. In contrast to the aged rabbits, young animals treated similarly with aluminum exhibit much less oxidative stress with no apoptosis, and maintain Bcl-2 immunopositivity and negative Bax staining. Our findings strongly support the key role that oxidative damage plays in the process of neurodegeneration and in the increased vulnerability to aluminum-induced injury in the aged animal. These are novel observations which may have important implications for aiding in our understanding of the pathogenesis of neurodegeneration occurring in Alzheimer's disease.

Aging↗
PubMed1998

Reversal by desferrioxamine of tau protein aggregates following two days of treatment in aluminum-induced neurofibrillary degeneration in rabbit: implications for clinical trials in Alzheimer's disease.

A clinical trial in patients with Alzheimer's disease has indicated that frequent intramuscular (i.m.) treatment with desferrioxamine (DFO) slows progression of the disease. Confirmatory trials have not been carried out, partly because of the rigors of twice daily intramuscular injections over a period of 2 years, even though the initial report gave promising results. The aim of the present study was to determine an optimal DFO treatment protocol in an animal model exhibiting Alzheimer's-like intraneuronal protein aggregates, previously shown to be partially reversed by such treatment. New Zealand white rabbits were injected intracisternally with either aluminum (Al) maltolate or with saline on day 0. Intramuscular injections of DFO were given to selected rabbits for 2 days prior to sacrifice on days 4, 6 or 8. Bielschowsky's silver impregnation demonstrated widespread neurofibrillary degeneration (NFD) in neuronal cell bodies and neurites of brain and spinal cord from Al-treated rabbits. Monoclonal antibodies Tau-2, AT8, PHF-1 and Alz-50, all of which characteristically stain neurofibrillary tangles associated with Alzheimer's disease, strongly labeled the Al-induced NFD. The number of positive neurons and staining intensities were much less in rabbits treated with Al and subsequently with DFO, than in animals only given Al. Control rabbit receiving intracisternal saline were negative for NFD. The results of quantitative immunohistochemistry using image analysis confirmed that immunostaining densities with all tau mAbs were higher in Al-treated than in Al-DFO-treated or in saline-treated controls. Furthermore, it appears that hyperphosphorylation of tau does not make this protein resistant to degradation once Al has been removed by DFO treatment. The effectiveness of only two days of DFO treatment in reversing Al-induced neurofibrillary degeneration suggests that further clinical trials of DFO for treatment of Alzheimer's disease should be attempted using much less frequent administration of DFO than in the initial study (Crapper McLachlan et al., 1991).

Aluminum↗
PubMed1998

Experimental aluminum encephalomyelopathy. Relationship to human neurodegenerative disease.

Alzheimer's disease has a complex pathogenesis and is a devastating neurologic disorder, predominantly of the elderly human population. Neuronal cell loss and neuritic pathology are a major neuropathologic feature of Alzheimer's disease, but there is no established mechanism to explain the degenerative process. The development of suitable animal systems would be of great value in helping to understand the basic mechanisms underlying the disease. We propose that the aluminum maltolate-treated elderly rabbit is a potentially useful animal system to model Alzheimer's disease neurofibrillary pathology. Details of such an experimental aluminum encephalopathy produced in the rabbit are discussed, along with other aspects of aluminum-induced neurodegeneration.

Aluminum↗
PubMed1997

Neurofibrillary lesions in experimental aluminum-induced encephalopathy and Alzheimer's disease share immunoreactivity for amyloid precursor protein, A beta, alpha 1-antichymotrypsin and ubiquitin-protein conjugates.

Neurofibrillary tangles of Alzheimer's disease contain predominantly tau protein and to a lesser degree amyloid precursor protein (APP), A beta protein, alpha 1-antichymotrypsin (ACT) and ubiquitin. Previously we have demonstrated the presence of phosphorylated tau and neurofilament proteins in neurofibrillary degeneration (NFD) induced by aluminum (Al) maltolate in rabbits [Savory et al., Brain Res. 669 (1995) 325-329; Savory et al., Brain Res. 707 (1996) 272-281]. Using the same animal system we have now detected APP, A beta, ACT and ubiquitin-like immunoreactivities in NFD-bearing neurons, often colocalizing in the NFD. Diffuse cytoplasmic staining for APP, A beta and ubiquitin was also present in neurons without NFD from Al maltolate-treated rabbits. This study provides additional support for immunochemical similarities between Al-induced NFD in rabbits and the neurofibrillary tangles in human subjects with Alzheimer's disease.

Aluminum↗
PubMed1996

Status and future concerns of clinical and environmental aluminum toxicology.

A wide range of toxic effects of aluminum (Al) have been demonstrated in plants and aquatic animals in nature, in experimental animals by several routes of exposure, and under different clinical conditions in humans. Aluminum toxicity is a major problem in agriculture, affecting perhaps as much as 40% of arable soils in the world. In fresh waters acidified by acid rain, Al toxicity has led to fish extinction. Aluminum is a very potent neurotoxicant. In humans with chronic renal failure on dialysis, Al causes encephalopathy, osteomalacia, and anemia. There are also reports of such effects in certain patient groups without renal failure. Subtle neurocognitive and psychomotor effects and electroencephalograph (EEG) abnormalities have been reported at plasma Al levels as low as 50 micrograms/L. Infants could be particularly susceptible to Al accumulation and toxicity, reduced renal function being one contributory cause. Recent reports clearly show that Al accumulation occurs in the tissues of workers with long-term occupational exposure to Al dusts or fumes, and also indicate that such exposure may cause subtle neurological effects. Increased efforts should be directed toward defining the full range of potentially harmful effects in humans. To this end, multidisciplinary collaborative research efforts are encouraged, involving scientists from many different specialties. Emphasis should be placed on increasing our understanding of the chemistry of Al in biological systems, and on determining the cellular and molecular mechanisms of Al toxicity.

Adolescent↗
PubMed1996

Can the controversy of the role of aluminum in Alzheimer's disease be resolved? What are the suggested approaches to this controversy and methodological issues to be considered?

Aluminum (Al) is unquestionably neurotoxic in both experimental animals and certain human diseases. Minute quantities injected intracerebrally into rabbits will induce severe neurological symptoms and neuropathological features of neurodegeneration. Hyper-aluminemia often develops in patients with renal failure being treated with intermittent hemodialysis on a chronic basis, and in severe cases results in an encephalopathy. Uremic adults and premature infants not on dialysis treatment also can develop encephalopathy due to Al toxicity, as is the case when large amounts of alum are used as a urinary bladder irrigant. There are many other examples of Al-induced neurotoxicity; however, the question as to whether Al presents a health hazard to humans as a contributing factor to Alzheimer's disease is still the subject of debate. Several lines of evidence are presented that have formed the basis of the debate concerning the possible pathogenic role for Al in Alzheimer's disease. Important evidence for an Al-Alzheimer's causal relationship is the observation by laser microprobe mass analysis (LMMS) of the presence of Al in neurofibrillary tangles, although there are conflicting data on the extent of the Al deposition. The relatively poor sensitivity of some of the analytical instruments available for these challenging in situ microanalyses could explain the discrepant results, although LMMS and perhaps secondary ion mass spectrometry (SIMS) appear to be sufficiently sensitive. Harmonization of the techniques is an essential next step. There is new evidence that exposure to Al from drinking water might result in cognitive impairment and an increased incidence of Alzheimer's disease. However, these epidemiological studies have inherent problems that must be scrutinized to determine if an association really does exist. An understanding of a possible enhanced bioavailability of Al in this type of exposure, versus other exposures such as antacid intake or industrial exposure, needs to be considered and explored. There has been one promising clinical trial of the treatment of Alzheimer's disease patients with the Al chelator desferrioxamine (DFO). Further studies are needed, and if confirmation is forthcoming then such data could also support an Al-Alzheimer's disease link as well as suggesting that DFO offers potential as a therapeutic agent. The possibility that iron might be the offending agent needs to be considered since DFO is a very strong iron chelator. The significance of Al-induced neurofibrillary degeneration in experimental animals should be assessed especially in light of new data showing that this model exhibits abnormally phosphorylated tau protein structures in the neuronal perikarya. Thus the key questions that must be answered before it can be asserted that Al possesses causal relationship to Alzheimer's disease, are as follows and are addressed in this present discussion: (1) Are there elevations of the concentration of Al in the brains of Alzheimer's disease patients? (2) Is there a relationship between environmental exposure to Al, particularly in drinking water, and an increased risk of Alzheimer's disease? (3) Is treatment with DFO a potentially useful therapeutic approach and to what extent might beneficial effects of DFO implicate Al in the etiology of Alzheimer's disease? (4) Are there similarities between the experimental animal studies and Alzheimer's disease particularly in the development of abnormal forms of tau seen in neurofibrillary tangles? (5) Does Al promote the deposition of the A beta peptide in Alzheimer's disease? (6) Does hyperaluminemia associated with long-term hemodialysis treatment induce neurofibrillary degeneration? If the answer to each of these six questions is yes, then does this assert that Al possesses a causal relationship to Alzheimer's disease? On the other hand, must all six be met to be able to make this assertion?

Aluminum↗