Altered accelerator pedal control in a driving simulator in people with diabetic peripheral neuropathy.

AIM: To investigate whether the sensory-motor impairment attributable to diabetic peripheral neuropathy would affect control of the accelerator pedal during a driving simulator task. METHODS: A total of 32 active drivers, 11 with diabetic peripheral neuropathy (mean ± sd age 67±5.0 years), 10 with diabetes but no neuropathy (diabetes group; mean ± sd age 62±10 years), and 11 healthy individuals without diabetes (healthy group; mean ± sd age 60±11 years), undertook a test on a dynamometer to assess ankle plantar flexor muscle strength and ankle joint proprioception function of the right leg, in addition to a driving simulator task. The following variables were measured: maximal ankle plantar flexor muscle strength; speed of strength generation (Nm/s); and ankle joint proprioception (ankle repositioning error, degrees). In the driving simulator task, driving speed (mph), accelerator pedal signal (degrees) and the duration of specific 'loss-of-control events' (s) were measured during two drives (Drive 1, Drive 2). RESULTS: Participants with diabetic peripheral neuropathy had a lower speed of strength generation (P<0.001), lower maximal ankle plantar flexor muscle strength (P<0.001) and impaired ankle proprioception (P=0.034) compared to healthy participants. The diabetic peripheral neuropathy group drove more slowly compared with the healthy group (Drive 1 P=0.048; Drive 2 P=0.042) and showed marked differences in the use of the accelerator pedal compared to both the diabetes group (P=0.010) and the healthy group (P=0.002). Participants with diabetic peripheral neuropathy had the longest duration of loss-of-control events, but after one drive, this was greatly reduced (P=0.023). CONCLUSIONS: Muscle function, ankle proprioception and accelerator pedal control are all affected in people with diabetic peripheral neuropathy, adversely influencing driving performance, but potential for improvement with targeted practice remains possible.

Oral aluminum administration during pregnancy and lactation produces gastric and renal lesions in rat mothers and delay in CNS development of their pups.

The expression of the neurofilament protein of the highest molecular weight (NF-H) is developmentally and spatially regulated. For example, the MAb RMO24.9, directed against a phosphorylated epitope in the tail domain of NF-H, immunohistochemically labels specific tracts within the rat brainstem prenatally, but does not label diencephalic tracts until after postnatal day 10 (P10). A diet providing 300 mg/kg/d Al (as Al lactate) to rat dams throughout gestation causes behavioral deficits in their offspring (Bernuzzi et al., 1989). We repeated this regimen by substituting 120 mM Al lactate (pH 6.5) for drinking water during gestation and lactation, and examined the distribution of immunolabeling by RMO 24.9 after exposure to Al. Tracts within the diencephalon that bind RMO 24.9 on P11 in control pups did not bind the MAb until P14 in Al-treated pups. In these preliminary experiments, Al seemed to have caused a developmental delay in the expression of phosphorylated NF-H in the pups of mothers that received Al during gestation. However, subsequent experiments showed that the neuropathology observed--and that reported by other investigators using similar Al levels--may not be the result of the direct effects of Al on the pups. Throughout lactation, treated dams appeared progressively more cachexic. Unlike the normal viscera of pair-watered controls, the stomachs of treated dams were ulcerated, and their kidneys had decreased cortical thickness and contained stones. Lesions such as these compromise a rat's ability to absorb nutrients, to excrete toxins, and to regulate water and electrolytes. In a lactating dam, these alterations could compromise the dam's ability to nourish her pups. Our experiments point out that the mechanisms of Al toxicity-- already complex in the adult--are further complicated in a system in which the pup is dependent on the mother for delivery of both nutrients and toxins. It is therefore impossible to determine the cause of any neuropathology in the pup in a system where Al delivery overlies a background of multisystem defect and altered maternal homeostasis.

Different effects of aluminum upon carbonic anhydrases and Na+/K+-ATPase activities in rat.

Aluminum (Al(III)) is a well established toxicant implicated as an etiological factor in several neuropathies. In this paper we report results regarding opposite effects produced by Al(III) on the activity of two enzymes utilized as models. While sodium-potassium ATP-ase (Na/K-ATPase) is strongly activated by Al(III) in a dose-effect dependent way, on the contrary, carbonic anhydrase (CA) is remarkably inhibited. The relevance of the metal speciation together with the enzymatic structural modification demonstrated by circular dichroism measurements could explain the observed modified enzymatic activities. In addition, a new experimental protocol for the preparation of Al(III) solutions at physiological pH useful in the standardization of Al(III) experimental toxicology is also proposed and discussed.

Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze.

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature.

Evaluation of heavy metal pollution in the Venetian lagoon by using Mytilus galloprovincialis as biological indicator.

This study reports the analysis of heavy metal (Cd, Co, Cu, Cr, Hg, Fe, Mn, Ni, Pb, Zn) and As accumulated in the mollusc Mytilus galloprovincialis collected in the Venetian lagoon between March and September 1988. This environmental biomonitoring project was carried out using natural population of the molluscs attached to the 'Briccole', which limit the navigation canals into the lagoon. These data were compared with those reported by other authors in analogous studies published about a decade ago. A small improvement on the heavy metal pollution of the Venetian lagoon can be deduced from this comparison, presumably depicting a positive signal of a new downward trend in metal concentrations. Continuous monitoring of the fragile lagoonal ecosystem must be an important commitment due to the economic and historical importance of the Venetian lagoon.

Effects of aluminum speciation on murine neuroblastoma cells.

Murine neuroblastoma cells behave differently in the presence of Al(acac)3 [acac = 2,4-pentanedionate; acetylacetonate] or Al(malt)3 [malt = 3-hydroxy, 2-methyl, 4-pyronate; maltolate] with respect to Al(lac)3 [lac = 2-hydroxypropionate; lactate]. Thus, a remarkable cytotoxic effect was observed in the first case; on the contrary, an evident cytostatic and neuritogenic effect was produced by aqueous Al(lac)3. The hydrolytically stable complexes Al(acac)3 and Al(malt)3 were both toxic in the concentration range of 0.10-0.30 and 0.10-0.50 mM, respectively, over 24 h. In contrast with this behavior Al(lac)3 displayed a potent cytostatic activity with induction of neurites at 0.2-10 mM. Al(OH)3 manifested biological effects comparable to those exhibited by Al(lac)3. AlPO4 was also cytostatic and led to a morphological differentiation of the neuroblastoma cells, qualitatively different from that elicited by Al(lac)3. The morphological effects induced by Al(lac)3, Al(OH)3, and AlPO4 were irreversible.

Aluminum(III) influences the permeability of the blood-brain barrier to [14C]sucrose in rats.

To determine the influence of the metal coordination sphere on the permeability of the blood-brain barrier (BBB), rats were injected intraperitoneally with aluminum lactate (Al(lact)3), aluminum acetylacetonate (Al(acac)3), aluminum maltolate (Al(malt)3) at pH 7.5, or with physiological saline. Two h after each treatment, [14C]sucrose physiological saline solution was injected in animals, and the radioactivity was measured in 5 brain regions (cerebral cortex, mesencephalon, diencephalon, medulla-pons, cerebellum). Radioactivity was significantly elevated in brains from animals treated with Al(malt)3 (hydrolytically stable and hydrophilic), and with Al(acac)3 (hydrolytically stable and lipophilic) but not with Al(lact)3. Time-course study carried out at 2, 4 and 24 h with different aluminum compounds showed a persistent radioactivity 24 h after treatment only in the brain from animals treated with Al(acac)3. Morin stain localized AlIII only in neurons from animals treated with Al(acac)3. These findings indicate that AlIII alters the BBB function in the rat either permanently or transiently depending on the physiochemical properties of the metal coordination sphere. Implications of these results, in terms of AlIII as a potential toxic factor in humans, are considered and discussed.

A long-term toxicological investigation on the effect of tris(maltolate)aluminum(III) in rabbits.

The toxicity of i.v. injected hydrophilic aluminum complex tris(maltolate)aluminum(III) was studied in New Zealand white rabbits for a period of time ranging from 5 to 63 wk. Animals were injected 3-5 times a week with 1 mL of 7.5 mM Al(malt)3 and one rabbit with a dose 10 times higher after 14 wk of treatment. Autopical examination was performed on all animals. Chemoclinical analysis (glucose, urea, creatinine, cholesterol, bilirubin, alanin aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl-transferase, LDH, CK, total protein, triglycerides, and Ca2+) gave no variation in treated animals with respect to the control. The toxicological data show a moderate systemic general toxicity at doses far higher than those used in similar previous experiments using Al(acac)3 (acac = 2,4 pentanedionate), a hydrolytically stable and more lipophilic aluminum(III) complex (1). The diversity of behavior is discussed in terms of metal speciation as well as respect to the thermodynamic and kinetic properties of the two complexes in aqueous solution. The toxicological model presented here emphasizes that neutral, water compatible aluminum(III) complexes are to be considered as promising tools for toxicological experiments providing biological models of human pathologies.

Experimental aluminum pathology in rabbits: effects of hydrophilic and lipophilic compounds.

Aluminum lactate [Al(lact)3] (hydrophilic, hydrolytically unstable) and aluminum acetylacetonate [Al(acae)3] (lipophilic, hydrolytically stable) were tested as potential toxicants to rabbits upon IV administration both as aqueous solutions and as liposome suspensions. Both chemicals behaved as cardiotoxic agents when administered as aqueous solutions, but Al(acae)3 was at least two orders of magnitude more active than Al(lact)3. Al(acae)3, but not Al(lact)3, caused myocardial infarcts resembling those in humans (with contraction bands) at doses as low as 0.24 mg/kg body weight, as well as a prominent acanthocytosis. Al(lact)3, when administered as a liposome suspension, was about 300 times more toxic than in aqueous solution, although cardiac damage was not infarctual in character. Both chemical and physical speciation of aluminum(III) thus play an essential role in determining the toxicity of the metal.

Gallium distribution in several human brain areas.

Gallium is an element of increasing biological interest: It is involved in problems related to environmental pollution (Ga compounds are used in electronics industry) and to clinical treatments (Ga radionuclides are employed to detect neoplastic lesions). Moreover, since its chemical behavior is similar to that of aluminum, gallium could play a role in the health effects attributed to this element. Data on naturally occurring Ga levels in human samples from healthy subjects are scanty; regarding the brain, the only reliable values available in the literature were published by Hamilton in 1972/73. In this work, the gallium distribution in several human brain areas, evaluated by radiochemical neutron activation analysis (RNAA), was found to be dishomogeneous. The element concentration determined in dry samples was, in any case, lower than the ppb level.

Tris acetylacetonate aluminium(III) induces osmotic fragility and acanthocyte formation in suspended erythrocytes.

Tris acetylacetonate aluminium(III) (Al(acac)3), dissolved in water, is effective in producing osmotic fragility in suspended erythrocytes in the concentration range of 0.034-0.34 mmol/l. Water solutions of Tris maltolate aluminium(III) (Al(malt)3) and aluminium lactate (Al(lac)3) are also effective but the dose-response behavior is less pronounced. Moreover, only Al(acac)3 induces a prominent generation of acanthocytes. The stronger effects of Al(acac)3 on membrane stability are attributed to the greater solubility of this complex in the cell membrane.