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PubMed1977

Current status of the search for virus in amyotrophic lateral sclerosis (ALS).

Clinicians have noted resemblance between ALS with predominantly lower motor involvement and a chronic type of poliomyelitis. Occasional cases of ALS show lymphocytic infiltrations in the neuropathology. Cytoplasmic inclusion bodies as well as possible transmission of ALS to the monkey, were noted by Soviet investigators. Major questions about the latter remain, but inclusion bodies have been seen in cases outside the USSR, and search for a virus has been pursued. So far, efforts at culture, including the technique of co-cultivation, have not been successful in 3 different laboratories using material from ALS autopsied within 2 hours of death. Nor has such material and specimens from other cases produced transmissible disease in animals of laboratories where kuru, Jakob's disease and SSPE have been transmitted. Study of serum antibodies has also been negative. These negative culture, transmission and antibody studies do not exclude a viral etiology: in kuru, for example, many years passed before transmission was demonstrated, which remains the only evidence of kuru's infectivity. Evidence of an immunologic disorder in ALS has been obtained from kidney biopsies, the lack of any clinical benefit from immunosuppression may indicate that the kidney finding reveals a response to infection, though whether viral or even relevant is unknown. Two recent ALS cases will be illustrated in which virus-like particles were demonstrated post mortem by electronmicroscopy. In one, myxovirus-like tubules were seen mainly in motor neurons; in the other, picorna-virus-like crystals were found in skeletal muscles. Different viruses can cause identical disease, but 2 different viruses in different sites in ALS also suggest that at least one type of particle is an adventitious finding of no general significance. An additional impetus to continue the search is the slowly progressive type C-virus myelitis in wild mice. This disease has many dissimilarities to ALS, including different morphology of the virus, but may provide a model for slow-virus amyotrophy.

Adult↗
PubMed2005

[11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS.

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.

Adult↗
PubMed2002

Early symptom progression rate is related to ALS outcome: a prospective population-based study.

OBJECTIVE: To define the factors related to ALS outcome in a population-based, prospective survey. METHODS: The 221 patients (120 men and 101 women) listed in the Piemonte and Valle d'Aosta ALS Register between 1995 and 1996 were enrolled in the study. The patients were prospectively monitored with a standard evaluation form after diagnosis. RESULTS: Mean age at onset was 62.8 (SD = 11.2) years. According to El Escorial diagnostic criteria (EEDC), 112 patients had definite ALS, 85 probable ALS, 18 possible ALS, and six suspected ALS. The median survival time from symptom onset was 915 days (95% CI = 790 to 1065). The median survival time from diagnosis was 580 days (95% CI = 490 to 670). In univariate analysis, outcome was significantly related to age, onset site, EEDC classification, and symptom progression rate (i.e., the rate of decline of muscle strength and bulbar and respiratory function in the 6 months after diagnosis). In the Cox multivariate model, age, progression rate of respiratory, bulbar, and lower limb symptoms, EEDC classification, percutaneous endoscopic gastrostomy, and treatment with riluzole were significantly related to outcome. CONCLUSIONS: The rate of progression of symptoms in early ALS is predictive of disease outcome.

Aged↗
PubMed1995

Reduced fecundity in male ALS gene-carriers.

In order to study genetic aspects in multicase families, 89 amyotrophic lateral sclerosis (ALS) and 214 Parkinson disease (PD) kindreds were analyzed in parallel studies. Obligate gene-carriers were identified as described previously [Chatkupt et al., 1992: Am J Med Genet 44:508-512]. There were fewer children per gene-carrier male (2.42) than per gene-carrier female (3.25, Student's t-test, P < .0003) for ALS but not for other diseases. The data taken together suggest that fecundity in ALS gene-carriers was reduced in males, possibly as a result of reduced fertility. Since childbearing is usually accomplished well before the onset of neurological symptoms in ALS, and since reduced fecundity was found in male ALS gene-carriers, these findings raise the possibility that an ALS gene might have a pleiotrophic effect on fertility in males occurring decades before the onset of neurological symptoms. Evidence is presented linking reactive oxygen species to reduced fertility in males. Alternatively, decreased or nonfunctional androgen receptors could play a role.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Electromyography of sternocleidomastoid muscle in ALS: a prospective study.

Needle electromyography (EMG) of the tongue is difficult to perform because of frequent uncontrollable movement. We chose the sternocleidomastoid (SCM) muscle as a possible alternative for assessing the involvement of the rostral neuraxis in amyotrophic lateral sclerosis (ALS). We prospectively studied 21 ALS patients during our initial diagnostic evaluation. EMG parameters that we recorded included the presence of abnormal spontaneous activity, pattern of motor unit potential recruitment, and configuration of motor unit action potentials. For the six patients with bulbar-onset ALS, three had abnormalities in the SCM and three had abnormalities in the tongue. In contrast, for the 15 patients with limb-onset ALS, 9 had abnormalities in the SCM, and only 3 had abnormalities in the tongue. Our results demonstrate the utility of needle EMG of the SCM in the evaluation of ALS. EMG of the SCM carries a similar sensitivity as the tongue in ALS patients with bulbar symptoms, but is more sensitive than the tongue in patients without bulbar symptoms. SCM innervation includes the rostral cervical cord and brainstem, and EMG abnormalities in this muscle support a diffuse involvement, which is unique to ALS.

Action Potentials↗
PubMed2005

Toxic effects of Al-based coagulants on Brassica chinensis and Raphanus sativus growing in acid and neutral conditions.

The ecotoxicological effects of aluminum (Al)-based coagulants are of concern because of their wide-ranging applications in wastewater treatment and water purification. As important Al-based coagulants, AlCl(3) and PAC (polyaluminum-chloride) were selected as examples to examine the toxic effects on representative vegetables including the cabbage Brassica chinensis and the radish Raphanus sativus over a range of exposure concentrations in neutral (pH 7.00) and acidic (pH 4.00) conditions, using seed germination and root elongation in the early-growth stage as indicators of toxicity. The results showed that root elongation of the two vegetables was a more sensitive indicator than was seed germination for evaluating the toxicity of Al. As a single influencing factor, H(+) had no significant direct effects on root elongation of Brassica chinensis and Raphanus sativus under the experimental conditions. The toxicity of Al played the main role in inhibiting root elongation and seed germination and was strongly related to changes in pH. There was a markedly positive relationship between the inhibitory rate of root elongation, seed germination, and the concentration of Al at pH 4.00 (p < 0.01). The toxic effect of AlCl(3) on Brassica chinensis was less with a neutral pH than at pH 4.00, but Raphanus sativus was more susceptible to AlCl(3) toxicity at a neutral pH than at pH 4.00. Both Raphanus sativus and Brassica chinensis had a more toxic response to a low concentration (<64 mg . L(-1)) of PAC in a neutral condition than in an acidic condition. Undoubtedly, the Al toxicity caused by Al-based coagulants at a neutral pH is relevant when treatment solids are used in agriculture.

Aluminum↗
PubMed2001

Ocular hypotensive and aqueous outflow-enhancing effects of AL-3037A (sodium ferri ethylenediaminetetraacetate).

AL-3037A (Sodium ferri ethylenediaminetetraacetate), a novel compound shown to stimulate the degradation of glycosaminoglycans, was evaluated for its effects on aqueous humor outflow and intraocular pressure (IOP) in four experimental models. Its effect on outflow facility was assessed in bovine and human ocular perfusion organ cultures. Its IOP effect was tested in normotensive and dexamethasone-induced ocular hypertensive rabbits. In bovine eyes, perfusion with AL-3037A (0.1% w/v, 2.3 m M) significantly increased the outflow facility well above the normal 'wash-out' effect. At 30 min after perfusion, the outflow facility of drug-treated eyes increased by 26.0+/-2.8% (mean +/- S.E.(M.), n = 8), significantly higher than the 12.1 +/- 2.8% increase in vehicle-treated eyes. This difference sustained throughout the study period (2 hr). The compound also enhanced aqueous outflow in perfused human anterior segments. In non-glaucomatous eyes, it produced a small decrease in IOP (15.4 +/- 4.6%, n = 17), but in tissues derived from glaucoma patients, bolus administration of 3 mg (7 micromol) of AL-3037A lowered the IOP by 52-68% (n = 2) lasting for at least 3 hr. This outflow-enhancing effect of AL-3037A in ex vivo studies was confirmed by in vivo results. In normotensive rabbits, oral (50 mg kg(-1)), intravenous (10 mg kg(-1)), or topical (2 mg; 50 microl of 4% w/v solution) administration of AL-3037A produced maximum reduction of IOP, when compared to vehicle-treated animals, by 34.7+/-3.5% (n = 10), 22.0 +/- 4.6% (n = 10), and 21.6 +/-4.5% (n = 10), respectively. In dexamethasone induced ocular hypertensive rabbits, topical application of the compound (0.5 mg; 25 microl of 2% w/v solution) reduced IOP significantly by 19.2+/- 0.4% (n = 7) at 3 hr after dosing. Importantly, the IOP lowering effect of AL-3037A did not diminish even after repeated treatments in consecutive days. Thus, in the four study models across three animal species, AL-3037A was demonstrated to be an efficacious ocular hypotensive compound whose effect is most likely mediated by augmentation of the aqueous outflow. Its proposed action on the metabolism of glycosaminoglycans may provide a new and unique mechanism for the treatment of glaucoma.

Animals↗
PubMed1996

Synaptophysin in spinal anterior horn in aging and ALS: an immunohistological study.

Aged-related spinal cord changes such as neuronal loss have been related to the degree of clinical severity of amyotrophic lateral sclerosis (ALS); morphological data on synapses are, however, wanting. Variations in synaptophysin (Sph) expression in aging and ALS were thus studied at the level of lower motor neurons in 40 controls with non-neurological diseases and 11 cases of ALS. Control sections of formalin fixed paraffin embedded cervical (C7/8), thoracic (T10) and lumbar spinal cord (L5) and C6, C7, C8 and L5 of ALS cases were stained with haematoxylin and eosin, luxol fast blue (LFB), and immunostained with a mouse monoclonal antibody against Sph. The neuropil of the anterior horn (AH) in all control cases demonstrated Sph positivity. A dot-like pattern of positivity of presynaptic terminals on soma of motor neurons and fine immunoreactivity along neuronal processes were observed. A significant reduction of Sph immunostaining was observed in the neuropil with increasing age and 3 different somatic patterns were seen: a- well preserved Sph reactivity around the soma and the proximal dendrites of histologically normal neurons; b- few chromatolytic neurons showing large numbers of dot-like presynaptic terminals around the cell body and in a "fused" pattern; c- intense, diffuse, and homogeneous reactivity of some neurons. Attenuation of Sph reactivity in the AH neuropil, to its complete loss, was observed in all ALS cases. In addition to patterns a-c, two additional microscopic findings were noted in ALS: d- chromatolytic neurons showing complete absence of Sph reactivity; e- absence of Sph reactivity around the soma and the proximal dendrites of histologically normal surviving neurons. Our findings demonstrate that there is a decrease in Sph immunostaining with aging, thus suggesting an alteration in dendritic networks of the AH with aging. Changes in the pattern of Sph immunoreactivity in cell bodies may represent synaptic plasticity and/or degeneration. Reinnervation may also be a possible mechanism as a response to neuronal loss in oldest control cases. Sph reactivity results may thus lend support to the presence of superimposed aging components in ALS cases which may give an insight into explaining the increasing severity of the disease which is encountered with advancing age.

Adult↗
PubMed2000

The effect of pH on the kinetics of intra- and extracellular uptake of Al in Fontinalis antipyretica: changes in the cellular contents of K, Mg, and Ca.

The effect of acidity on the accumulation of Al in the aquatic bryophyte Fontinalis antipyretica was studied. The main interest of this study was in characterizing the relationship between the two parameters, as Al is typically mobilized in acidic environments, where it becomes extremely toxic. With this aim, a series of laboratory experiments were carried out where samples of F. antipyretica were held in tanks of water with different concentrations of Al (0.1-3 mg L(-1)) and levels of acidity (pH 3-5. 8). The incubation time varied between 1 and 24 h. In general, the greatest accumulations of both intra- and extracellular Al were found at a pH of 4.4. With the results obtained, the kinetics of both intra- and extracellular Al uptake was characterized, and models constructed for different combinations of Al and acidity. The study was completed by examining the relationship between the pH of the holding water and bioaccumulation of Al and the variation in concentration of cations essential to plant life, which are also indicators of changes in cellular physiology (K, Mg, Ca). In general, losses of these elements were found at intra- and extracellular locations, especially at high pH.

Aluminum↗
PubMed1993

Functional identification of al-3 from Neurospora crassa as the gene for geranylgeranyl pyrophosphate synthase by complementation with crt genes, in vitro characterization of the gene product and mutant analysis.

In this work the Neurospora crassa al-3 gene function was determined. Geranylgeranyl pyrophosphate (GGPP) synthase activity was measured in al-2 FGSC 313 and al-3 RP100 FGSC 2082 mutant strains by in vitro synthesis methods. This experiment showed that al-3 RP100 mutant expresses a reduced GGPP synthase activity. The mutated al-3 gene was cloned and sequenced; a single missense mutation was found changing serine into asparagine. Genetic complementation was performed by Escherichia coli transformation, with clusters of crt genes from Erwinia uredovora. Carotenoid accumulation was observed in E. coli transformants when the N. crassa al-3 gene substitutes the GGPP synthase gene (crtE) in the carotenogenic crt cluster. Cell-free studies with E. coli transformants gave direct evidence of the function of the al-3 protein as GGPP synthase and indicated that a short-chain prenylpyrophosphate, such as dimethylallyl pyrophosphate, is the genuine substrate.

Alkyl and Aryl Transferases↗
PubMed2006

Genetic analysis of the cystatin C gene in familial and sporadic ALS patients.

Bunina bodies, small eosinophilic intraneuronal inclusions, stain positive for cystatin C and are the only specific pathological hallmark of amyotrophic lateral sclerosis (ALS). We screened the cystatin C gene (CST3) for mutations in 57 sporadic ALS patients and 12 familial ALS cases that did not possess a SOD1 mutation. We detected the known polymorphism in exon 1, a G/A transition at +73, in both familial and sporadic ALS patients. However, the allelic and genotypic frequencies of the +73 G/A polymorphism did not differ between ALS patients and control samples. No other mutation was detected in the ALS patients. The results reported here indicate that there may not be a direct genetic link between cystatin C and ALS, and it may be that deficits occur in proteins that interact with cystatin C.

Aged↗
PubMed2006

Short administration of polyclonal anti-T cell antibody (ALS) in NOD mice with extensive insulitis prevents subsequent development of autoimmune diabetes.

Treatment of overtly diabetic NOD mice with antilymphocyte serum (ALS), a polyclonal anti-T cell antibody, leads to cure of diabetes. Here, we investigated whether ALS-treatment of NOD mice after development of extensive insulitis prevents onset of diabetes. Female NOD mice were treated with two doses of ALS at 14, 19 or 23 weeks of age. No further treatment was given. In untreated female NOD mice, diabetes developed starting at 13 weeks and reached 68% by 37 weeks. ALS-treatment at 14, 19 or 23 weeks when histology showed progressive insulitis completely prevented onset of overt diabetes in 9/12, 11/12 or 12/12 mice, respectively. Intraperitoneal glucose tolerance tests in 43 week-old ALS-treated, diabetes-free mice showed a normal pattern. Co-adoptive transfer of lymphoid cells prepared from ALS-treated diabetes-free mice together with splenocytes from overtly diabetic NOD mice resulted in marked delay in diabetes onset in NOD.SCID mice, suggesting the presence of autoimmune regulatory cells in ALS-treated mice. Autoimmune regulatory cells were CD4(+)CD25(+), but not CD4(+)CD25(-), T cells. Thus, treatment of euglycemic individuals who already show signs of autoimmune diabetes with a short course of polyclonal anti-T cell antibody may effectively prevent onset of type 1 diabetes mellitus.

Animals↗
PubMed2006

Adsorption of phthalic acid and salicylic acid and their effect on exchangeable Al capacity of variable-charge soils.

Low-molecular-weight (LMW) organic acids may be adsorbed by soils and the adsorption could affect their biodegradation and efficiency in many soil processes. In the present study, the adsorption of phthalic acid and salicylic acid and their effect on the exchangeable Al capacity of variable-charge soils were investigated. The results indicated that phthalic acid and salicylic acid were adsorbed by four variable-charge soils to some extent, oxisols showed a greater adsorption capacity for organic acids than ultisols, and the ability of the four variable-charge soils to adsorb the organic acids at different pH generally followed the order Kunming oxisol > Xuwen oxisol > Jinxian ultisol > Lechang ultisol, which was closely related to their content of free iron oxides and amorphous iron and aluminum oxides. The adsorption of organic acids induced a decrease in the zeta potentials of soils and oxides. Goethite has greater adsorption capacity for organic acid than Xuwen oxisol and the adsorption of organic acids resulted in a bigger decrease in the zeta potential of goethite suspensions. After free iron oxides were removed, less organic acid was adsorbed by Xuwen oxisol and no change was observed in zeta potential for the soil suspension after organic acid was added. The presence of phthalic acid increased the capacity of exchangeable Al and the increment in the four variable-charge soils also followed the order Kunming oxisol > Xuwen oxisol > Lechang ultisol and Jinxian ultisol. The presence of salicylic acid increased the capacity of exchangeable Al in Kunming oxisol, Xuwen oxisol, and Jinxian ultisol, but decreased it in Lechang ultisol due to less adsorption of the acid and formation of soluble Al-salicylate complexes in solution. After free iron oxides were removed, less effect of organic acid on exchangeable Al was observed for Xuwen oxisol, which further confirmed that the iron oxides played a significant role in organic acid adsorption and had a consequent effect on the capacity of exchangeable Al in variable-charge soils. Therefore, the higher the content of iron oxides, the greater the adsorption of organic acids by soils and the greater the increase in soil exchangeable Al induced by the organic acids.

Journal Article↗
PubMed2005

Linear scan voltammetric indirect determination of Al(III) by the catalytic cathodic response of norepinephrine at the hanging mercury drop electrode.

The biological effects of aluminum (Al) have received much attention in recent years. Al is of basic relevance as concern with its reactivity and bioavailability. In this paper, the electrochemical behaviors of norepinephrine (NE) in the absence and presence of Al(III) at the hanging mercury drop electrode have been studied and applied to the practical analysis. Highly selective catalytic cathodic peak of NE is yielded by linear scan voltammetry (LSV) at -1.32 V (vs. SCE). A linear relationship holds between the cathodic peak current and the Al(III) concentration. It has been successfully applied to the determination of Al(III) in real waters and synthetic biological samples with satisfying results, which are in accordance with those obtained by ICP-AES method. The electrochemical properties and the mechanisms of the peaks in the presence and absence of Al(III) have been explored. The results show that they are irreversible adsorptive hydrogen catalytic waves. These studies not only enrich the methods of determining Al, but also lay foundations of further understanding of the mechanisms of neurodementia.

Aluminum↗
PubMed2006

Late appearance of glutamate transporter defects in a murine model of ALS-parkinsonism dementia complex.

Excitotoxicity has been widely hypothesized to play a major role in various neurodegenerative diseases. We have used a mouse model of ALS-parkinsonism dementia complex (ALS-PDC) of the Western Pacific to explore this hypothesis. Mice fed washed cycad flour, the major epidemiological link to ALS-PDC, showed significant and progressive motor, cognitive, and sensory behavioural deficits [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221]. In addition, glutamate transporter (GLT-1/EAAT2) levels measured by immunohistochemistry with antibodies specific for two glial glutamate transporter splice variants (GLT-1alpha and GLT-1B) were significantly down-regulated showing a 'patchy' loss of antibody label centered on blood vessels [Wilson, J.M., Khabazian, I., Pow, D.V., Craig, U.K., Shaw, C.A., 2003. Decrease in glial glutamate transporter variants and excitatory amino acid receptor down-regulation in a murine model of ALS-PDC. Neuromol. Med. 3 (2), 105-118]. Receptor binding assays showed decreased NMDA and AMPA receptor levels combined with increased GABA(A) receptor levels in various CNS regions. The alterations in GLT-1 variants and the ionotropic receptors are consistent with an increased level of extracellular glutamate. The interaction between environmental toxicity and genetic susceptibility was also tested using mice expressing various Apolipoprotein E (ApoE) genotypes. Mice lacking the ApoE gene showed relative resistance to cycad-induced toxicity as measured by GLT-1B labeling, but all mice expressing the human ApoE isoforms showed a similar loss of GLT-1B. We have further shown that an isolated cycad toxin (beta-sitosterol-beta-d-glucoside, BSSG), previously shown to release glutamate in vitro [Wilson, J.M., Khabazian, I., Wong, M.C., Seyedalikhani, A., Bains, J.S., Pasqualotto, B.A., Williams, D.E., Andersen, R.J., Simpson, R.J., Smith, R., Craig, U.K., Kurland, L.T., Shaw, C.A., 2002. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromol. Med. 1 (3), 207-221], can be directly toxic to motor neurons in vivo [Wilson, J.M., Petrik, M.S., Moghadasian, M.H., Shaw, C.A., 2005. Examining the interaction of apo E and neurotoxicity on a murine model of ALS-PDC. Can. J. Physiol. Pharmacol. 83 (2), 131-141]. However, BSSG-fed mice did not show altered GLT-1B labeling in the spinal cord suggesting that an initial excitotoxic mechanism may not be responsible for the final neuronal loss observed. While glutamate-mediated excitotoxicity is likely involved in the outcomes following cycad/BSSG exposure, the precise location in the cascade of events ultimately leading to neuronal death remains to be determined.

Amino Acid Transport System X-AG↗
PubMed2006

DNA interaction with Al-N,N'-bis(salicylidene)2,2'-phenylendiamine complex.

The Al(III) complex, [Al(salophen)2H2O]NO3, was synthesized and characterized by spectroscopic (NMR and FT-IR) techniques. Then the binding of Schiff base complex of [Al(salophen)]+ type, where salophen denotes N,N'-bis(salicylidene) 2,2-phenylendiamine to calf thymus DNA, has been investigated by spectrophotometric, circular dichroism, spectrofluorometric, melting temperature and viscosimetric techniques. This Al(III) complex showed absorption hyperchromism in the range of 310-390 nm, increase in melting temperature, some structural changes in specific viscosity, when bound to calf thymus DNA. The binding constant has been determined using absorption measurement and found to be 1.82 x 10(3)M(-1) and 1.31 x 10(3)M(-1) in HEPES and Tris-HCl buffers, respectively. Also the fluorescence spectral characteristics and interaction of Al-salophen complex with DNA have been studied. Al-salophen bound to DNA showed a marked increase in the fluorescence intensity along with a bathochromic shift (5 nm). The intersection point of the binding isotherm indicated a binding site size of 12 bp per bound complex molecule in both HEPES and Tris-HCl buffers. The experimental results showed that the Al-salophen complex bound to DNA by non-intercalative mode and major groove binding was the preferred mode of interaction.

Animals↗
PubMed2000

Comparison of electrocardiographic findings in patients with AL (primary) amyloidosis and in familial amyloid polyneuropathy and anginal pain and their relation to histopathologic findings.

To assess the prevalence of chest pain and ischemic electrocardiographic (ECG) changes and relate them to histopathologic findings of coronary arteries in cardiac amyloidosis, 33 patients with AL (primary) amyloidosis and 60 patients with familial amyloid polyneuropathy (FAP) were examined. Five patients (15%) with AL amyloidosis had recurrent anginal pain with exertion and 2 of them also experienced anginal pain after orthostatic hypotension. The chest pain was associated with transient downsloping or horizontal ST-segment depression with or without T-wave inversion in right precordial leads, whereas the remaining patients with AL amyloidosis and all patients with FAP did not show anginal pain or ischemic ST-T changes. Histologic sections of coronary arteries were obtained in 12 patients with AL amyloidosis, including 4 of the 5 patients who had angina pectaris and in 25 patients with FAP. Three patients with anginal pain had variable degrees of stenoses of the intramural coronary arteries by amyloid deposition predominantly in the media with normal or nearly normal epicardial arteries. One patient with AL amyloidosis who had effort angina showed marked stenosis and complete occlusion of the small coronary vessels by transmural amyloid deposition. The remaining 8 patients with AL amyloidosis and 25 with FAP without chest pain did not exhibit any stenosis or occlusion of both the epicardial and intramural vessels. These findings suggest that ischemic ST-T changes with chest pain are not so rare in patients with AL amyloidosis, and that markedly decreased myocardial oxygen supply due to diffuse stenotic or occlusive disease of the small coronary vessels by amyloid deposition contributes to the development of clinically significant ischemic heart disease in these patients.

Aged↗
PubMed2000

Decreased striatal dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA): D2 receptor down-regulation versus striatal cell degeneration.

Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.

Amyotrophic Lateral Sclerosis↗