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PubMed2025

Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention. FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster.

Journal Article↗

PubMed1999

Diagnostic challenges in ALS.

Although the essential requirements for diagnosis of amyotrophic lateral sclerosis (ALS) are clearly defined by the El Escorial criteria, many physicians, including neurologists, still miss the diagnosis. Physician misdiagnosis of ALS relates to lack of knowledge about ALS and skill and to diagnostic difficulty. The differential diagnosis must exclude nonmotor neuron diseases and other adult-onset motor neuron diseases with restricted presentations, e.g., progressive bulbar palsy (pure bulbar), progressive muscular atrophy (pure lower motor neuron) and primary lateral sclerosis (pure upper motor neuron), ALS-like syndromes and ALS variants, and adult-onset spinal muscular atrophies. Although the diagnosis of ALS remains a clinical one, laboratory testing can be used to exclude other diseases and to confirm the diagnosis. Such tests include EMG and nerve conduction studies, MRI and CT of the spine and brain, identification of biochemical markers in blood and CSF, and muscle or nerve biopsy. Genetic testing can identify gene defects in some types of familial ALS and in certain other inherited motor neuron diseases that mimic ALS. At present there is no widely accepted protocol for laboratory testing in cases of suspected ALS, but it is hoped that laboratory tests will improve in the future to facilitate earlier confirmation of a diagnosis of ALS. However, correct and early diagnosis of ALS can only be achieved when the first, second, or third physician who sees the patient knows about ALS and includes it in a differential diagnosis.

Adult↗

PubMed2004

Calculation of 19F and 27Al NMR parameters for rosenbergite, AlF[F0.5(H2O)0.5]4.H2O, a possible model for Al hydroxyfluorides in solution.

(19)F and (27)Al NMR chemical shifts are calculated for the F and Al atoms of the mineral rosenbergite, AlF[F(0.5)(H(2)O)(0.5)](4).H(2)O The structure of rosenbergite consists of infinite chains of F-corner-sharing Al[F(4)(H(2)O)(2)] octahedra and isolated water molecules. An F-centered molecular cluster of composition Al(2)F(3)(OH(2))(8) (3+) was initially used to model the mineral, with geometries taken both from the two different available x-ray crystal structures and from equilibrium geometries calculated at the 6-31G* B3LYP level (both with and without polarizable continuum solvation). Related Al(F)F(n) em leader clusters, with additional F(-) replacing H(2)O, were also studied. A larger Al-centered cluster model Al(3)F(4)(OH(2))(12) (5+) was also generated from one of the x-ray geometries and produced very similar bridging F shieldings but slightly different Al shieldings. The NMR shieldings were calculated using both HF and B3LYP GIAO methods, with 6-311+G(2df,p) basis sets, and the HF and B3LYP results averaged for the F shieldings as described in previous work. Calculated (19)F NMR shifts (relative to CCl(3)F) using this procedure were within a few ppm of experiment when either set of x-ray crystal structure coordinates was used, but differed by as much as 20 ppm for the energy-optimized geometries. Rosenbergite-like fragments with geometries optimized in water, simulated by a PCM, were used to model Al hydroxyfluoride species in solution. The (19)F NMR shifts for the bridging F atoms in several such model complexes are very similar to those usually attributed to monomeric species such as Al(OH(2))(5)F(2+) in solution, suggesting that the solution species are actually corner bridging oligomers. The F in the monomeric Al(OH(2))(5)F(2+) solution species is too strongly shielded by about 20 ppm to match the experimental peak usually assigned to it.

Journal Article↗

PubMed1998

AL 288-1--Lucy or Lucifer: gender confusion in the Pliocene.

Häusler & Schmid (1995) challenged the long held opinion that AL 288-1 (Australopithecus afarensis), popularly known as "Lucy", was female. They concluded that AL 288-1 was most probably male ("Lucifer") and, by extension, the hypodigm for A. afarensis consists of two species which differ from one another in body size; in their opinion, AL 288-1 was most probably a male of the smaller of the two species. Häusler & Schmid based their conclusion on an obstetric analysis of AL 288-1 and Sts 14 (A. africanus) and on a comparison of the two australopithecine pelves with those of modern humans. This study evaluates the pelvic anatomy and probable sex of AL 288-1 by both assessing the obstetric adequacy of its pelvis and critically reviewing Häusler & Schmid's (1995, 1997) analyses of australopithecine pelvic dimorphism and relative body size of AL 288-1. Three results are shown. First, using Häusler & Schmid's own data, AL-288-1's and Sts 14's pelves are seen not to be dimorphic with respect to each other, as are human males and females, but they are in fact comparable in both size and shape. Second, AL 288-1's pelvis would have been obstetrically adequate, even with an inferred newborn brain size (as suggested by Häusler & Schmid) for A. afarensis that is likely overestimated. Third, AL 288-1 is shown to be one of the smallest adult individuals in A. afarensis. We conclude that AL 288-1 and Sts 14 were the same sex, and that the name "Lucy" correctly identifies AL 288-1's gender as female.

Adult↗

PubMed2005

Comparison of the antibody in lymphocyte supernatant (ALS) and ELISPOT assays for detection of mucosal immune responses to antigens of enterotoxigenic Escherichia coli in challenged and vaccinated volunteers.

In the present study we compared the ELISPOT and antibody in lymphocyte supernatants (ALS) assays as surrogate measures of mucosal immunity. In separate studies, 20 inpatient volunteers received oral doses of 6 x 10(8) or 4 x 10(9)cfu of ETEC strain E24377A (LT+, ST+, CS1+, CS3+) and 20 subjects received 1 (n = 9) or 2 (n = 11) oral doses of the attenuated ETEC vaccine, PTL-003 expressing CFA/II (CS1+ and CS3+) (2 x 10(9)cfu/dose). Peripheral blood mononuclear cells (PBMCs) from all subjects were assayed for anti-colonization factor or toxin-specific IgA antibody responses using the ALS and ELISPOT procedures. ALS responses were measured using a standard ELISA, as well as by time-resolved fluorescence (TRF). Following challenge with E24377A, significant anti-CS3, CS1 and LT ALS responses were detected in the lymphocyte supernatants of 75-95% of the subjects. A similar proportion (75%) of subjects mounted an ALS response to CFA/II antigen after vaccination with the PTL-003 vaccine. Inter-assay comparisons between ALS and ELISPOT methods also revealed a high degree of correlation in both immunization groups. ALS sensitivity versus the ELISPOT assay for LT, CS3 and CS1-specific responses following challenge were 95%, 94% and 78%, respectively and 83% for the ALS response to CFA/II antigen after vaccination with PTL-003. Correlation coefficients for the LT and CS3 antigens were 0.94 (p<0.001) and 0.82 (p<0.001), respectively after challenge and 0.78 (p<0.001) after vaccination. The association between ALS and ELISPOT for the CS1 antigen was however, significant only when ALS supernatants were tested by TRF (r = 0.91, p<0.001). These results demonstrate the value and flexibility of the ALS assay as an alternative to ELISPOT for the measurement of mucosal immune responses to ETEC antigens, particularly when the complexities of ELISPOT may make it impractical to perform.

Adult↗

PubMed1997

Aluminum interaction with plasma membrane lipids and enzyme metal binding sites and its potential role in Al cytotoxicity.

The trivalent cation aluminum can cause chronic cytotoxicity in plants, animals and microorganisms. It has been suggested that Al interaction with cell membranes and enzyme metal binding sites may be involved in Al cytotoxicity. In this study, the binding of Al to microsomes and liposomes was found to be lipid dependent with the signal transduction element phosphatidylinositol-4,5-bisphosphate having the highest affinity for Al with an Al:lipid stoichiometry of 1:1. Al binding was only reduced in the presence of high concentrations of Ca2+ (> 1 mM). Both citrate and, to a lesser extent, malate were capable of preventing Al lipid binding, which is consistent with the involvement of these organic acids in a recently described Al detoxification mechanism in plants. The effects of AICl3, Al-citrate and ZnSO4 on metal-dependent enzyme activities (enolase, pyruvate kinase, H+-ATPase, myosin, Calpain, proteinase K, phospholipase A2 and arginase) was assayed in vitro. While Zn2+ was capable of inhibiting all the enzymes except the H+-ATPase, AlCl3 and Al-citrate had minimal effects except for with phospholipase A2 where an interaction with AlCl3 occurred. However, this could be negated by the addition of citrate. The results indicate that, contrary to current hypotheses, the toxic mode of Al is not through an interaction with enzymatic catalytic metal binding sites but may be through the interaction with specific membrane lipids.

Aluminum↗

PubMed2001

The uptake and speciation of various Al species in the Brassica rapa pekinensis.

An investigation was carried out on the uptake and speciation of Al species in Al tolerant Chinese cabbage (Brassica rapa L. ssp. pekinensis). Plants were exposed to 10 microg cm(-3) of Al in the chemical forms of Al3+, Al-citrate and Al-malate in a time span from 1 up to 24 h. In each experiment the nutrient solution and stem sap were analysed by a combination of FPLC ICP AES and ES MS MS techniques. Speciation analysis enabled determination of particular chemical forms of Al present in the nutrient solution or in stem sap. The results indicate that Al3+ added to the nutrient solution remained as Al3+ in the solution during the experiments, but in the roots transformation to Al-malate occurred. Al was transported from roots to the upper parts of the plant as Al-malate (70%) and Al3+ (30%). Al-citrate or Al-malate added to the nutrient solution were transferred to the upper parts of the plant without transformation of their chemical forms.

Aluminum↗

PubMed2003

The effects of Al(III) speciation on the activity of trypsin.

The effects of the different forms of Al(III) on the catalytic activity of the serine protease trypsin were studied. Enzyme activity was measured by BAEE assay in the presence of AlCl(3), Al(III):lactic acid 1:3, Al(III):maltol 1:3 or Al(III):nitrilotriacetic acid (NTA) 1:1 at a nominal Al(III) concentration of 0.01 M, and the ligand alone at pH 7.4 at 25 degrees C. Maltol and NTA caused approximately 30% inhibition, while that for the corresponding Al(III) complex was less than half of this. Al(III) in the form of the chloride or in three equivalents of lactic acid did not influence the activity of the enzyme, probably because most of the Al(III) was precipitated as Al(OH)(3). No direct interaction could be detected between the enzyme and the Al(III) complexes, either by ultrafiltration or by CD spectroscopy. These results strongly suggest that there is no direct involvement of Al(III) in the enzymatic reactions of trypsin.

Acetates↗

PubMed1998

Action of Al-ATP on the isolated working rat heart.

ATP is an important extracellular messenger in the coronary vasculature of the heart. To be effective its extracellular concentration must be tightly controlled and this is achieved via ectonucleotidases located in the luminal surface of the coronary endothelium. Al-ATP is a potent inhibitor of the hydrolysis of ATP and we speculated that Al-ATP released by cells into the blood would disrupt the signalling function of extracellular ATP. We tested this hypothesis by perfusing isolated working Wistar rat hearts with buffers containing either ATP or Al-ATP. The functional parameters measured were, coronary flow, heart rate and pulsatile power. A number of control perfusions including adenosine, ATP-gamma-S and Al were used to identify those effects which might be specific to ATP and Al-ATP. Al-ATP did not appear to inhibit the function of the endothelial ectonucleotidases. Both ATP and Al-ATP produced a significant increase in coronary flow and this could be attributed to a coronary vasodilation. Interestingly, whilst the effect of ATP was reversible that of Al-ATP was not. ATP caused a reduction in heart rate which was potentiated by aluminium. The negatively chronotropic effect of Al-ATP was mediated via a mechanism which was either distinct from or in addition to the similar response known to be caused by adenosine. We have demonstrated for the first time an influence of Al-ATP on heart function. Perhaps more pertinently we present the first evidence that Al-ATP may influence the function of ATP-specific receptors.

Adenosine Triphosphatases↗

PubMed2006

An in situ Al K-edge XAS investigation of the local environment of H+- and Cu+-exchanged USY and ZSM-5 zeolites.

Aluminum coordination in the framework of USY and ZSM-5 zeolites containing charge-compensating cations (NH4+, H+, or Cu+) was investigated by Al K-edge EXAFS and XANES. This work was performed using a newly developed in-situ cell designed especially for acquiring soft X-ray absorption data. Both tetrahedrally and octahedrally coordinated Al were observed for hydrated H-USY and H-ZSM-5, in good agreement with 27Al NMR analyses. Upon dehydration, water desorbed from the zeolite, and octahedrally coordinated Al was converted progressively to tetrahedrally coordinated Al. These observations confirmed the hypothesis that the interaction of water with Brønsted acid protons can lead to octahedral coordination of Al without loss of Al from the zeolite lattice. When H+ is replaced with NH4+ or Cu+, charge compensating species that absorb less water, less octahedrally coordinated Al was observed. Analysis of Al K-edge EXAFS data indicates that the Al-O bond distance for tetrahedrally coordinated Al in dehydrated USY and ZSM-5 is 1.67 angstroms. Simulation of k3chi(k) for Cu+ exchanged ZSM-5 leads to an estimated distance between Cu+ and framework Al atoms of 2.79 angstroms.

Aluminum↗

PubMed2006

Structure, metastability, and electron density of Al lattices in light of the model of anions in metallic matrices.

This paper reports a theoretical investigation of the structure, stability, and electron charge density of cubic, rhombohedral, hexagonal, and monoclinic Al lattices. The equations of state and the elastic constants are computed from total energy calculations at different volumes and unit cell strains using the density functional theory approximation. The topology of the electron density is analyzed within the crystalline implementation of the atoms in molecules formalism. The results are discussed in light of the so-called anions in metallic matrices model, which permits the interpretation of the chemical bonding and the explanation of the existence of particular symmetries of inorganic crystals. First, the Al sublattices are identified as the reference building blocks of AlX(3) (X = F, Cl, OH) compounds. The calculations reveal that the equilibrium zero-pressure Al-Al shortest distance is around 2.75 A in all of the Al matrixes, similar to the value observed in the stable face centered cubic structure of Al at room conditions. Second, at their zero-pressure equilibrium geometries, the Al sublattices are found to fulfill the mechanical stability criteria or, alternatively, to show mechanical instabilities that are compatible with the distortions observed for the structures in AlX(3) crystals. However, at the equilibrium volumes of the AlX(3) crystals, all of the Al matrices violate the spinodal condition, and the cohesion and stabilization are provided by the nonmetallic X atoms. Third, the structural anisotropy of the Al sublattices seems to be the main factor to discriminate metallic matrices able to host nonmetallic elements. The inhomogeneities of the electron charge density, which favor the arrival of nonmetallic elements and the crystal formation, are notably enhanced in passing from the fcc structure of pure Al to the less isotropic Al matrices observed in AlX(3) compounds.

Journal Article↗

PubMed1997

Immunoblot studies of the acid-labile subunit (ALS) in biological fluids, normal human serum and in children with GH deficiency and GH receptor deficiency before and after long-term therapy with GH or IGF-I respectively.

OBJECTIVE: The aims of this investigation were (a) to study the presence of immunoreactive forms of the acid-labile subunit (ALS) in different human biological fluids, (b) to define the age dependence of serum ALS in normal children and adults and (c) to compare the regulation of ALS by GH or IGF-I in children with GH deficiency (GHD) and GH receptor deficiency (GHRD) before and after 1 year of therapy with GH or IGF-I, respectively. DESIGN AND PATIENTS: Selected human biological fluids from different consenting volunteers and serum from 68 normal children and 5 adults were analysed. Four children diagnosed as GHD and 7 children diagnosed as GHRD were treated with recombinant human (rh) GH at a dosage of 0.05 mg/kg/day s.c. or rhIGF-I at a dosage of 120 micrograms/kg twice daily s.c., respectively, for 12 months. MEASUREMENTS: Immunoreactive forms of ALS were studied by Western immunoblot using a specific rabbit antiserum derived against synthetic human ALS and quantified by laser densitometry analysis. Serum from children with GHD or GHRD were sampled before and at 6 and 12 months of therapy; serum from these patients had been also assayed at baseline for determination of IGF-I and IGF binding protein (IGFBP)-3 by radioimmunoassay and immunoradiometric assay, respectively. RESULTS: An immunoreactive 85 kDa doublet of ALS was detected in serum, plasma, follicular, peritoneal and synovial fluid, but not in urine, seminal plasma, amniotic or extra-embryonic coelomic fluids. Assessment of serum from newborns to adults revealed an age dependence; the ALS doublet was low, but detectable, in newborns, increased during adolescence and remained constant in adulthood. ALS levels were significantly lower in GHD (P = 0.02) and in GHRD children (P = 0.001) than in age-matched controls. Treatment with rhGH in GHD children produced a 2.7-fold increase in serum ALS concentrations at 6 months of therapy (P = 0.01), which was maintained after 1 year of treatment (P = 0.006), leading to normalization of ALS concentrations. In contrast, administration of rhIGF-I to GHRD children failed to increase and normalize serum ALS levels either at 6 or 12 months of therapy. CONCLUSIONS: Immunoreactive forms of acid-labile subunit are present in serum and plasma, as well as in follicular, peritoneal and synovial fluids, suggesting that acid-labile subunit can either cross the capillary barrier or be secreted locally. Acid-labile subunit concentrations are age-dependent with a sharp increase during adolescence, and are reduced in GH deficient and GH receptor deficient children. While treatment with rhGH is able to increase and normalize acid-labile subunit concentrations in GH deficient children, therapy with rhIGF-I fails to increase serum acid-labile subunit levels in GH receptor deficient patients. These data suggest that acid-labile subunit is directly GH-regulated, and that IGF-I cannot increase acid-labile subunit levels, as assessed by Western immunoblot.

Adolescent↗

PubMed2000

Problems in shortening the time to confirmation of ALS diagnosis: lessons from the 1st Consensus Conference, Chicago, May 1998.

The 2nd Consensus Conference (Versailles) on the early diagnosis of amyotrophic lateral sclerosis (ALS) developed themes identified at the 1st Consensus Conference (Chicago) on defining optimal management in ALS. These themes included describing the problems and limitations in current diagnostic practices, identifying consequences of early diagnosis on patient management, establishing recommendations to help healthcare personnel achieve the early diagnosis and proposing solutions to facilitate early diagnosis of ALS. Lessons from the ISIS Survey and the 1st Consensus Conference focused on the variability of the first-contact physician, supply factors for specialists and variability of application of medical techniques. The recently introduced concept of 'ALS health states or stages' was reviewed in terms of ongoing and potential prospective studies. The relative contribution of neuroimaging or clinical neurophysiological investigations to accelerating the diagnosis of ALS in clinical practice was debated. The role of a common ALS knowledge-base among patients, initial healthcare providers, diagnosing neurologists and confirming neurologists was critically appraised with regard to simplified 'ALS diagnostic algorithm', 'ten aphorisms in the diagnosis of ALS' and 'ALS axioms of referral'. Refining this ALS knowledge-base is required to identify a minimum dataset required for the evaluation and diagnosis of ALS.

Diagnostic Imaging↗

PubMed2006

Identification of dominant mutations that confer increased aluminium tolerance through mutagenesis of the Al-sensitive Arabidopsis mutant, als3-1.

Aluminium (Al) toxicity is a global agricultural problem that occurs in acid soil environments and severely limits root growth and crop productivity. The isolation and characterization of a gene, ALS3, which is absolutely required by Arabidopsis seedlings for growth in an Al-toxic environment was reported previously. Since the als3-1 loss-of-function mutant has extreme root growth inhibition even in the presence of very low levels of Al, it was an excellent candidate for using a mutagenesis approach to identify suppressor mutations that would increase either Al resistance or tolerance in Arabidopsis roots. EMS-mutagenized als3-1 seedlings were screened for mutants that could sustain root growth in an Al-containing environment that is highly toxic to als3-1 but not Col-0 wt. This approach resulted in identification of 12 strong suppressor mutants that reversed the als3-1 phenotype and grew as well or better than Col-0 wt in the presence of high levels of Al. Subsequent analysis of three representative suppressor mutants revealed that the phenotype of each probably arises from dominant gain-of-function mutations at the same locus. Detailed analysis of one of these, alt1-1 (Al tolerant), suggests that this mutation positively impacts Al resistance in a manner dependent on pH adjustment rather than enhanced Al exclusion. Identification of these suppressor mutations, should not only further elucidate the biochemical and molecular mechanisms underlying Al toxicity and tolerance but also will develop a collection of mutations that may be useful for engineering crop plants that can grow and thrive in Al-toxic environments.

ATP-Binding Cassette Transporters↗

PubMed1998

Alterations of skin glycosaminoglycans in patients with ALS.

BACKGROUND AND OBJECTIVE: Collagen abnormalities of skin have been reported among patients with ALS. However, little is known concerning glycosaminoglycans of the skin in ALS. Our objective was to clarify morphologic and biochemical findings of skin glycosaminoglycans among patients with ALS. METHODS: We performed morphologic studies and biochemical analysis of glycosaminoglycans of skin from 8 patients with ALS, 6 patients with other neurologic or muscular diseases (control group A), and 7 patients without neurologic disorders (control group B). RESULTS: The wide spaces that separate collagen bundles reacted strongly with Alcian blue stain in skin from patients with ALS and stained more markedly as ALS progressed. Staining with Alcian blue was virtually eliminated by Streptomyces hyaluronidase. The content of hyaluronic acid was significantly higher (p < 0.001) among patients with ALS than in control groups A and B. There was a significant positive correlation between content of hyaluronic acid and duration of illness among patients with ALS (r = 0.88, p < 0.01). However, there was no significant difference in content of dermatan sulfate, chondroitin sulfate-4S, or chondroitin sulfate-6S between patients with ALS and control groups A and B. There was also an appreciable positive correlation between optical density of Alcian blue and content of hyaluronic acid among patients with ALS (r = 0.92, p < 0.01). CONCLUSIONS: The data suggest that a metabolic alteration of glycosaminoglycans related to the increased amount of hyaluronic acid may take place in the skin of patients with ALS.

Aged↗

PubMed1998

Antibodies from ALS patients inhibit dopamine release mediated by L-type calcium channels.

OBJECTIVE: To examine the presence of anti-L-type calcium channel antibodies in the serum of ALS patients. BACKGROUND: Autoimmunity has been hypothesized as one of the mechanisms underlying the pathogenesis of sporadic ALS. Previous studies reported that sera from patients with sporadic ALS contain antibodies against voltage-gated calcium channels (L-type and P-type), but others do not support these findings. METHODS: Regulated secretion of tritiated dopamine ([3H]DA) in PC12 cells is mediated exclusively by calcium entry through L-type calcium channels. To examine whether purified ALS immunoglobulin G (IgG) inhibits [3H]DA release by interfering with calcium entry through L-type calcium channels, evoked release in PC12 cells was determined in the presence of ALS IgG. This functional assay provides a sensitive way to examine L-type calcium channel interaction with IgG from ALS patients. RESULTS: A significant inhibition of depolarization-evoked [3H]DA release (32+/-4%) was observed by purified IgG from ALS patients compared with control subjects (11+/-2%; p < 0.01). Significant inhibition by IgG occurred in 79% (15/19) of the ALS patients compared with only 29% (5/17) in the control group (p < 0.01). The level of calcium channel inhibition by ALS IgG correlated positively with disease duration (r = 0.68; p < 0.01) and correlated negatively with age (r = -0.48; p < 0.05). CONCLUSIONS: These results confirm the presence of antibodies against the L-type calcium channel in the majority of sera from ALS patients, supporting their role in the pathogenesis of ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2000

Two consecutive fasciculation potentials having different motor unit origins are an electromyographically pathognomonic finding of ALS.

To electrophysiologically diagnose amyotrophic lateral sclerosis (ALS), fasciculation potentials (FPs) were evaluated in each wasted muscle in 12 ALS and 14 other neurogenic disorders (non-ALS patients). Various types of FPs were observed in ALS. The number of discharged FPs and firing rate of FPs were significantly increased in ALS compared to those in non-ALS. These findings indicate that more motor units take part in discharging FPs in ALS than in non-ALS, and that injured lower motor neurons exhibit hyperexcitability. Although nine of 12 ALS patients showed two consecutive FPs having different motor unit origins, non-ALS patients did not show such FPs. Since the two consecutive FPs having different motor unit origins reflect an involvement of both upper and lower motor neurons, these potentials are an electrophysiologically pathognomonic finding to ALS.

Action Potentials↗

PubMed2002

PX4+, P2X5+, and P5X2+ (X=Br, I) salts of the superweak Al(OR)4- anion [R=C(CF3)3].

PX(4) (+)[Al(OR)(4)](-) (X=I: 1 a, X=Br: 1 b) was prepared from X(2), PX(3), and Ag[Al(OR)(4)] [R=C(CF(3))(3)] in CH(2)Cl(2) at -30 degrees C in 69-86 % yield. P(2)X(5) (+) salts were prepared from 2 PX(3) and Ag[Al(OR)(4)] in CH(2)Cl(2) at -30 degrees C yielding almost quantitatively P(2)X(5) (+)[Al(OR)(4)](-) (X=I: 3 a, X=Br: 3 b). The phosphorus-rich P(5)X(2) (+) salts arose from the reaction of cold (-78 degrees C) mixtures of PX(3), P(4), and Ag[Al(OR)(4)] giving P(5)X(2) (+)[Al(OR)(4)](-) (X=I: 4 a, X=Br: 4 b) with a C(2v)-symmetric P(5) cage. Silver salt metathesis presumably generated unstable PX(2) (+) cations from PX(3) and Ag[Al(OR)(4)] (X=Br, I) that acted as electrophilic carbene analogues and inserted into the Xbond;X (Pbond;X/Pbond;P) bond of X(2) (PX(3)/P(4)) leading to the highly electrophilic and CH(2)Cl(2)-soluble PX(4) (+) (P(2)X(5) (+)/P(5)X(2) (+)) salts. Reactions that aimed to synthesize P(2)I(3) (+) from P(2)I(4) and Ag[Al(OR)(4)] instead led to anion decomposition and the formation of P(2)I(5)(CS(2))(+)[(RO)(3)Al-F-Al(OR)(3)](-) (5). All salts were characterized by variable-temperature solution NMR studies (3 b also by (31)P MAS NMR), Raman and/or IR spectroscopy as well as X-ray crystallography (with the exception of 4 a). The thermochemical volumes of the Pbond;X cations are 121 (PBr(4) (+)), 161 (PI(4) (+)), 194 (P(2)Br(5) (+)), 271 (P(2)I(5) (+)), and 180 A(3) (P(5)Br(2) (+)). The observed reactions were fully accounted for by thermochemical calculations based on (RI-)MP2/TZVPP ab initio results and COSMO solvation enthalpy calculations (CH(2)Cl(2) solution). The enthalpies of formation of the gaseous Pbond;X cations were derived as +764 (PI(4) (+)), +617 (PBr(4) (+)), +749 (P(2)I(5) (+)), +579 (P(2)Br(5) (+)), +762 (P(5)I(2) (+)), and +705 kJ mol(-1) (P(5)Br(2) (+)). The insertion of the intermediately prepared carbene analogue PX(2) (+) cations into the respective bonds were calculated, at the (RI-)MP2/TZVPP level, to be exergonic at 298 K in CH(2)Cl(2) by Delta(r)G(CH(2)Cl(2))=-133.5 (PI(4) (+)), -183.9 (PBr(4) (+)), -106.5 (P(2)I(5) (+)), -81.5 (P(2)Br(5) (+)), -113.2 (P(5)I(2) (+)), and -114.5 kJ mol(-1) (P(5)Br(2) (+)).

Journal Article↗