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Background: Previous studies have shown that patients with amyotrophic lateral sclerosis (ALS) have hyperexcitability in both the motor cortex and peripheral motor axons, but the relationship between central and peripheral excitability has not been fully disclosed.Methods: Threshold tracking transcranial magnetic stimulation (TMS) and motor nerve excitability testing were prospectively performed in 53 patients with ALS and 50 healthy subjects, and their relations to compound muscle action potential (CMAP) amplitude and revised ALS Functional Rating Scale were cross-sectionally analysed.Results: Compared with controls, patients with ALS showed both cortical and peripheral hyperexcitability; TMS showed reduced short-interval intracortical inhibition (interstimulus interval 1-7 ms) (p<0.001) and shortened silent period (p<0.05), and median nerve excitability testing revealed greater changes in depolarising threshold electrotonus (TEd) and greater superexcitability (p<0.0001, both), suggesting reduced axonal potassium currents. Significant correlations between cortical and peripheral excitability indices were not found. Greater changes in TEd (90-100 ms) (R=-0.33, p=0.03) and superexcitability (R=0.36, p=0.01) were associated with smaller amplitude of CMAP, whereas cortical excitability indices had no correlation with CMAP amplitude. More rapid motor functional decline was associated with only greater TEd (90-100 ms) (β=0.46, p=0.001).Conclusions: Our results suggest that in ALS, cortical excitability is continuously high regardless of the extent of the peripheral burden, but peripheral hyperexcitability is associated with the extent of the peripheral burden and disease evolution speed. Alterations of ion channel function may play an important role in ALS pathophysiology. [ABSTRACT FROM AUTHOR]

Introduction: In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG.Methods: One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses.Results: MG patients showed a significantly greater MCD mean (MG: control, 26.3 μs; 13.5 μs [median]; P < .0001), MCD SD (MG: control, 12.8 μs; 5.1 μs [median]; P < .0001), and MCD CV (MG: control, 46.1; 37.5 [median]; P < .001) than those without MG. An ROC curve of SD showed a large area under the curve (0.88), and a cut-off value of 7.2 μs, which was calculated by maximum Youden index, exhibited high diagnostic sensitivity (86%) for MG. Combined MCD mean, outliers, and SD criteria showed higher sensitivity (88%) than conventional criteria alone (82%), at the expense of lower specificity. Five MG patients with normal MCD mean and abnormal MCD SD had only ocular symptoms.Discussion: The dispersion of MCD as measured by MCD SD greater than 7.2 μs is significantly increased in patients with MG and may be a useful measure of abnormal jitter in the diagnosis of MG, especially for identifying patients with mild disease. [ABSTRACT FROM AUTHOR]

The purpose of this study was to test whether chronically enhanced [O.sub.2] delivery to tissues, without arterial hyperoxia, can change acute ventilatory responses to hypercapnia and hypoxia. The effects of decreased hemoglobin (Hb)-[O.sub.2] affinity on ventilatory responses during hypercapnia (0, 5, 7, and 9% C[O.sub.2] in [O.sub.2]) and hypoxia (10 and 15% [O.sub.2] in [N.sub.2]) were assessed in mutant mice expressing Hb Presbyterian (mutation in the [beta]-globin gene, [beta]108 Asn [right arrow] Lys). [O.sub.2] consumption during normoxia, measured via open-circuit methods, was significantly higher in the mutant mice than in wild-type mice. Respiratory measurements were conducted with a whole body, unrestrained, single-chamber plethysmograph under conscious conditions. During hypercapnia, there was no difference between the slopes of the hypercapnic ventilatory responses, whereas minute ventilation at the same levels of arterial PC[O.sub.2] was lower in the Presbyterian mice than in the wild-type mice. During both hypoxic exposures, ventilatory responses were blunted in the mutant mice compared with responses in the wild-type mice. The effects of brief hyperoxia exposure (100% [O.sub.2]) after 10% hypoxia on ventilation were examined in anesthetized, spontaneously breathing mice with a double-chamber plethysmograph. No significant difference was found in ventilatory responses to brief hypoxia between both groups of mice, indicating possible involvement of central mechanisms in blunted ventilatory responses to hypoxia in Presbyterian mice. We conclude that chronically enhanced [O.sub.2] delivery to peripheral tissues can reduce ventilation during acute hypercapnic and hypoxic exposures. hyperoxia; hypoxia; hypercapnia; tissue; breathing

Introduction: Distal nerve terminals, where the blood-nerve barrier is anatomically deficient, are preferentially affected in immune-mediated neuropathies. Excitability alterations near the motor nerve terminals may be more prominent than the nerve trunk in typical chronic inflammatory demyelinating polyneuropathy (CIDP).Methods: In 20 patients with typical CIDP, motor nerve excitability testing was performed at the motor point and wrist of the ulnar nerve, and results were compared with those in 20 healthy persons.Results: Chronic inflammatory demyelinating polyneuropathy patients showed greater threshold changes in hyperpolarizing threshold electrotonus at the motor point (P < .05) but not at the wrist. Strength-duration time constant did not show significant differences between CIDP and controls at both sites.Discussion: Axonal property changes in CIDP are more prominent in distal portions of axons compared with the nerve trunk, presumably due to salient demyelination near the distal nerve terminals. Motor point excitability measurements could elucidate underlying pathophysiology in immune-mediated neuropathies. [ABSTRACT FROM AUTHOR]

Objective: The 'split hand' sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both cortical and spinal/peripheral excitotoxic mechanisms have been proposed. We aimed to study split hand and axonal excitability in spinal and bulbar muscular atrophy (SBMA) in which cortical motor neurons are intact.Methods: In 35 patients with genetically confirmed SBMA, 55 with ALS, 158 with other neuromuscular diseases and 90 normal controls; split hand was strictly determined by amplitudes of compound muscle action potentials. Nerve excitability testing of median motor axons was performed in 35 SBMA and 55 patients with ALS and 45 normal controls.Results: Split hand was as frequently found for patients with SBMA (57%) and ALS (62%), compared with disease (20%) and normal (0%) controls. Excitability testing showed that in both SBMA and ALS, strength-duration time constant was longer, and threshold changes in depolarising threshold electrotonus and superexcitability in the recovery cycle were greater than in normal controls (p<0.01).Conclusions: Split hand is not specific to ALS and can be caused by the peripheral mechanism alone in SBMA, whereas the effect of upper motor neuron lesion cannot be excluded in ALS. Our results also suggest that SBMA and ALS share common axonal excitability changes; increased nodal persistent sodium and reduced potassium currents that may accelerate motor neuronal death and differently affect axons-innervating different muscles. Ion channel modulators could be a therapeutic option for both SBMA and ALS. [ABSTRACT FROM AUTHOR]

Hb Presbyterian is a variant hemoglobin that carries Lys at Asn-108 of β-globin. This variant Lysβ108 residue enhances the stability of Hb in the deoxy-state, conferring the low affinity for oxygen-binding in vitro. In the present study, we generated mutant mice carrying the Presbyterian mutation (Asnβ108→Lys) at the β-globin locus by a targeted knock-in strategy. Heterozygous mice showed the expression of Hb Presbyterian in 27.7% of total peripheral blood without any hematological abnormalities, which well mimicked human cases. On the other hand, homozygous mice exclusively expressed Hb Presbyterian in 100% of peripheral blood associated with hemolytic anemia, Heinz body formation, and splenomegaly. Hb Presbyterian showed instability in an in vitro precipitation assay. Erythrocytes from homozygous mice showed a shortened life span when transfused into wild-type mice, confirming that the knocked-in mutation of Lysβ108 caused hemolysis in homozygous mice. This is the first report on the hemolytic anemia of unstable hemoglobin in an animal model. These results confirm the notion that the higher ratio of an unstable variant β-globin chain in erythrocytes triggers the pathological precipitation and induces hemolysis in abnormal hemoglobinopathies. [Copyright &y& Elsevier]

Studies the role of oxygen affinity of hemoglobin in the regulation of oxygen consumption, metabolism and physical activity in mice. Experimental procedures; Effect of mutation on oxygen delivery; Molecular mechanisms regulating ventilation.

Hb Presbyterian is a variant hemoglobin that carries Lys at Asn-108 of beta-globin. This variant Lys(beta108) residue enhances the stability of Hb in the deoxy-state, conferring the low affinity for oxygen-binding in vitro. In the present study, we generated mutant mice carrying the Presbyterian mutation (Asn(beta108)-->Lys) at the beta-globin locus by a targeted knock-in strategy. Heterozygous mice showed the expression of Hb Presbyterian in 27.7% of total peripheral blood without any hematological abnormalities, which well mimicked human cases. On the other hand, homozygous mice exclusively expressed Hb Presbyterian in 100% of peripheral blood associated with hemolytic anemia, Heinz body formation, and splenomegaly. Hb Presbyterian showed instability in an in vitro precipitation assay. Erythrocytes from homozygous mice showed a shortened life span when transfused into wild-type mice, confirming that the knocked-in mutation of Lys(beta108) caused hemolysis in homozygous mice. This is the first report on the hemolytic anemia of unstable hemoglobin in an animal model. These results confirm the notion that the higher ratio of an unstable variant beta-globin chain in erythrocytes triggers the pathological precipitation and induces hemolysis in abnormal hemoglobinopathies.