Over the past 10 years, mitochondrial defects have been implicated in a wide variety of degenerative diseases, aging, and cancer. Studies on patients with these diseases have revealed much about the complexities of mitochondrial genetics, which involves an interplay between mutations in the mitochondrial and nuclear genomes. However, the pathophysiology of mitochondrial diseases has remained perplexing. The essential role of mitochondrial oxidative phosphorylation in cellular energy production, the generation of reactive oxygen species, and the initiation of apoptosis has suggested a number of novel mechanisms for mitochondrial pathology. The importance and interrelationship of these functions are now being studied in mouse models of mitochondrial disease.

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Mitochondrial diseases in man and mouse.

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

https://science.sciencemag.org/content/sci/242/4884/1427.full.pdf

Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy

Introduction to linear and nonlinear programming

Muscle fatigue encompasses a class of acute effects that impair motor performance. The mechanisms that can produce fatigue involve all elements of the motor system, from a failure of the formulation of the descending drive provided by suprasegmental centers to a reduction in the activity of the contractile proteins. We propose four themes that provide a basis for the systematic evaluation of the neural and neuromuscular fatigue mechanisms: 1) task dependency to identify the conditions that activate the various mechanisms; 2) force-fatigability relationship to explore the interaction between the mechanisms that results in a hyperbolic relationship between force and endurance time; 3) muscle wisdom to examine the association among a concurrent decline in force, relaxation rate, and motor neuron discharge that results in an optimization of force; and 4) sense of effort to determine the role of effort in the impairment of performance. On the basis of this perspective with an emphasis on neural mechanisms, we suggest a number of experiments to advance our understanding of the neurobiology of muscle fatigue.

Neurobiology of muscle fatigue.

Fifty patients with acquired immune deficiency syndrome had complications affecting the central or peripheral nervous systems or both. The patients were either male homosexuals, intravenous drug abusers, or recently arrived Haitian refugees. They ranged in age from 25 to 56. Central nervous system complications were of four kinds: (1) Infections included Toxoplasma gondii abscesses in 5 patients, progressive multifocal leukoencephalopathy in 2, cryptococcal meningitis in 2, Candida albicans in 1, and possible Mycobacterium avium intracellulare in 3. Eighteen patients suffered a subacute encephalitis possibly attributable to cytomegalovirus infection. (2) Tumors consisted of primary lymphoma of the brain in 3 patients and meningeal invasion by systemic lymphoma in 4. (3) Vascular complications included nonbacterial thrombotic endocarditis in 2 patients and cerebral hemorrhages in the setting of thrombocytopenia in 3. (4) Undiagnosed central nervous system problems were evidenced as focal brain lesions in 3 patients and self-limiting aseptic meningitis in 4. Peripheral neuropathy occurred in 8 patients.

Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients

Somatosensory evoked potential (SEP) latencies, motor and sensory nerve conduction velocities (CVs), and F-wave latenies were measured in 15 elderly normal subjects (mean age 74.1 years), and the results were used to derive indirect estimates of spinal cord CVs. These measurements were compared to those from 15 younger normal adults (mean age 31.6 years), and the nerve conduction characteristics of all 30 subjects were analyzed with respect to age. Peripheral motor and sensory CVs slowed progressively, and the onset latencies of F-waves and SEPs increased gradually with advancing age. Spinal cord CVs showed little change until approximately age 60, and declined sharply thereafter. In addition, the latencies of F-waves and SEPs were positively associated with height. Human clinical and experimental studies utilizing SEP and F-wave measurements must allow for morphologic differences between individuals, and for the systematic changes which accompany normal aging.

Age‐related changes in peripheral and central nerve conduction in man

We describe a new, automatic signal-processing method (ADEMG) for extracting motor-unit action potentials (MUAP's) from the electromyographic interference pattern for clinical diagnostic purposes. The method employs digital filtering to select the spike components of the MUAP's from the background activity, identifies the spikes by template matching, averages the MUAP waveforms from the raw signal using the identified spikes as triggers, and measures their amplitudes, durations, rise rates, numbers of phases, and firing rates. Efficient new algorithms are used to align and compare spikes and to eliminate interference from the MUAP averages. In a typical 10-s signal recorded from the biceps brachii muscle using a needle electrode during a 20 percent-maximal isometric contraction, the method identifies 8-15 simultaneously active MUAP's and detects 30-70 percent of their occurrences. The analysis time is 90 s on a PDP-11/34A.

Automatic Decomposition of the Clinical Electromyogram

Waveforms are often sampled faster than the Nyquist rate to obtain desired temporal resolution, even though, theoretically, oversampling adds no information and should not be necessary. This paper shows how high resolution can be achieved efficiently from data sampled at the Nyquist rate by working with coefficients of the Fourier-series expansion of the continuous interpolating waveform. Practical algorithms are presented for aligning and comparing waveforms, locating peaks, resolving superimpositions, and averaging overlapping waveforms. The algorithms prove to be more accurate, and to require fewer computations and less storage than techniques which employ continuous oversampling in many signal-processing applications, particularly template matching.

High-Resolution Alignment of Sampled Waveforms

The electrical stimulus pulse and the surface electrodes commonly used to study compound action potentials of peripheral nerves give rise to an artifact consisting of an initial spike and a longer lasting tail which often interferes with the recorded signal. The artifact has four sources: 1) the voltage gradient between the recording electordes caused by stimulus current flowing through the limb, 2) the common-mode voltage of the limb caused by current escaping through the ground electrode, 3) the capacitive coupling between the stimulating and recording leads, and 4) the high-pass filtering characteristics of the recording amplifier. This paper models these sources and presents several methodological rules for minimizing their effects. Also presented are three computer-based methods for subtracting the residual artifact from contaminated records using estimates of the artifact obtained from: 1) subthreshold stimulation, 2) a second recording site remote from the nerve, or 3) stimulation during the refractory period of the nerve.

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On the Nature and Elimination of Stimulus Artifact in Nerve Signals Evoked and Recorded Using Surface Electrodes

We studied a kindred in which 8 members had the neuroretinopathy of Leber's disease; 14 had a progressive, generalized dystonia attributed to striatal degeneration; and 1 had both disorders. The mode of inheritance was compatible with maternal transmission. This neurologic disorder may be a mitochondrial disease.

Leslie J. Dorfman

Papers

Age‐related changes in peripheral and central nerve conduction in man

Automatic Decomposition of the Clinical Electromyogram

High-Resolution Alignment of Sampled Waveforms

On the Nature and Elimination of Stimulus Artifact in Nerve Signals Evoked and Recorded Using Surface Electrodes

Leber's disease and dystonia: A mitochondrial disease