Tremor, fasciculations, and movement disorders.
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Biomedical subjects
Michael Podell
Publications and source records attributed to Michael Podell.
A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy.
5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.
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Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease?
A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high-steppage pelvic-limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size-frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X-linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants.
Action Potentials↗
Proton magnetic resonance imaging and spectroscopy identify metabolic changes in the striatum in the MPTP feline model of parkinsonism.
We administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult, male cats to model Parkinson's disease (PD), and utilized proton magnetic resonance imaging (MRI) and spectroscopy (MRS) at a field strength of 1.5 T to identify metabolic degenerative changes in the striatum in vivo. Neurologic status and somatosensory-evoked potentials in vivo, as well as postmortem striatal histopathological and immunohistochemical parameters, were examined. Nine cats were equally divided into three groups and treated daily for 10 days as follows: saline, MPTP, and pargyline (a monoamine oxidase inhibitor) plus MPTP. The MPTP-treated cats displayed bradykinesia, head tremor, and reduced oculovestibular reflex activity. MRI showed a diffuse increase of the T2-weighted signal in the striatum of two MPTP-treated cats. Analysis of the MRS spectra indicated significantly lower N-acetylaspartate/creatine (CR) and glutamine-glutamate complex/CR ratios than the control baseline. Two MPTP-treated cats had low choline-containing compounds/CR ratio, whereas a lactate peak was present in all MPTP-treated cats. In the striatum of the MPTP-treated cats, there was a significant decline of tyrosine hydroxylase immunoreactivity and histological evidence for a diffuse cytotoxic reaction. Pretreatment with pargyline attenuated the MPTP-induced clinical signs, MRI and MRS changes, and the histopathological and immunoreactivity alterations. We conclude that proton MRI/MRS is a sensitive, noninvasive measure of neural toxicity and biochemical alteration of the striatum in a feline model of PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Inflammatory myopathies.
Inflammatory myopathies are the result of infiltration of inflammatory cells into striated muscle, with or without an association with an underlying cause. Two broad classifications are IIMs and secondary inflammatory myopathies associated with other diseases. Standard diagnostic criteria for inflammatory myopathy include the presence of weakness or loss of specific muscle group function, an increase in CK, EMG changes associated with muscle membrane instability, and histologic evidence of inflammation. Not all these criteria, however, must be present. Fresh-frozen biopsy from two proximal muscles is recommended for biopsy confirmation. IIM can either focally affect head or neck muscles or be more diffuse. MMM is an immune-mediated disease characterized by a humoral antibody produced against the unique type IIM and type I variant mvofibers of masticatory muscles of dogs, which causes inflammation and loss of function of the muscles of mastication. Idiopathic polymyositis can affect focal muscle groups (extraocular, laryngeal) or present as multifocal or diffuse involvement of skeletal muscle in the cat and dog. Familial canine DM is an inflammatory disease of the striated muscle, skin, and vasculature in young Collies, Shetland Sheepdogs (Shelties), and, rarely, Collie-crossbred dogs. Immunosuppressive therapy is the key to successful treatment. Protozoal parasitic myopathies are the most common cause of clinically relevant secondary inflammatory myopathies. The degree of systemic involvement is often the limiting factor to successful treatment. Early recognition of the clinical signs for proper diagnostic testing and institution of appropriate therapy can result in a rewarding outcome in treating inflammatory myopathies in the cat and dog.
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Methamphetamine enhances cell-associated feline immunodeficiency virus replication in astrocytes.
Human immunodeficiency virus (HIV) infection among substance abusers is on the rise worldwide. Psychostimulants, and in particular methamphetamine (METH), have detrimental effects on the immune system as well as causing a progressive neurodegeneration, similar to HIV infection. Many Lentivirinae, including feline immunodeficiency virus (FIV), penetrate into the central nervous system early in the course of infection with astrocytes serving as a reservoir of chronic brain infection. We demonstrate that the FIV-Maryland isolate infects feline primary and cell line (G355-5)-cultured astrocytes only under cell-associated conditions. Infected astrocytes yielded a new astrocytotropic isolate, capable of cell-free infection (termed FIV-MD-A). This isolate contained four amino acid substitutions in the envelope polyprotein resulting in a change in net charge as compared to FIV-MD. Infection for both isolates was dependent upon a functional astrocyte CXCR4 receptor. Methamphetamine increased significantly FIV replication in feline astrocytes for cell-associated infection only, with no effect on peripheral blood mononuclear cells or astrocytes infected with FIV-MD-A. This viral replication was related to proviral copy number, suggesting the effect of METH is at the viral entry or integration into host genome levels, but not at the translational level. Thus, lentiviral infection of the brain in the presence of the psychostimulant METH may result in enhanced astrocyte viral replication, producing a more rapid and increased brain viral load.
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Use of a disposable real-time CT stereotactic navigator device for minimally invasive dog brain biopsy through a mini-burr hole.
We assessed the feasibility, accuracy, and safety of securing site-selective brain biopsy specimens by using a real-time CT-guided stereotactic navigation system through a mini-burr hole in the skulls of two dogs. Two beagle dogs each underwent two biopsy procedures. Our results indicated that the navigation system was accurate, safe, fast, and reliable for performing real-time brain biopsy in dogs and eliminated the need or risk of a standard-flap craniotomy.
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