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Biomedical subjects

B R Brooks

Publications and source records attributed to B R Brooks.

At least 55 records · Page 3Linked to original sources
PubMed1996

CD8 and CD4 T cell-mediated polymyositis complicating the HTLV-1 associated myelopathy. Quantitative evaluation of corticosteroid treatment.

INTRODUCTION: Inflammatory myopathy is a treatable cause of worsening in the spectrum of neurological conditions that may develop during the course of HTLV-1 infection. MATERIAL AND METHODS: To investigate the cause of subacute worsening in the strength of a 46-y-old black male with HTLV-1 associated myelopathy we performed electrodiagnostic examination and a muscle biopsy which was studied with histochemistry, immunocytochemistry and electron microscopy. Serial measurements of isometric muscle strength were performed during the course of corticosteroid treatment. RESULTS: The muscle biopsy showed evidence of denervation atrophy and prominent inflammatory changes with autoaggressive features. Lymphocyte typing showed a predominance of CD8+ T cells. The patient had sustained, marked improvement in strength, especially of the upper extremities, with oral, high single-dose, alternate-day prednisone therapy. CONCLUSION: A muscle biopsy should be considered in all patients with HTLV-1 associated weakness, especially when electromyography indicates possible coexisting primary muscle involvement and/or serum creatine kinase levels are elevated. HTLV-1-associated polymyositis can be successfully treated with corticosteroids.

Anti-Inflammatory Agents↗
PubMed1996

ts1-Induced spongiform encephalomyelopathy: physical forms of high-mobility DNA in spinal cord tissues of paralyzed mice are products of premature termination of reverse transcription.

ts1 is a temperature-sensitive mutant of Moloney murine leukemia virus that causes hind-limb paralysis in mice. In tissues of the central nervous systems of paralyzed moribund FVB/N mice, a major component of the unintegrated viral DNA of ts1 consists of highly mobile physical forms of viral-specific DNA (HM DNA). Previous studies with ecotropic virus-specific polarity probes showed that the gp70-coding region of the env gene in the HM DNA was minus-sense single-stranded DNA. The physical forms of the HM DNA have now been characterized in more detail with additional ecotropic virus-specific probes that hybridized to the p15E-coding region of the env gene and two locations within the U3 region of the long terminal repeat. Two major classes of HM DNA were found: class I molecules consist of short minus-sense single-stranded DNA; class II molecules are partial DNA duplexes that are longer than the class I molecules. The two classes of HM DNA molecules are intermediate products of reverse transcription of the viral RNA of ts1. Since tissues that are infected with cytopathic retroviruses may contain high levels of unintegrated viral DNA, the HM DNA may have a role in inducing neurodegeneration in the central nervous systems of mice that are infected with ts1.

Animals↗
PubMed1995

Deoxyglucose uptake by mouse astrocytes: effects of temperature and retrovirus infection.

Deoxyglucose uptake by FVB/N mouse astrocytes was studied before and after infection by ts1 retrovirus which causes a neurodegenerative disease in mice similar to HIV-1 encephalopathy in man. The Michaelis-Menten kinetic parameters, Km and Vmax, of 2-deoxy-D-glucose uptake by brain and cerebellar astrocytes were measured following culture at 34 degrees C where ts1 retrovirus replicates optimally, and at 37 degrees C. Compared to astrocytes cultured at 37 degrees C, astrocytes cultured at 34 degrees C had increased Km and decreased deoxyglucose uptake despite increased or unchanged Vmax. Following ts1 retrovirus infection, brain astrocyte deoxyglucose uptake doubled [132%] associated with decreased Km but unchanged Vmax, whereas cerebellar astrocyte deoxyglucose uptake doubled [102%] associated with increased Vmax but unchanged Km. These observations of altered deoxyglucose uptake kinetic parameters following retrovirus infection indicate different neurochemical mechanisms for the regional variation in deoxyglucose uptake observed following retrovirus infection of the CNS in vivo.

AIDS Dementia Complex↗
PubMed1995

Development of physical forms of unintegrated retroviral DNA in mouse spinal cord tissue during ts1-induced spongiform encephalomyelopathy: elevated levels of a novel single-stranded form in paralyzed mice.

ts1 is a murine leukemia virus that causes rapidly evolving hindlimb paralysis in susceptible strains of mice. Following perinatal infection, three physical forms of unintegrated viral DNA were detected in the spinal cord by Southern blot hybridization. Linear and supercoiled closed-circle viral double-stranded DNAs were detected in both the central nervous system and non-central nervous system tissues. An elevated level of a novel minus-sense single-stranded form of viral DNA, which had a very high mobility in agarose gels, was correlated with the onset of symptoms of paralysis. As the severity of paralysis progressed, the level of this single-stranded form increased rapidly, with the highest level in the spinal cords of moribund mice. Since the virulence of a number of cytopathic retroviruses has been associated with the presence of increased amounts of unintegrated viral DNA in the tissues of the infected hosts, this novel form of highly mobile unintegrated single-stranded DNA may have a role in the neuropathogenesis of ts1.

Animals↗
PubMed1995

Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Effect of orientation on spatiotemporal contrast sensitivity in multiple sclerosis.

Spatiotemporal contrast sensitivity at three orientations, vertical, horizontal and oblique, was studied in 18 patients with clinically definite and laboratory-confirmed definite multiple sclerosis (MS). Nineteen age-matched control subjects were also studied under identical experimental conditions. Contrast thresholds for detecting steady and counterphase modulated (5 Hz) gratings ranging in spatial frequency from 0.5 to 12 c/deg were measured by a modified psychophysical method of limits. With the exception of two patients (three eyes) whose Snellen acuity scores were 20/70, all observers had acuity scores of 20/30 or better. All subjects were corrected for astigmatism. Orientation, spatial frequency and temporal frequency interacted differently in determining contrast sensitivity in the two groups of observers. For the controls, an oblique effect was present for both the steady and counterphase modulated gratings of high spatial frequencies, and there was no orientation-dependent loss of sensitivity for low spatial frequencies. For the observers with MS, there was no oblique effect, but sensitivity was dependent on orientation for the low spatial frequencies. Most patients with MS had reduced contrast sensitivity, compared to the controls, at one or more orientations. Counterphase modulation increased sensitivity to the low spatial frequencies and decreased sensitivity to the high spatial frequencies for both normal controls and patients with MS. In patients with MS this effect of temporal modulation on contrast sensitivity was markedly enhanced.

Adult↗
PubMed1993

Protein hydration elucidated by molecular dynamics simulation.

Molecular dynamics (MD) simulation covering a wide range of hydration indicate that myoglobin is fully hydrated by 350 water molecules, in agreement with experiment. These waters, originally placed uniformly about the protein, form clusters that hydrate every charged group throughout the entire simulation. Some atoms in charged groups are hydrated by two water layers while 37% of the protein surface remains uncovered. The locations of the 350 waters are consistent with those of crystallographic waters resolved by x-ray and neutron diffraction. Hydration by 350 waters at 300 K stabilizes the conformation of carboxymyoglobin measured by x-ray diffraction throughout the entire protein, halves the rate of torsional transitions, and promotes alternative conformations for surface atoms. The glass transition observed experimentally in hydrated myoglobin near 220 K is also seen in the simulations and correlates with an increase in the number of dihedral angles undergoing transitions. The anharmonic protein motion above 220 K is enhanced by protein hydration.

Computer Simulation↗
PubMed1993

Metabolism-based transformation of myoglobin to an oxidase by BrCCl3 and molecular modeling of the oxidase form.

The stoichiometric reductive debromination of BrCCl3 to a trichloromethyl radical by myoglobin caused the prosthetic heme to become covalently cross-linked to the protein moiety and transformed myoglobin from an oxygen storage protein to an oxidase. This was shown in experiments in which oxygen consumption was measured during redox cycling of the altered myoglobin in the presence of ascorbate or an enzymatic reducing system containing diaphorase and NADH. Redox cycling eventually led to loss of the protein-bound heme adduct and oxidase activity of myoglobin. We have used molecular modeling and the known structure of the protein-bound heme adduct to identify probable mechanisms for transformation of myoglobin to an oxidase. Based on these modeling studies, the most likely structure of the experimentally observed adduct involves ligation to the heme iron of the epsilon-nitrogen atom of histidine 97 and/or that of histidine 64. The model structures revealed access of solvent to the heme active site, which could facilitate oxygen reduction. The transformation of myoglobins and perhaps other hemoproteins to oxidases may have toxicological importance in causing the tissue damage resulting from exposure to various xenobiotics and endogenous chemicals as well as explaining how hemoproteins are inactivated during catalysis.

Animals↗
PubMed1993

Theoretical studies of relaxation of a monomeric subunit of HIV-1 protease in water using molecular dynamics.

The dynamic behavior of one 99-residue subunit of the dimeric aspartyl protease of HIV-1 was studied in a 160 psec molecular dynamics simulation at 300 K in water. The crystal structure of one of the identical subunits of the dimer was the starting point, with the aqueous phase modeled by 4,331 explicit waters in a restrained spherical droplet. Analysis of the simulations showed that the monomer displayed considerable flexibility in the interfacial portions of the flap (the region which folds over the substrate), the N- and C-termini, and, to a lesser extent, the active site. The flap undergoes significant motion as an independent rigid finger, but without the cantilever previously reported in a simulation of the dimer. The N-terminus displayed the greatest fluctuational disorder whereas the C-terminus exhibited the greatest root mean square movement from the crystal structure. The central core of the monomer had a heavy-atom root mean square deviation from the initial structure of about 3.0 A during the latter half of the simulation. Although this is larger than the 1.6 A found for comparable simulations of typical globular proteins, the general features of the tertiary structure were preserved over the course of the simulation. Overall, these results indicate that the relaxed structure obtained in these simulations may provide a better model for the tertiary structure of the solvated HIV-1 protease monomer than the subunit conformation seen in the X-ray crystallographic structure of the dimer. Except in the flap region, the design of compounds intended to interfere with dimerization should take this relaxation and the flexibility of the solvated monomer, especially at the termini, into account.

Amino Acid Sequence↗
PubMed1993

Multiple orofacial indices in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by significant speech and swallowing problems resulting from upper and lower motor neuron loss. Weakness is the primary ALS disease-related sign, and measures of muscle strength have revealed nonuniform patterns of muscle weakness in orofacial muscles. To a large extent, muscle strength measures in these studies have not been evaluated in terms of functional significance, and few researchers have addressed the relation between weakness and motor neuron loss. This study addressed whether multiple measures, including static isometric maximum voluntary contraction (MVC), a dynamic measure of the peak rate of change of force (PRCF), an upper motor neuron (UMN) index, and a functional disability score (FDS) might enhance understanding of speech dysfunction in ALS. Ten males diagnosed with sporadic ALS showing mild speech impairment and an equal number of matched controls were studied. Tongue MVC and PRCF were more impaired than those of the lip and jaw, irrespective of the time post onset and site of initial symptoms. Results also suggested that disproportionate tongue impairment may be related to UMN deficits. However, impairments in the rate of contraction did not appear to be related to UMN deficits. Tongue weakness and tongue and lower lip PRCF were related to the degree of speech severity, but none of the measures was related to speech intelligibility. The value of a functional outcome measure like speech intelligibility and its role in characterizing orofacial involvement in the early stages of ALS bulbar impairment are discussed.

Adult↗
PubMed1993

Correlation of specific virus-astrocyte interactions and cytopathic effects induced by ts1, a neurovirulent mutant of Moloney murine leukemia virus.

ts1 is a highly neuropathogenic and lymphocytopathic mutant of Moloney murine leukemia virus TB (MoMuLV-TB). We previously reported that the primary neuropathogenic determinant of ts1 maps to a single amino acid substitution, Val-25-->Ile, in precursor envelope protein gPr80env. This Val-25-->Ile substitution apparently renders gPr80env inefficient for transport from the endoplasmic reticulum to the Golgi apparatus. These findings suggest that the cytopathic effect of ts1 in neural cells might be due to the accumulation of gPr80env in the endoplasmic reticulum. Since endothelial and glial cells are targets of ts1 infection in the central nervous system, we established primary endothelial and astrocyte cultures to investigate the mechanism of cell killing caused by ts1. A continuous cell line, TB, was used as a control. Our results showed that both ts1 and MoMuLV-TB replicated and induced a cytopathic effect in astrocyte cultures, albeit to different degrees; ts1 appeared to be more lethal than MoMuLV-TB. On the other hand, ts1 and MoMuLV-TB infections of endothelial or TB cells were not cytopathic. The cytopathic effect in infected astrocytes correlated with the inefficiency of gPr80env transport and the intracellular accumulation of gPr80env as well as aberrant virus particles.

Animals↗
PubMed1993

Home ventilation for amyotrophic lateral sclerosis patients: outcomes, costs, and patient, family, and physician attitudes.

We conducted this study to better inform amyotrophic lateral sclerosis (ALS) patients about home ventilation and to assist them in decision-making. We gathered data on the prevalence of ALS patients on home ventilation in northern Illinois and the percentage who chose it, and we asked identified subjects, their families, and physicians for their attitudes toward home ventilation. Fewer than 10% of ALS patients had chosen home ventilation, and fewer than 5% were still on it. Seventeen patients (90%) were glad to have chosen home ventilation and would choose it again. Family caregivers reported major burdens, and only half would choose it for themselves. The mean yearly cost of home ventilation was $153,252. Home ventilation is effective for ALS patients had desired by the small number who undergo it, but it imposes significant burdens on families.

Adult↗