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Biomedical subjects

B R Brooks

Publications and source records attributed to B R Brooks.

At least 37 records · Page 2Linked to original sources
PubMed1999

Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology committee on Research.

BACKGROUND: In 1994 consensus guidelines were developed for conducting clinical trials in ALS. With growing experience in clinical trials, it has become clear that a number of further guidelines were needed. METHODS: Under the auspices of the World Federation of Neurology Committee on Research, a multinational group of neurologists, statisticians, patient advocates, representatives from the pharmaceutical industry as well as regulatory agencies developed consensus about a number of revisions to the existing guidelines during a 2 day conference in April 1998. RESULTS: Expanded areas of focus include greater protection of patient rights, more detailed guidelines for outcome measures statistical analyses, disclosure of study results and improved interaction between investigators and the corporate sector. COMMENT: Substantial progress has been made in standardizing and improving the quality of clinical trials in ALS through these consensus guidelines.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Diagnostic dilemmas in amyotrophic lateral sclerosis.

The El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis (ALS) were introduced in 1990 to provide a standardised and diagnostically reliable approach to the early recognition of this disease. It is still unclear, however, whether these are the best criteria available for the early diagnosis of ALS. We applied these criteria retrospectively to clinical material available from 34 cases of autopsy proven ALS in an attempt to validate their usefulness in a pathological series. The clinical material was reviewed and specific clinical signs and anatomical levels of involvement recorded. Only signs listed in the criteria were included in the analysis. The El Escorial criteria for clinically definite ALS demonstrated high sensitivity and accuracy when validated in this clinicopathological study. Neuroimaging and electromyography were important in shortening the time in which patients were given a diagnosis of clinically definite ALS. Other diagnostic dilemmas in ALS and the role of early diagnosis of this disease are discussed.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Zidovudine [AZT] myotoxicity: quantitative separation of AZT effects on proliferation and differentiation of muscle cells in vitro. Lack of myotoxicity potentiation by retrovirus.

We compared quantitatively the myotoxicity of 3'-azido-2',3'-dideoxythymidine (AZT) against uninfected and ts1 retrovirus infected mouse skeletal muscle (ATCC CRL 1772) cells at different stages of maturation in vitro. The AZT half inhibitory concentration (IC50) for myoblast proliferation was determined for uninfected myoblasts and parallel cultures infected with ts1 virus. The AZT IC50 for muscle cell differentiation was determined in cultures where myoblasts were grown to confluence and then changed to the fusion medium to which AZT was added at increasing concentrations. Creatine kinase activity was used as a marker of muscle cell differentiation and was determined in homogenates after 7 days. Total cellular mitochondrial DNA was analyzed by Southern blotting. The estimated AZT IC50 for muscle cell proliferation (2-5 microM) was significantly less than the AZT IC50 for muscle cell differentiation (100 microM). Infection with ts1 retrovirus did not significantly shift the IC50 for either proliferation or differentiation of muscle cells. Toxic concentrations of AZT did not cause selective depletion of mitochondrial DNA. The myotoxic effects of AZT on myoblast proliferation and muscle cell differentiation in vitro were quantitatively different and were not changed by productive ts1 retrovirus infection of muscle cells. These results suggest that AZT may impair muscle fiber regeneration in the course of retrovirus associated myopathy. The mechanism of AZT myotoxicity was not explained by alterations in total mitochondrial DNA content.

Animals↗
PubMed1999

Defining optimal management in ALS: from first symptoms to announcement.

The advances in treatment for amyotrophic lateral sclerosis (ALS) have demonstrated the need to diagnose this disease precisely and directly. Two international initiatives, at El Escorial in 1990 and at Airlie House in 1998, have grappled with the clinical and laboratory elements that may accelerate the diagnostic process. Shortly after the Airlie House meeting in 1998, an international group of clinical neurologists met to discuss optimal management strategies in ALS. The goals were to examine current diagnosis and treatment pathways and to attempt to devise an algorithm that would foster early diagnosis, thus enhancing the possibility of optimal treatment.

Algorithms↗
PubMed1999

What are the implications of early diagnosis? Maintaining optimal health as long as possible.

As yet, there is no staging system for amyotrophic lateral sclerosis (ALS). One early attempt to define disease stages consisted of post-hoc analysis of the international, placebo-controlled, clinical trials of riluzole. In this analysis, five health states were defined for ALS (mild, moderate, severe, terminal, death) to determine whether therapeutic intervention with riluzole could favorably influence the time spent in the different stages. The time spent in the mild and moderate disease states (taken together) was considerably longer in patients treated with riluzole than in those treated with placebo (317 days compared with 242 days). Riluzole did not influence the median time in the mild, severe, or terminal ALS stages but did slightly shorten the time in the moderate ALS stage compared with placebo. In all the ALS stages, the 75th percentile of time in that state appeared to be extended. Survival analysis indicated that the relative risk was less than 1.0 with riluzole treatment in the moderate, severe, and terminal health states but not in the mild health state, when it remained at 1.0. The time to failure was longer in patients in the moderate, severe, and terminal ALS stages but was significantly longer only in the moderate ALS stage. These findings indicate that future studies of therapeutic intervention should examine rigorously defined stages of disease to examine end points other than death. The development of a staging system, analogous to the ones used in oncology, has implications for the concept of early diagnosis.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Earlier is better: the benefits of early diagnosis.

The concept of earlier diagnosis of amyotrophic lateral sclerosis (ALS) requires in-depth investigation of its benefits and consequences. First, how good must a treatment be before ALS is determined to be a treatable condition? Analogy with cancer therapy suggests that a good quality of life after treatment is an essential feature of a "good" therapy. Survival in some diseases may be prolonged without a significant improvement in the patient's quality of life. Neurologists need to be clear about what they are trying to achieve in prolonging survival and maintaining a good quality of life for their patients with ALS. Second, can early diagnosis extend apparent survival in the absence of a therapeutic intervention that significantly affects the disease process? Earlier diagnosis on the basis of confirmed clinical signs and earlier institution of therapy may lead to a perception of improved survival, which is greater in young ALS patients. Third, can early diagnosis provide a benefit through prolongation of the time the patient remains able to work? Any therapeutic intervention to slow the early stages of the disease would benefit patients who wanted to maintain their self-esteem by continuing to work. Finally, earlier diagnosis of ALS requires decisions to be made concerning the acceptable rate of misdiagnosis, which at present reaches 10% false-positive and up to 44% false-negative.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Catalytic mechanism of aldose reductase studied by the combined potentials of quantum mechanics and molecular mechanics.

The catalytic reduction of D-glyceraldehyde to glycerol by aldose reductase has been investigated with the combined potentials of quantum mechanics (QM) and molecular mechanics (MM) to resolve the question of whether Tyr48 or His110 serves as the proton donor during catalysis. Site directed mutagenesis studies favor Tyr48 as the proton donor while the presence of a water channel linking the N delta 1 of His110 to the bulk solvent suggests that His110 is the proton donor. Utilizing the combined potentials of QM and MM, the binding mode of substrate D-glyceraldehyde was investigated by optimizing the local geometry of Asp43, Lys77, Tyr48, His110 and NADPH at the active site of aldose reductase. Reaction pathways for the reduction of D-glyceraldehyde to glycerol were then constructed by treating both Tyr48 and His110 as proton donors. Comparison of energetics obtained from the reaction pathways suggests His110 to be the proton donor. Based on these findings, a reduction mechanism of D-glyceraldehyde to glycerol is described.

Aldehyde Reductase↗
PubMed1998

CuZnSOD and MnSOD immunoreactivity in brain stem motor neurons from amyotrophic lateral sclerosis patients.

Motor neurons from the brain stems of amyotrophic lateral sclerosis (ALS) and control patients were examined with immunoantibodies to CuZn-superoxide dismutase (CuZnSOD) and Mn-superoxide dismutase (MnSOD). We found that there was a marked staining for CuZnSOD in all the motor nuclei, the hypoglossus, ambiguus, facialis and trigeminus from the ALS patients, but not in the controls. The same neurons from the ALS patients also stained very intensely for MnSOD, whereas the neurons from the control patients stained weakly or not at all. Loss of neurons was also a very consistent finding and was noted in all the motor nuclei from the ALS patients. There was a proliferation of glial cells which stained strongly both for CuZnSOD and for MnSOD accompanying the loss of the neurons. These results indicated that there was an apparent increase of superoxide dismutase immunoreactivity in motor neurons of ALS patients. We conclude that CuZnSOD and MnSOD immunoreactivity is increased in motor neurons and glia in the brain stems of patients with ALS, specific for the terminal phase of this disease.

Aged↗
PubMed1998

Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group.

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

Adult↗
PubMed1997

Epidemic heat stroke in a midwest community: risk factors, neurological complications and sequelae.

We studied the admission rate, risk factors, neurological complications and sequelae of heat stroke (HS) during the 1995 heat wave in Madison, Wisconsin. HS was epidemic in 1995 (2.3 cases/1000 admissions), compared to the ten-fold lower endemic rate in 1994 (0.2/ 1000). There were 11 cases of HS, 9 males and 2 females. Contributing factors were athletic events (2), working outdoors (3) and indoor activity with malfunctioning air-conditioning (6). Medical conditions contributing to poor temperature regulation included schizophrenia with neuroleptic treatment (2), amyotrophic lateral sclerosis receiving nortriptiline (1), multiple sclerosis (1), attention deficit disorder (1), cystic fibrosis (1) and alcoholism (1). Acute neurological complications occurred in all patients on presentation including coma (8/11.73%), stupor (2/ 11.18%) and seizures (1/11.9%). Two patients (1856) had persistent neurological sequelae in the form of a pan-cerebellar syndrome while the remaining 9 recovered fully. Importantly, avoidable factors contributed to all of the patients with underlying diseases. These patients are particularly at risk and should take adequate precautions during summer months.

Adolescent↗
PubMed1996

Positioning of positively charged residues in the V3 loop correlates with HIV type 1 syncytium-inducing phenotype.

Although the V3 loop of the envelope glycoprotein (gp120) plays a role in determining the phenotype, pathogenesis, and tropism of human immunodeficiency virus-1 (HIV-1), there has not been any consistent correlation between structure and phenotype. Theoretically determined structures of the V3 loop of gp120, from 20 different viral strains, 10 syncytium-inducing (SI) and 10 non-syncytium-inducing (NSI) phenotype, revealed that all V3 loops from SI phenotypic strains had at least two positively charged residues in close proximity, on the same face of the loop. All of the SI phenotypic V3 loop structures were capable of forming strong divalent electrostatic interactions with disulfated sugars. The ability to form this interaction may be a determinant of the phenotype, tropism, and pathogenicity of HIV-1 viral strains. This structural motif was absent in all V3 loops from viral strains with the NSI phenotype.

Amino Acid Sequence↗
PubMed1996

Hydrated myoglobin's anharmonic fluctuations are not primarily due to dihedral transitions.

To characterize the functionally important anharmonic motions of proteins, simulations of carboxymyoglobin (MbCO) dynamics have been performed during which dihedral transitions were prohibited. Comparison of torsionally restrained and unrestrained protein dynamics simulated at three levels of hydration and at temperatures ranging from 100 to 400 K suggests that hydration "catalyzes" protein mobility by facilitating collective anharmonic motions that do not require dihedral transitions. When dihedral transitions were prohibited, dehydrated MbCO, to a good approximation, exhibited only harmonic fluctuations, whereas hydrated MbCO exhibited both harmonic and anharmonic motions. The fluctuation of helix centers of mass also remained highly anharmonic in the torsionally restrained hydrated system. Atomic mean-square fluctuation at 300 K was reduced upon prohibition of dihedral transitions by only 28% and 10% for MbCO hydrated by 350 and 3830 water molecules, respectively.

Biophysical Phenomena↗
PubMed1996

Clinical epidemiology of amyotrophic lateral sclerosis.

The introduction of palliative therapies in amyotrophic lateral sclerosis (ALS) will alter the epidemiology of ALS as it is known now. Although incidence rates will remain unchanged in the near future, prevalence rates will likely increase dramatically. Better understanding of the age-specific presentation of motor neuron diseases worldwide will shed light on the vexing questions concerning the variable incidence rates in some countries and apparent incidence gradients in North America and Europe.

Adult↗