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Biomedical subjects

D Brooks

Publications and source records attributed to D Brooks.

At least 91 records · Page 5Linked to original sources
PubMed1995

Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6.

In preclinical in vitro and in vivo systems, mAbs to human transferrin (Tf) receptors blocked iron uptake from Tf and showed antitumor activity. However, Tf receptors are also displayed by normal tissues, and a large, soluble pool of circulating serum Tf receptors has been detected. We report results of a Phase Ia trial of IgA monoclonal anti-Tf receptor antibody 42/6. Twenty-seven patients with advanced refractory cancer received 33 treatments with 42/6 administered as a 24-h infusion at doses ranging from 2.5 to 300 mg/m2. 42/6 was generally well tolerated, although one patient receiving a second treatment experienced an allergic-type response associated with a human antimouse antibody response. Three patients with hematological cancers showed mixed tumor responses; there were no partial or complete remissions. Peak serum levels of antibody were obtained at the termination of the 24-h infusion. At doses >/=25 mg/m2, there was a linear relationship between the 42/6 dose and average peak serum 42/6 levels ranging from <1 to 36 microgram/ml. Serum Tf receptors showed a dose-dependent decrease during 42/6 infusion to 20-30% of baseline, and remained depressed for at least 48 h after terminating the infusion. Serum 42/6 levels rose in an inverse relationship to the drop in Tf receptors. 42/6 induced an increase in serum iron and Tf saturation consistent with blockade of peripheral iron uptake, and reduced Tf receptor display by bone marrow cells. Human antimouse antibody was detected in nine patients. Anti-Tf receptor antibody was well tolerated and mediated in vivo effects on iron uptake and Tf display. Antibody concentrations capable of inhibiting malignant blood cell growth were obtained without toxicity. This represents the first clinical trial of an IgA mouse mAb, and one of only a few trials in which an antibody reacting with a broad range of normal tissues has been administered. Additional clinical trials of anti-Tf receptor antibodies in blood cell cancers are indicated.

Adult↗
PubMed1994

Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease.

Two patients with idiopathic Parkinson's disease (Patients 3 and 4 in our series) were followed up to 3 years after grafting of human embryonic dopamine-rich mesencephalic tissue unilaterally into the putamen. During the first postoperative year both patients showed significant amelioration of parkinsonian symptoms and increased 6-L-[18F]-fluorodopa uptake in the grafted putamen, as assessed with positron emission tomography. Three years after grafting the patients still exhibited increased fluorodopa uptake in the grafted putamen and significant clinical improvements, evidenced by a reduction of the severity of symptoms and of the time spent in the "off" phase, and by a prolongation of the effect of a single dose of L-dopa. Between 1 and 3 years after surgery, Patient 3 showed only minor changes of parkinsonian symptoms on the side contralateral to the graft, whereas there was a worsening on the ipsilateral side. Fluorodopa uptake decreased in the nongrafted putamen but was unchanged in the grafted putamen. Patient 4 continued to improve after the first postoperative year and L-dopa was withdrawn after 32 months. The reduction of parkinsonian symptoms on the side contralateral to the graft became more pronounced between 1 and 3 years after surgery. Fluorodopa uptake further increased in the grafted putamen, whereas no change was detected on the non-grafted side. These results indicate that grafts of embryonic dopamine neurons can survive, grow, and exert functional effects up to at least 3 years after surgery in the parkinsonian brain, despite an ongoing disease process leading to degeneration of the intrinsic dopamine system.

Brain Tissue Transplantation↗
PubMed1994

Determination of proton magnetization transfer rate constants in heterogeneous biological systems.

Two procedures are currently in use for the determination of proton magnetization transfer rate constants between macromolecular tissue components and water. The first method assumes that there are only two spin baths (macromolecular plus solvent) and that during off-resonance irradiation complete saturation of the "immobile" proton spin bath occurs (S. H. Koenig, R. D. Brown, III, R. Ugolini, Magn. Reson. Med. 29, 311 (1993)). This approach neglects the possibility of incomplete saturation and polydispersity, and yields an apparent magnetization transfer rate constant, Kapp. The second approach utilizes a formalism which can account for polydispersity and incomplete saturation of the immobile spin bath (K. Kuwata, D. Brooks, H. Yang, T. Schleich, J. Magn. Reson., in press). In this work magnetization transfer rate constants derived by the use of both methods for two systems, ocular lens tissue and cross-linked bovine serum albumin (BSA) were compared. For both samples Kapp was dependent on B2 off-resonance irradiation frequency and power when the first method was used. The second method provided values of the magnetization transfer rate constant that were similar to the values obtained by the first method, as the limit of complete saturation was approached.

Animals↗
PubMed1994

Relaxation-matrix formalism for rotating-frame spin-lattice proton NMR relaxation and magnetization transfer in the presence of an off-resonance irradiation field.

The derivation of a generalized relaxation matrix equation for the off-resonance rotating-frame spin-lattice experiment, representing N macromolecular components, is presented. The applicability of the derived formalism was demonstrated using water proton off-resonance rotating-frame spin-lattice relaxation data obtained for calf lens cortical and nuclear homogenates, a tissue system characterized by the presence of both mobile and solid-like protein domains, whose relative amounts vary in a protein-concentration-dependent manner. Protein concentration and temperature were utilized as variables in the magnetization-transfer experiments. Curve fitting to obtain the relevant magnetization-transfer parameters was accomplished by simulated annealing and the method of steepest descents. In all cases, the best fit, as reflected by the smallest root-mean-square deviation, was obtained by assuming the presence of three components representing bulk-water and mobile and solid-like macromolecular components, characterized by Lorentzian (water and mobile protein) and Gaussian proton resonance lineshapes (solid-like protein). A two-component relaxation model gave unsatisfactory fits. Dilution of nuclear homogenate resulted in physically realistic changes in the derived magnetization-transfer parameters, which included a decrease in the fraction of solid-like protein, in agreement with previously published 13C NMR studies. Changes in magnetization-transfer parameters occurred as a result of the cold cataract phase transition in nuclear homogenate. The utility and limitations of the derived formalism are discussed.

Animals↗
PubMed1993

Accuracy and reliability of 'specialized' physical therapists in auscultating tape-recorded lung sounds.

This study investigated the accuracy and inter-rater reliability of 'specialized' physical therapists in the auscultation of tape-recorded lung sounds. In addition, a correlation was investigated between accuracy of interpretation and the number of years of specialization in the field of cardiorespiratory physical therapy. This research follows an earlier study which investigated the accuracy and inter-rater reliability of auscultating tape-recorded lung sounds in a 'non-specialized' cohort of physical therapists. The subjects were 26 'specialized' cardiorespiratory physical therapists working in acute urban teaching hospitals. These individuals were required to have been practising currently and exclusively for at least one year in the area of cardiorespiratory physical therapy. Participants listened with a stethoscope to five different sounds and identified them from a standardized list of terms. One of three tapes with the same lung sounds in different order was randomly selected for each physical therapist. The percentage of correct answers for all subjects was calculated. An accurate response in the detection of lung sounds was arbitrarily defined as a percentage of correct answers of 70% or greater. The difference between the pooled correct response rate of 50% and the arbitrarily set value of 70% was statistically significant (z = 2.23, p < 0.05), indicating that the 'specialized' physical therapists were not accurate in identifying lung sounds. There was no relationship evident between the accuracy and the number of years of cardiorespiratory 'specialization' (r = 0.08). Analysis of inter-rater reliability revealed 'fair agreement' (kappa = 0.26) among subjects. These results were similar to those found in the previous study.(ABSTRACT TRUNCATED AT 250 WORDS)

Auscultation↗
PubMed1992

Role of upper cervical inspiratory neurons studied by cross-correlation in the cat.

Axonal projections and synaptic connectivity of upper cervical inspiratory neurons (UCINs) were investigated in anaesthetised cats to clarify their role as propriospinal respiratory interneurons. Antidromic mapping showed axonal collaterals near phrenic and intercostal motonuclei. Of the UCINs tested, 37% had collaterals at T3-4; 55% had ipsilateral projections and 45% had contralateral projections. Ipsilateral or contralateral cross-correlations of the activity of pairs of UCINs (one on each side of the spinal cord) with the discharge of internal intercostal, external intercostal (T3-4) or phrenic nerves revealed similar features. Those with the internal intercostal and phrenic nerves were interpreted as evidence for shared or oligosynaptic excitation, those with the external intercostal nerve as shared excitation and inhibition. No evidence for monosynaptic connections was found. Monosynaptic connections could also not be demonstrated between inspiratory intercostal neurons located near (less than 0.5 mm) the UCINs collateral arborizations in T3-4, examined by cross-correlation. Afferent feedback from internal intercostal nerves (T3-4) was investigated by cross-correlating nerve stimulation with UCINs activity. Ipsilateral and contralateral cross-correlograms had similar features, providing evidence for excitation in some cases and inhibition in others. Finally, cross-correlations between ipsilateral UCINs and cervical sympathetic nerves were featureless. The results suggest that the role of UCINs as part of a respiratory propriospinal control system analogous to forelimb motor control is untenable, although they may be part of an intercostal afferent feedback loop.

Action Potentials↗
PubMed1992

Unusual cleaning behavior in the luteal phase.

18 undergraduate women recorded episodes of unusual cleaning, defined as excessive cleaning or cleaning of things not usually cleaned, and the dates of their menstruation over a 2-mo. period. Unusual cleaning was significantly more likely to occur during the luteal phase than at any other time in women not using oral contraceptives. Possible links between changes in progesterone levels and obsessive compulsive disorders are suggested.

Adolescent↗
PubMed1991

Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). An intermediate clinical phenotype caused by substitution of valine for glycine at position 137 of arylsulfatase B.

The Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is a lysosomal storage disease with autosomal recessive inheritance caused by deficiency of the enzyme arylsulfatase B. Severe, intermediate, and mild forms of the disease have been described. The molecular correlate of the clinical heterogeneity is not known at present. To identify the molecular defect in a patient with the intermediate form of the disease, arylsulfatase B mRNA from his fibroblasts was reverse-transcribed, amplified by the polymerase chain reaction, and subcloned. Three point mutations were detected by DNA sequence analysis, two of which, a silent A to G transition at nucleotide 1191 and a G to A transition at nucleotide 1126 resulting in a methionine for valine 376 substitution, were polymorphisms. A G to T transversion at nucleotide 410 causing a valine for glycine 137 substitution (G137V) was identified as the mutation underlying the Maroteaux-Lamy phenotype of the patient, who was homozygous for the allele. The kinetic parameters of the mutant arylsulfatase B enzyme toward a radiolabeled trisaccharide substrate were normal excluding an alteration of the active site. The G137V mutation did not affect the synthesis but severely reduced the stability of the arylsulfatase B precursor. While the wild type precursor is converted by limited proteolysis in late endosomes or lysosomes to a mature form, the majority of the mutant precursor was degraded presumably in a compartment proximal to the trans Golgi network and only a small amount escaped to the lysosomes accounting for the low residual enzyme activity in fibroblasts of a patient with the juvenile form of the disease.

Alleles↗
PubMed1991

Paucity of dorsal inspiratory neuron collateral projections to ventral inspiratory neurons.

The inspiratory region of the ventral respiratory group was mapped in six Nembutal anaesthetized cats. Records multi-unit activity were taken in five or six locations at 0.5 mm spacings. These locations were then used as stimulating sites to test for the antidromic activation of 40 bulbospinal, inspiratory neurons recorded in the ipsilateral, dorsal respiratory group. Only four (10%) were antidromically activated. In a single anatomical experiment, rhodamine labelled microspheres were injected into the ventral group, and Flurogold was injected into the contralateral spinal cord. No neurons in the dorsal group were found to be double-stained. It was concluded that, ipsilateral collaterals from inspiratory dorsal group neurons to the inspiratory region of the ventral group are rare.

Animals↗