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Biomedical subjects

A Brooks

Publications and source records attributed to A Brooks.

At least 37 records · Page 2Linked to original sources
PubMed2001

Senescence-related changes in gene expression in muscle: similarities and differences between mice and men.

A microarray study of the effect of senescence in mice on gene expression in muscle has been published recently. The present analysis was done to evaluate the extent to which the age-related differences in gene expression in murine muscle are also evident in human muscle. RNA extracted from muscle of young (21-24 yr) and old men (66-77 yr) was studied both by serial analysis of gene expression (SAGE) and by oligonucleotide microarrays. SAGE tags were detected for 61 genes homologous to genes reported to be differentially expressed in young and old murine muscle. The microarray had probe sets for 70 homologous genes. For 17 genes, there was evidence for a similar age-related change in expression in muscles of mice and men. For 32 other genes, there was evidence that the effect of age on the level of expression is not the same in mice and men. There was no evidence that older human muscle has increased expression of the stress response genes that are increased in old murine muscle.

Adult↗
PubMed2001

Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency.

Congenital insensitivity to pain with anhidrosis is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The human TRKA gene (NTRK1), located on chromosome 1q21-q22 encodes the receptor tyrosine kinase for nerve growth factor. We reported that TRKA is the gene responsible for CIPA and we developed a comprehensive strategy to screen for TRKA mutations and polymorphisms, as based on the gene's structure and organization. Here we report eight novel mutations detected as either a homozygous or heterozygous state in nine CIPA families from five countries. Mendelian inheritance of the mutations was confirmed in seven families for which samples from either parent were available. However, non-mendelian inheritance seems likely for the family when only samples from the mother and siblings, (but not from the father) were available. A paternal uniparental disomy for chromosome 1 is likely to be the cause of reduction to homozygosity of the TRKA gene mutation in this family. Interestingly, a Hispanic patient from the USA has two autosomal genetic disorders, CIPA and pyruvate kinase deficiency, whose genetic loci are both mapped to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR genes from the homozygous proband, respectively. Thus, concomitant occurrence of two disorders is ascribed to a combination of two separate mutant genes, not a contiguous gene syndrome. This finding suggests a mechanism responsible for two autosomal genetic disorders in one patient. All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorder.

Adolescent↗
PubMed2001

Toxicity and pharmacokinetics of isolated lung perfusion with cisplatin in rat.

OBJECTIVE: This study was designed to evaluate the toxicity and the pharmacokinetics of cisplatin administered via isolated lung perfusion in Fischer 344 rat. METHODS: Toxicity study; Cisplatin dosages of 3.3, 5.0, 6.7, and 10.0 mg/kg were injected intravenously in four groups, respectively. Cisplatin dosages of 3.3, 5.0, and 6.7 mg/kg were perfused via isolated lung perfusion in a further three groups, respectively. The maximum tolerated dosage of cisplatin was determined by assessing the survival rate on day 21. Pharmacokinetics study; Animals received 6.7 mg/kg of cisplatin intravenously or 3.3 mg/kg of cisplatin via isolated lung perfusion. The cisplatin levels of the lung were measured by flameless atomic spectrometry. RESULTS: Toxicity study; The maximum tolerated dosage of cisplatin via intravenous injection was 6.7 mg/kg, and via isolated lung perfusion was 3.3 mg/kg. Pharmacokinetics study; The cisplatin level in the perfused lung was significantly higher than that in the lung of the animal treated intravenously (16.6 +/- 6.2 micrograms/g of tissue and 7.5 +/- 3.2 micrograms/g of tissue, respectively) (p = 0.0096). CONCLUSION: Isolated lung perfusion with 3.3 mg/kg of cisplatin was pharmacokinetically superior to the maximum tolerated intravenous injection of cisplatin.

Animals↗
PubMed2001

Carboplatin and gemcitabine in metastatic transitional cell carcinoma of the urothelium: effective treatment of patients with poor prognostic features.

PURPOSE: To evaluate the activity and toxicity of gemcitabine and carboplatin in consecutive patients presenting with locally advanced or metastatic transitional cell carcinoma of the urothelium (TCC). PATIENTS AND METHODS: Seventeen consecutive patients referred to a single institution with locally advanced or metastatic TCC were treated with carboplatin AUC 5 on day 1 and gemcitabine 1000 mg/m2 on day 1 and 8 of a 21-day cycle. All patients were assessable for response and toxicity. Minimal eligibility criteria were used to minimize patient selection. RESULTS: Seventeen patients with measurable stage IV TCC of the urothelium were treated. The median age was 69 years (range 54-78), the median creatinine clearance was 56 ml/min (range 34-90) and 30% of patients had an ECOG performance score of two. Nine patients (53%) had visceral metastases and the majority of patients had multiple sites of metastases. There were three complete responses, seven partial responses, for an overall response rate of 58.8%. Responses were seen at all sites including the liver. One patient had a response within a previously irradiated field and three patients with prior chemotherapy had responses. Median overall survival was 10.5 months and median time to progression was 4.6 months. Toxicity was primarily haematologic with six patients having grade 3 neutropenia and six patients with grade 4 neutropenia. There were five cases of grade 3 and three cases of grade 4 thrombocytopenia. There were no episodes of febrile neutropenia and only one patient required admission for management of toxicity. Thirteen patients required dose reduction or delay due to neutropenia or thrombocytopenia. There were no treatment-related deaths. CONCLUSION: The combination of carboplatin and gemcitabine is active in metastatic transitional cell carcinoma of the urothelium with manageable toxicity in a relatively elderly group of patients with some poor prognostic features.

Aged↗
PubMed2001

Perceptual strategies to improve skin cancer discriminations in naive observers.

The aim of these experiments was to assess the effect of an educational brochure on the ability of naive observers to discriminate skin cancers from benign lesions, and to investigate possible new strategies to assist observers in performing this task. A two-alternative forced choice paradigm was used to investigate the ability of observers to correctly identify different types of benign and malignant lesions before and after exposure to an educational brochure. The method of pair comparisons was used to assess the ability of observers to discriminate between benign and malignant lesions under different instruction conditions. Subjects were undergraduate students from Sydney University. An educational brochure did not facilitate the ability to correctly identify malignant lesions, and appeared to result in deterioration of performance in the identification of benign lesions. Similarly, observers were unable to discriminate between benign and malignant lesions on the basis of how dangerous they looked. However, judgements of lesions in terms of perceived distinctiveness resulted in relatively accurate discriminations between benign and malignant lesions. These data suggest current skin cancer detection strategies may be ineffective in improving the ability to visually identify benign and malignant lesions. Discriminating between lesions in terms of how distinctive they appear may form the basis of a new and effective strategy for the detection of skin cancer.

Adult↗
PubMed2001

Phytoestrogens and gonadotropin-releasing hormone pulse generator activity and pituitary luteinizing hormone release in the rat.

Phytoestrogens can produce inhibitory effects on gonadotropin secretion in both animals and humans. The aims of this study were 2-fold: 1) to determine in vivo whether genistein and coumestrol act on the GnRH pulse generator to suppress hypothalamic multiunit electrical activity volleys and associated LH pulses and/or on the pituitary to suppress the LH response to GnRH; and 2) to examine the effect of these phytoestrogens on GnRH-induced pituitary LH release in vitro and to determine whether estrogen receptors are involved. Wistar rats were ovariectomized and chronically implanted with recording electrodes and/or indwelling cardiac catheters, and blood samples were taken every 5 min for 7--11 h. Intravenous infusion of coumestrol (1.6-mg bolus followed by 2.4 mg/h for 8.5 h) resulted in a profound inhibition of pulsatile LH secretion, a 50% reduction in the frequency of hypothalamic multiunit electrical activity volleys, and a complete suppression of the LH response to exogenous GnRH. In contrast, both genistein (1.6-mg bolus followed by 2.4 mg/h for 8.5 h) and vehicle were without effect on pulsatile LH secretion. Coumestrol (10(-5) M; over 2 or 4 h) suppressed GnRH-induced pituitary LH release in vitro, an effect blocked by the antiestrogen ICI 182,780. It is concluded that coumestrol acts centrally to reduce the frequency of the hypothalamic GnRH pulse generator. In addition, the inhibitory effects of coumestrol on LH pulses occur at the level of the pituitary by reducing responsiveness to GnRH via an estrogen receptor-mediated process.

Animals↗
PubMed2001

Relative effectiveness of HZE iron-56 particles for the induction of cytogenetic damage in vivo.

One of the risks of prolonged manned space flight is the exposure of astronauts to radiation from galactic cosmic rays, which contain heavy ions such as (56)Fe. To study the effects of such exposures, experiments were conducted at the Brookhaven National Laboratory by exposing Wistar rats to high-mass, high-Z, high-energy (HZE) particles using the Alternating Gradient Synchrotron (AGS). The biological effectiveness of (56)Fe ions (1000 MeV/nucleon) relative to low-LET gamma rays and high-LET alpha particles for the induction of chromosome damage and micronuclei was determined. The mitotic index and the frequency of chromosome aberrations were evaluated in bone marrow cells, and the frequency of micronuclei was measured in cells isolated from the trachea and the deep lung. A marked delay in the entry of cells into mitosis was induced in the bone marrow cells that decreased as a function of time after the exposure. The frequencies of chromatid aberrations and micronuclei increased as linear functions of dose. The frequency of chromosome aberrations induced by HZE particles was about 3.2 times higher than that observed after exposure to (60)Co gamma rays. The frequency of micronuclei in rat lung fibroblasts, lung epithelial cells, and tracheal epithelial cells increased linearly, with slopes of 7 x 10(-4), 12 x 10(-4), and 11 x 10(-4) micronuclei/binucleated cell cGy(-1), respectively. When genetic damage induced by radiation from (56)Fe ions was compared to that from exposure to (60)Co gamma rays, (56)Fe-ion radiation was between 0.9 and 3.3 times more effective than (60)Co gamma rays. However, the HZE-particle exposures were only 10-20% as effective as radon in producing micronuclei in either deep lung or tracheal epithelial cells. Using microdosimetric techniques, we estimated that 32 cells were hit by delta rays for each cell that was traversed by the primary HZE (56)Fe particle. These calculations and the observed low relative effectiveness of the exposure to HZE particles suggest that at least part of the cytogenetic damage measured was caused by the delta rays. Much of the energy deposited by the primary HZE particles may result in cell killing and may therefore be "wasted" as far as production of detectable micronuclei is concerned. The role of wasted energy in studies of cancer induction may be important in risk estimates for exposure to HZE particles.

Animals↗
PubMed2000

Peptide-MHC class I tetrameric complexes display exquisite ligand specificity.

The production of synthetic MHC-peptide tetramers has revolutionized cellular immunology by revealing enormous CD8(+) T cell expansions specific for peptides from various pathogens. A feature of these reagents, essential for their staining function, is that they bind T cells with relatively high avidity. This could, theoretically, promote cross-reactivity with irrelevant T cells leading to overestimates of epitope-specific T cell numbers. Therefore, we have investigated the fine specificity of CTL staining with these reagents for comparison with functional data. Using a panel of CTL clones with distinct fine specificity patterns for analogs of an HLA-B8-binding EBV epitope, together with B8 tetramers incorporating these peptides, we show a very good correlation between tetramer staining and peptide activity in cytotoxicity assays. Significant staining only occurred with tetramers that incorporate strong stimulatory agonist peptides and not weak agonists that are unlikely to induce full T cell activation at physiological levels of presentation. In almost every case where a peptide analog had >10-fold less activity than the optimal EBV peptide in cytotoxicity assays, the corresponding tetramer stained with >10-fold less intensity than the EBV epitope tetramer. Furthermore, by examining an EBV-specific clonotypic T cell expansion in EBV-exposed individuals, we show similar fine specificity in tetramer staining of fresh peripheral T cells. Collectively, our data demonstrate the exquisite specificity of class I MHC-peptide tetramers, underlining their accuracy in quantifying only those T cells capable of recognizing the low levels of cell surface peptide presented after endogenous Ag processing.

Antigen Presentation↗
PubMed2000

The surgical management of cricopharyngeal achalasia in children.

OBJECTIVE: The objective of this study was to evaluate the clinical presentation of children with cricopharyngeal achalasia and to document the diagnostic process followed and evaluate the immediate and long-term results of those children treated with a cricopharyngeal myotomy. METHODS: Five children who underwent cricopharyngeal myotomies since 1976 were identified and the hospital records were reviewed in detail. Four patients were followed up to establish the long-term results of surgery. RESULTS: The age of initial presentation ranged from birth to 6 months with a universal delay in establishing the diagnosis ranging from 11 to 138 months. Two children had pre- and post-operative manometry of the upper esophageal sphincter. Post-operative upper esophageal sphincter pressures were reduced to 29 and 47% in relation to pre-operative values. Nissen fundoplications were performed in two patients to control documented gastro esophageal reflux. No post-operative complications were noted and complete symptomatic relief was obtained in all children. The long-term follow up was 2, 10, 12 and 14 years with all children remaining free of symptoms. CONCLUSION: Cricopharyngeal achalasia is an important but relatively seldom diagnosed cause of dysphagia in children. The diagnosis is almost always delayed because the condition is not widely recognised amongst physicians. If the diagnosis and effective treatment is delayed significant morbidity or even mortality, mainly due to pulmonary aspiration, may result. Cricopharyngeal myotomy is a safe and effective operation with excellent results. Symptomatic relief is immediate and complete with no long-term recurrence documented in this series.

Child, Preschool↗
PubMed2000

Differential splicing of antigen-encoding RNA reduces endogenous epitope presentation that regulates the expansion and cytotoxicity of T cells.

The activation of CTLs is dependent on the recognition of MHC-bound peptide present on the surface of APCs. We give evidence in this study that differential splicing of Ag-encoding RNA can decrease the antigenic dose in APCs and regulate the recall of human memory CTLs. Differential splicing of RNA that encoded an immunodominant HLA-B8-restricted CTL epitope of EBV reduced the functional presentation of this epitope, and consequently the in vitro expansion and activity of CTLs, as measured by MHC/peptide-tetramer staining and cytotoxicity assays. The reduced activity of the stimulated CTLs was not only due to lower numbers of Ag-specific CTLs but, surprisingly, was also characterized by decreased cytotoxicity of the CTLs to target cells presenting limiting amounts of the peptide epitope. As indicated by TCR repertoire analysis, the reduction in CTL activity was not caused by stimulation of distinct populations of TCR clonotypes. This study demonstrates how a common eukaryotic posttranscriptional mechanism of gene regulation can modulate the endogenous presentation of Ag and ultimately contribute to the fine tuning of immunological memory cells, which are important in the fight against pathogens and tumors and in autoimmunity.

Alternative Splicing↗
PubMed2000

Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system.

HIV-1 infection of the brain results in chronic inflammation, contributing to the neuropathogenesis of HIV-1 associated neurologic disease. HIV-1-infected mononuclear phagocytes (MP) present in inflammatory infiltrates produce neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosis. Neurologic disease is correlated with the relative number of MP in and around inflammatory infiltrates and not viral burden. It is unclear whether these cells also play a neuroprotective role. We show that the chemokine, fractalkine (FKN), is markedly up-regulated in neurons and neuropil in brain tissue from pediatric patients with HIV-1 encephalitis (HIVE) compared with those without HIVE, or that were HIV-1 seronegative. FKN receptors are expressed on both neurons and microglia in patients with HIVE. These receptors are localized to cytoplasmic structures which are characterized by a vesicular appearance in neurons which may be in cell-to-cell contact with MPs. FKN colocalizes with glutamate in these neurons. Similar findings are observed in brain tissue from an adult patient with HIVE. FKN is able to potently induce the migration of primary human monocytes across an endothelial cell/primary human fetal astrocyte trans-well bilayer, and is neuroprotective to cultured neurons when coadministered with either the HIV-1 neurotoxin platelet activating factor (PAF) or the regulatory HIV-1 gene product Tat. Thus focal inflammation in brain tissue with HIVE may up-regulate neuronal FKN levels, which in turn may be a neuroimmune modulator recruiting peripheral macrophages into the brain, and in a paracrine fashion protecting glutamatergic neurons.

Adult↗
PubMed2000

Junctional biases in the naive TCR repertoire control the CTL response to an immunodominant determinant of HSV-1.

The enormous diversity of the T cell pool makes it difficult to determine whether inherent biases in the naive TCR repertoire can influence T cell responsiveness. In C57BL/6 mice the cytotoxic T lymphocyte response to an immunodominant HSV-1 determinant (gB) is characterized by a prominent bias in Vbeta element usage, associated with a conserved and preferentially D element-encoded CDR3 sequence. Comparison of naive and gB-specific T cell populations revealed a similar enrichment of germline D element-encoded CDR3 sequences in the preimmune repertoire. Strikingly, eliminating the germline coding of the gB-specific CDR3 sequence caused an almost complete loss of the dominant subset of gB-specific T cells, illustrating that CDR3 biases can significantly alter both the composition and strength of an immune response.

Animals↗
PubMed2000

Comparison of orbital colour Doppler findings with computed tomography angiography.

Colour Doppler imaging (CDI) of orbital vessels is noninvasive but may be fallacious, while computed tomography (CT) angiography displays a visual outline of orbital vessels. We compared clinical findings of the two methods in 33 patients with a wide variety of clinical conditions. It was not possible to visualize the central retinal arteries with CT angiography, but it was possible to show the intracranial carotid, which CDI could not. Changes in the ophthalmic arteries on CDI usually showed changes in calibre on CT angiography. Patients with unexplained or gross visual loss often showed marked abnormalities on CT scanning, not entirely consistent with the clinical picture. Several patients showed marked ectasia of the intracranial carotid along with variable clinical findings. Findings on CT angiography complement and augment those on CDI, and are likely to be more clinically valuable in the future.

Adult↗
PubMed2000

A meningioma-mimicking tumor caused by Mycobacterium avium complex in an immunocompromised patient.

Intracranial tuberculomas manifesting radiologically as typical dural-based "meningiomas" have been reported, most frequently in immunosuppressed patients. Their incidence is high in developing countries; they are only sporadically observed in Western Europe and North America, usually in patients with acquired immunodeficiency syndrome (AIDS). According to published reports, intracranial tuberculomas are always due to infection by Mycobacterium tuberculosis. We report a case of a 50-year-old woman with systemic lupus erythematosus (SLE) who presented with a dural based, meningioma-like mass in the right frontal region, resulting from a localized infection by Mycobacterium avium complex. Histologically, the mass resembled a meningioma in being composed of spindly cells arranged in a fascicular pattern. Immunohistochemical stains showed this tumor to consist of a large aggregate of AFB-laden histiocytes without caseating necrosis or multinucleated giant cells.

Anti-Inflammatory Agents↗
PubMed2000

Aberrant development of thymocytes in mice lacking laminin-2.

In previous in vitro studies, we proposed a role for the extracellular matrix component, laminin-2, and its integrin receptor, VLA-6, in thymocyte development. The characterization of two dystrophic mouse strains with different defects in laminin-2 allowed us to examine this proposal in vivo. Mice deficient in laminin-2, dy/dy, show a significant reduction in thymus size and number of thymocytes compared to normal littermates. These mice also exhibited apparent alterations of thymic architecture. Examination of the CD4/CD8 populations in dy/dy thymi showed large relative increases in the DN (CD4- CD8-) and SP (CD4+ CD8-, CD4- CD8+) populations and a significant decrease in the DP (CD4+ CD8+) population. Further examination of the DN population for CD44 and CD25 expression showed a remarkable decrease in the more mature pre-T cell populations. Analysis of apoptosis in situ, and by flow cytometry, in dy/dy thymi revealed a significant increase in apoptotic DN thymocytes in the capsule and subcapsular regions. Interestingly, thymocyte development appeared to proceed normally in dystrophic mice expressing a mutant form of laminin-2, dy2J, as well as, in fetal and neonatal dy/dy mice. We propose that laminin-2 plays an active role in thymocyte development by delivering cell survival and differentiation signals at specific stages of development in young adult mice.

Animals↗