Listening to deaf medics. Interview by Marion Angell Garza.
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Clinical Competence↗
Biomedical subjects
K Brown
Publications and source records attributed to K Brown.
Type I antithrombin deficiency: five novel mutations associated with thrombosis.
The genetic basis of Type I antithrombin deficiency has been investigated in six unrelated kindred with positive histories of thrombosis using a PCR amplification/direct sequencing approach. Four frameshift mutations, all introducing premature translation termination codons were identified. Thus, deletions, of a C at nucleotide position 2599 or 2600, a G at position 2601-2602 and a CT dinucleotide at position 7428-7429 were detected in three kindred and confirmed by restriction enzyme analysis. The identical insertion, of a T at nucleotide 2770, was observed in two apparently unrelated families. This finding may have been due to a founder effect since antithrombin gene polymorphism analysis showed all affected individuals to share a common haplotype. An in frame deletion of 6 bp at nucleotide position 2690-2696 causing the removal of codons 76 and 77 encoding Ile 76 and Phe 77 was also detected indicating that these amino acids are essential for stability of the mature antithrombin.
Adult↗
Rounded atelectasis.
Rounded atelectasis (RA) is a special type of peripheral lung collapse that develops as a result of pleural disease. Most cases have been attributed to asbestos inhalation, but many other causes have also been implicated. It is usually detected incidentally in an asymptomatic older man. RA can be diagnosed by a constellation of radiologic findings. It appears as a rounded masslike opacity in the peripheral lung adjacent to thickened pleura and with curvilinear opacities of bronchi and vessels (comet tail) extending from the site of RA toward the hilum. Volume loss of the affected lobe is uniformly present. In addition to the classic lesion, a spectrum of atypical lesions has also been described. Computed tomography (CT) and high-resolution CT demonstrate the full extent of disease better than chest radiography. Familiarity with this benign condition is important to differentiate it from other pulmonary and pleural diseases and to prevent unnecessary invasive procedures and surgical resection.
Diagnosis, Differential↗
Opioid and opioid-like drug effects on whole-gut transit measured by scintigraphy.
UNLABELLED: We studied the effects of several drugs on gastrointestinal transit (tramadol HCl, acetaminophen with codeine and placebo) in a randomized, double-blind, crossover study. METHODS: Combined gastric emptying, small bowel and colonic transit scintigraphy was performed in 12 normal subjects. Each subject received a standardized diet and study drug on Days 1-5. On Day three, subjects received a radiolabeled solid and liquid phase meal. RESULTS: No significant difference in the gastric T1/2 (mean +/- s.e.m.) of solids for placebo (69 +/- 7 min), APAP/C (74 +/- 15 min) or tramadol (686 +/- 8 min) (p = 0.86) were seen. Similarly there was no significant difference in the T1/2 of liquids for placebo (31 +/- 4 min), APAP/C (41 +/- 6 min) (p = 0.29). Orocecal transit times were not significantly different for placebo (237 +/- 20 min), APAP/C (311 +/- 26 min) or tramadol (311 +/- 10 min) (p = 0.12). Colon geometric centers (GC) for placebo at 24, 48 and 72 hr were 4.6 +/- 0.35, 6.0 +/- 0.28 and 6.8 +/- 0.08. The GC for tramadol and APAP/C were all significantly lower at 72 hr, 6.4 +/- 0.17 and 6.2 +/- 0.17, respectively compared to the placebo. The GC of tramadol at 24 and 48 hr (3.8 +/- 0.4, 5.4 +/- 0.26) were not significantly different from placebo. In contrast, the GC for APAP/C at 24 and 48 hr (3.3 +/- 0.31, 5.0 +/- 0.26) were significantly delayed. All subjects recorded a significant increase in constipation on drugs compared to placebo (p = 0.04). CONCLUSION: Tramadol and APAP/C had no effect on gastric emptying or small bowel transit. At equianalgesic doses, tramadol caused less delay in colonic transit than APAP/C for 48 hr and delay in the GC agreed with the subjective complaints of constipation on both drugs.
Acetaminophen↗
Haemoglobin Hallamshire (beta146 HIS --> TYR): a new high oxygen affinity haemoglobin responsible for familial erythrocytosis.
A new high oxygen affinity haemoglobin with the beta chain mutation beta146 HIS --> TYR is described. This variant was detected in a fit 34-year-old man with true erythrocytosis. The abnormal haemoglobin was identified as an extra band on cellulose acetate electrophoresis at pH 6.3 and was later confirmed by beta globin gene sequencing and oxygen dissociation studies. Whole blood containing Haemoglobin Hallamshire has a P50 of 18 mmHg. This newly described haemoglobin variant was also responsible for erythrocytosis in the mother and maternal half cousin of the index case. The identification of Haemoglobin Hallamshire provides confirmatory evidence of the important role of the C-terminal end of the chain in haemoglobin function.
Adult↗
Evidence in support of a role for human T-cell leukemia virus type I Tax in activating NF-kappa B via stimulation of signaling pathways.
The human T-cell leukemia virus type I Tax protein activates NF-kappa B transcription factors from preformed cytoplasmic pools, including those pools that are retained by the I kappa B-alpha inhibitory protein. Degradation of I kappa B-alpha is enhanced by Tax, resulting in the liberation of some NF-kappa B, which then translocates into the nucleus. Here we have investigated the mechanism by which Tax causes degradation of I kappa B-alpha. Two I kappa B-alpha mutants defective in extracellular signal-induced degradation of I kappa B-alpha also blocked Tax-mediated kappa B-dependent transactivation when cotransfected into Jurkat T cells. Cotransfected wild-type I kappa B-alpha or an irrelevant mutant did not significantly effect transactivation induced by Tax. The signal-defective I kappa B-alpha proteins are mutated at either of two closely spaced serines in the N terminus of the protein (Ser32 and Ser36). In wild-type I kappa B-alpha, one or both of these serines are inducibly phosphorylated with extracellular stimuli, and such phosphorylation appears necessary for subsequent degradation and thus activation of NF-kappa B. These results suggest that Tax triggers I kappa B-alpha degradation and thus NF-kappa B activation by a mechanism that converges with that induced by extracellular stimulation such as phorbol 12-myristate 13-acetate/ionomycin or tumor necrosis factor alpha. A role for Tax in activating signal transduction pathways upstream of I kappa B-alpha is implied.
Gene Expression Regulation↗
Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation.
I kappa B-alpha inhibits transcription factor NF-kappa B by retaining it in the cytoplasm. Various stimuli, typically those associated with stress or pathogens, rapidly inactivate I kappa B-alpha. This liberates NF-kappa B to translocate to the nucleus and initiate transcription of genes important for the defense of the organism. Activation of NF-kappa B correlates with phosphorylation of I kappa B-alpha and requires the proteolysis of this inhibitor. When either serine-32 or serine-36 of I kappa B-alpha was mutated, the protein did not undergo signal-induced phosphorylation or degradation, and NF-kappa B could not be activated. These results suggest that phosphorylation at one or both of these residues is critical for activation of NF-kappa B.
Amino Acid Sequence↗
Activation of NF-kappa B requires proteolysis of the inhibitor I kappa B-alpha: signal-induced phosphorylation of I kappa B-alpha alone does not release active NF-kappa B.
The transcription factor NF-kappa B is retained in the cytoplasm by its inhibitor I kappa B-alpha. Upon cellular stimulation with a variety of pathogen- or stress-related agents, I kappa B-alpha is functionally inactivated and NF-kappa B translocates to the nucleus to trigger transcription of a large array of genes, many of which encode proteins critical for immune or stress responses. Here, we demonstrate that signal-induced proteolysis of I kappa B-alpha is an obligatory step for activation of NF-kappa B: calpain inhibitors I and II, which inhibit cysteine proteases, block activation of NF-kappa B by blocking degradation of I kappa B-alpha without affecting signal-induced phosphorylation of this inhibitor. This contrasts with previous models in which phosphorylation of I kappa B-alpha was postulated to be sufficient for activation. We demonstrate further that signal-induced phosphorylation of I kappa B-alpha does not by itself lead to dissociation of the inhibitor from NF-kappa B, providing a rationale for and confirmation of the need to proteolyze I kappa B-alpha in order to activate NF-kappa B. Signal-controlled, target-specific proteolysis is an unexpected, yet likely more general, mechanism for regulating transcription factors.
Calpain↗
Fulminant hepatic failure secondary to herpes simplex virus hepatitis. Successful outcome after orthotopic liver transplantation.
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Adult↗
Two antithrombin mutations in a compound heterozygote: Met20Thr and Tyr166Cys.
The molecular basis for a family with Type I antithrombin deficiency has been established. Amplification and sequencing of the antithrombin gene identified two mutations: Met20Thr (2523T-->C) within exon 2 and Tyr166Cys (5493A-->G) within exon 3a. Further analysis indicated that the propositus was a compound heterozygote but in addition provided evidence for phase disruption during the amplification and/or cloning procedure. The Met20Thr mutation appears to be a neutral mutation with no functional consequences. In contrast, the Tyr166Cys mutation is associated with a Type I phenotype.
Antithrombin III↗
Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 Ha-ras gene regulated by a mouse tyrosinase promoter.
The tyrosinase promoter has been used to target expression of the mutated human T24 Ha-ras oncogene in pigment-producing cells of transgenic mice. Two independent founder mice carrying the transgene survived and showed the same distinct phenotype of mutated coat color, deeply pigmented skin with multiple nevi, and twirling behavior. The offspring of one of these founders were developed into a line that stably expressed the same phenotype. Histopathological analysis of the tissues revealed hyperpigmentation and/or melanocytic hyperplasia in the skin, eyes, inner ear, and meningeal membranes in the brain. Reverse transcriptase-polymerase chain reaction analysis revealed expression of the transgene in skin, brain, and spleen. We propose that these transgenic mice will be a model for studying the process of multistage melanoma carcinogenesis and a system for evaluating potential chemopreventive agents.
Animals↗
Transgenic mice and squamous multistage skin carcinogenesis.
The use of animals models of human cancers has proved useful in the elucidation of molecular events which occur during tumour development. Mouse skin has been used as a model for human squamous cancer for a number of decades, and analysis of this model has identified a number of changes important for the evolution of malignancy. Transgenic mice offer a further avenue of advancement, allowing refinement of the model, and the ability to examine the consequences of individual events in vivo in greater detail. This article reviews the impact of transgenic approaches to our understanding of multistage squamous carcinogenesis in mouse skin.
Animals↗
Transgenic approaches to understanding the mechanisms of chemical carcinogenesis in mouse skin.
The use of animal models for human cancer has proved effective in the elucidation of those molecular events which are responsible for the various stages of tumour development. Chemical carcinogenesis in mouse skin has been studied as a model for human squamous cancer for several decades, and analysis of this model has led to the identification of a number of the changes which are involved in the evolution of malignancy. The use of transgenic and knockout mice offers a further avenue of advancement, allowing refinement of the model, and the ability to examine the consequences of individual events in vivo in greater detail. Additionally, crossing different transgenic or knockout animals represents a powerful tool to study the cumulative effects of several genetic alterations acting in concert.
Animals↗
Dissociation of centrosome replication events from cycles of DNA synthesis and mitotic division in hydroxyurea-arrested Chinese hamster ovary cells.
Relatively little is known about the mechanisms used by somatic cells to regulate the replication of the centrosome complex. Centrosome doubling was studied in CHO cells by electron microscopy and immunofluorescence microscopy using human autoimmune anticentrosome antiserum, and by Northern blotting using the cDNA encoding portion of the centrosome autoantigen pericentriolar material (PCM)-1. Centrosome doubling could be dissociated from cycles of DNA synthesis and mitotic division by arresting cells at the G1/S boundary of the cell cycle using either hydroxyurea or aphidicolin. Immunofluorescence micros-copy using SPJ human autoimmune anticentrosome antiserum demonstrated that arrested cells were able to undergo numerous rounds of centrosome replication in the absence of cycles of DNA synthesis and mitosis. Northern blot analysis demonstrated that the synthesis and degradation of the mRNA encoding PCM-1 occurred in a cell cycle-dependent fashion in CHO cells with peak levels of PCM-1 mRNA being present in G1 and S phase cells before mRNA amounts dropped to undetectable levels in G2 and M phases. Conversely, cells arrested at the G1/S boundary of the cell cycle maintained PCM-1 mRNA at artificially elevated levels, providing a possible molecular mechanism for explaining the multiple rounds of centrosome replication that occurred in CHO cells during prolonged hydroxyurea-induced arrest. The capacity to replicate centrosomes could be abolished in hydroxyurea-arrested CHO cells by culturing the cells in dialyzed serum. However, the ability to replicate centrosomes and to synthesize PCM-1 mRNA could be re-initiated by adding EGF to the dialyzed serum. This experimental system should be useful for investigating the positive and negative molecular mechanisms used by somatic cells to regulate the replication of centrosomes and for studying and the methods used by somatic cells for coordinating centrosome duplication with other cell cycle progression events.
Animals↗
Acute childhood diarrhoea and maternal time allocation in the northern central Sierra of Peru.
Interventions to improve child health depend, at least implicitly, on changing maternal knowledge and behaviour and a reallocation of maternal time. There have been few studies, however, of the time cost involved in the adoption of new health technologies and even fewer that examine changes in maternal activities in response to child illness. The present study examines maternal daytime activities and investigates changes that occur when children are ill. We examine the impact of acute childhood diarrhoea episodes on the activity patterns of the mother/caretaker in this setting. The results show that mothers alter their usual activity patterns only slightly in response to acute diarrhoea episodes in their children. They continue to perform the same variety of activities as when the children are healthy, although they are more likely to perform them with the child 'carried' on their back. There is some indication that diarrhoea perceived to be more severe did result in the mother acting as caretaker more frequently. These findings have important implications for health interventions that depend on changing the amount of maternal or caretaker time spent for child health technologies, but the implications may vary depending on the reasons for the observed lack of changes in caretaker activities.
Child Care↗
Parent satisfaction with services in an emergency department located at a paediatric teaching hospital.
OBJECTIVE: To evaluate parents' satisfaction with the services provided in an emergency department located at a paediatric hospital. METHODOLOGY: A descriptive study in which the parents of children with non-life-threatening illnesses attending an emergency department completed a questionnaire describing their satisfaction with services in the department. RESULTS: The majority of parents were satisfied with the services provided. However, less satisfied parents reported having to wait significantly longer before receiving medical attention than satisfied parents. Consistent with this finding, 77% of less satisfied parents reported that staff did not attend to their children's needs quickly enough and 62% felt that there were insufficient staff available to provide help. Twenty-nine per cent of the less satisfied parents reported that they did not know what was required for the ongoing care of their children after their discharge from the emergency department. CONCLUSIONS: In order to address the concerns of less satisfied parents, emergency departments need to give careful attention to the maintenance of reasonable waiting times, the provision of adequate staffing, and the quality of staff-parent communication. Addressing these issues may improve the ongoing care of children after their discharge from emergency departments.
Adolescent↗
Can the immunobead assay for detecting sperm antibodies in fresh samples be reproduced in cryopreserved/thawed human spermatozoa?
PROBLEM: To evaluate the reproducibility of the Immunobead Assay (IBA) on sperm samples before and after cryopreservation. METHOD: Sperm samples (fresh and post-thaw) from known antibody negative donors (N = 20) were evaluated for percent immunobead binding by IBA following incubation with known antibody-positive serum. RESULTS: In both fresh and thawed negative samples, the mean sperm head binding was 0.5% +/- 0.5, the mean sperm tail binding was 2.0% +/- 2.0 and the mean sperm head-tail binding was 3.0% +/- 2.0 for IgG, IgA and IgM type antibodies, respectively. The same samples exposed to positive sera showed 40.0% +/- 10.0 mean head binding, 7.0% +/- 8.0 mean tail binding and 47.0% +/- 11.0 mean head-tail binding. CONCLUSIONS: IBA is highly reproducible for detecting sperm antibodies in both fresh and cryopreserved/thawed samples of human spermatozoa.
Autoantibodies↗
Uptake kinetics and intracellular localization of hypocrellin photosensitizers for photodynamic therapy: a confocal microscopy study.
Hypocrellins are naturally occurring compounds with photosensitizing properties in biological systems. We have prepared synthetic derivatives of hypocrellin B, which have promise as photosensitizers in the clinical application of photodynamic therapy. The intracellular localization and uptake kinetics of hypocrellin B and several selected hypocrellin congeners were determined semiquantitatively by fluorescence confocal microscopy in monolayer cultures of EMT6/Ed murine tumor cells. Each compound had unique uptake kinetics. Although no compound tested to date has demonstrated nuclear labeling, most could be detected in lysosomes, Golgi, endoplasmic reticulum and, to a minor extent, in cellular membranes. No two compounds gave identical labeling distributions. The differences are assumed to originate in physicochemical properties characteristic of each compound, which may ultimately impact upon the primary modality of phototoxicity.
Animals↗