Have adult neurologists learned from paediatric neurology?
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Continuity of Patient Care↗
Biomedical subjects
K Brown
Publications and source records attributed to K Brown.
Prognostic validity of short-term abstinence in alcoholism.
A demonstrated period of abstinence is often viewed as a good prognostic sign in alcoholism. For example, short-term abstinence is one factor often considered important as a selection criteria for alcoholics who are being evaluated as liver transplant candidates. However, the prognostic validity of short-term abstinence is unclear. We evaluated the effects of 3 and 6 months of abstinence on readmission rates in a series of 299 alcoholics following discharge from inpatient treatment. Readmission rates were stratified using a 3-factor model of alcoholism severity. This 3-factor model defined groups with 1-year readmission rates, ranging from 15.8% to 62.7%. Short-term abstinence did not have strong effects on readmission rates for the most severe alcoholics, nor did short-term abstinence produce clinically significant reduction for readmission rates for the least severe alcoholics. We conclude that short-term abstinence has minimal effect on prognosis for alcoholics with various levels of baseline severity.
Adult↗
Identification of subtypes of problem drinkers based on neuropsychological performance.
The key issue addressed in this paper is: Can specific subtypes of drinkers be identified on the basis of their neuropsychological performance? A multivariate model of neuropsychological deficits related to alcohol abuse was proposed and cluster analysis was used to see if subtypes could be identified which matched those indicated in the multivariate model. A neuropsychological cognitive assessment battery was given to a wide variety of drinkers (N = 88). Factor analysis yielded scores on four factors which formed the basis for the cluster analysis. Seven stable clusters were identified based on cognitive performance alone. Additionally, clusters were significantly differentiated by age, IQ, education, number of units of alcohol consumed on a heavy drinking day, nutritional status, stress and the Eysenck Personality Questionnaire Lie score. The seven clusters were eventually profiled as healthy males, healthy females, males with stress-related deficits, females with stress-related deficits, mildly impaired males, deficits related to liver dysfunction and mild alcoholic Korsakoff syndrome. The clusters successfully mapped onto the proposed model reinforcing the need for a multivariate approach to the study of neuropsychological deficits in problem drinkers.
Adult↗
Binding of the protease-sensitive form of PrP (prion protein) to sulfated glycosaminoglycan and congo red [corrected].
Congo red and certain sulfated glycans are potent inhibitors of protease-resistant PrP accumulation in scrapie-infected cells. One hypothesis is that these inhibitors act by blocking the association between protease-resistant PrP and sulfated glycosaminoglycans or proteoglycans (e.g., heparan sulfate proteoglycan) that is observed in amyloid plaques of scrapie-infected brain tissue. Accordingly, we have investigated whether the apparent precursor of protease-resistant PrP, protease-sensitive PrP, binds to Congo red and heparin, a highly sulfated glycosaminoglycan with an inhibitory potency like that of heparan sulfate. Protease-sensitive PrP released from the surface of mouse neuroblastoma cells bound to heparin-agarose and Congo red-glass beads. Sucrose density gradient fractionation provided evidence that at least some of the PrP capable of binding heparin-agarose was monomeric. Free Congo red blocked PrP binding to heparin and vice versa, suggesting that these ligands share a common binding site. The relative efficacies of pentosan polysulfate, Congo red, heparin, and chondroitin sulfate in blocking PrP binding to heparin-agarose corresponded with their previously demonstrated potencies in inhibiting protease-resistant PrP accumulation. These results are consistent with the idea that sulfated glycans and Congo red inhibit protease-resistant PrP accumulation by interfering with the interaction of PrP with an endogenous glycosaminoglycan or proteoglycan.
Animals↗
Kinetic analysis of human T-cell leukemia virus type I Tax-mediated activation of NF-kappa B.
The human T-cell leukemia virus type I (HTLV-I) Tax protein induces the expression of cellular genes, at least in part, by activating the endogenous NF-kappa B transcription factors. Induced expression of cellular genes is thought to be important for transformation of T cells to continued growth, a prelude to the establishment of adult T-cell leukemia. However, neither underlying mechanisms nor kinetics of the Tax-mediated activation of NF-kappa B are understood. We have analyzed a permanently transfected Jurkat T-cell line in which the expression of Tax is entirely dependent on addition of heavy metals. The initial NF-kappa B binding activity seen after induction of Tax is due almost exclusively to p50/p65 heterodimers. At later times, NF-kappa B complexes containing c-Rel and/or p52 accumulate. The early activation of p50/p65 complexes is a posttranslational event, since neither mRNA nor protein levels of NF-kappa B subunits had increased at that time. We demonstrate for the first time a Tax-induced proteolytic degradation of the NF-kappa B inhibitor, I kappa B-alpha, which may trigger the initial nuclear translocation of NF-kappa B. As nuclear NF-kappa B rapidly and potently stimulates resynthesis of I kappa B-alpha, the steady-state level of I kappa B-alpha does not significantly change. Thus, the dramatic Tax-induced increase in the I kappa B-alpha turnover may continually weaken inhibition and activate NF-kappa B. Additional, distinct actions of Tax may contribute further to the high levels of NF-kappa B activity seen.
Chlorides↗
Increase in asthma: a more toxic environment or a more susceptible population?
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Adolescent↗
Structure, regulation and function of NF-kappa B.
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Amino Acid Sequence↗
Intrathoracic calcifications: radiographic features and differential diagnoses.
Intrathoracic calcifications occur in a wide variety of disorders. Although they are usually harmless sequelae of remote processes, calcifications provide important information for establishing the diagnosis or for evaluating the progression of known disease. They may arise in the pulmonary parenchyma, mediastinum, hilar and mediastinal lymph nodes, pleura, chest wall, or any combination of these structures. The cause of the calcification may be determined by means of the location and pattern of the calcifications within the lung parenchyma and knowledge of the associated clinical features. Calcifications in the thorax are frequently manifestations of previous infectious processes. Less often, they may be due to neoplasms, metabolic disorders, occupational exposure, or previous medical therapy. Large intrathoracid calcifications are usually identified on conventional chest radiographs; detection of smaller calcifications may require use of other imaging modalities, such as dual-energy digital radiography, fluoroscopy, radionuclide scanning, computed tomography (CT), and high-resolution CT.
Calcinosis↗
Breathing patterns in infants and children under halothane anesthesia: effect of dose and CO2.
We studied the amplitude, timing, and shape of the airflow waveform at the mouth of spontaneously breathing children under two sets of conditions: 1) in 30 children aged 9 wk-4.5 yr at 2, 1, and 0% inspired halothane concentration and 2) in 22 children aged 5 mo-7 yr during hyperoxic CO2 rebreathing while recovering from anesthesia. Compared with control values, the relative changes in breath parameters at 1 and 2% halothane were, respectively, as follows: total cycle time -19 and -31%, tidal volume (VT) -30 and -44%, minute ventilation -11 and -17%, and VT/inspiratory time (TI) -16 and -20%. Parameters of timing and breath shape did not change except for the significant but small increase in TI/total cycle time (by 6 and 8%, respectively). With CO2 rebreathing, parameters reflecting inspiratory drive increased significantly in all patients as shown by the slopes of the regressions of these parameters against end-tidal PCO2. Mean slopes expressed in %control value per millimeter of mercury CO2 were 12.1 for minute ventilation, 8.3 for VT, and 10.67 for VT/TI. Parameters reflecting the timing and breath shape remained essentially unchanged. Our results suggest that, in children under halothane anesthesia, the amplitude, timing, and shape of the breathing pattern are controlled independently. In particular, the amplitude and timing of the breath may vary widely without any significant change in the shape.
Airway Resistance↗
Quantitating familial cancer risk: a resource for clinical oncologists.
PURPOSE: Because a family history of cancer constitutes an important risk factor, estimation and communication of cancer risk can facilitate efforts toward early detection and prevention. This review provides a resource for health professionals called to draw upon a multidisciplinary literature to provide quantitative risk estimates to families with cancer. DESIGN: Descriptive population-derived, epidemiologic, genetic, genetic epidemiologic, and molecular studies are critically reviewed in the context of cancer genetic counseling. RESULTS: Data are presented that document the increased lifetime relative risk to relatives of individuals with cancers of the breast, ovary, colon, prostate, or other sites. In general, risk ratios are poorly suited for clinical counseling. Age-specific absolute risks are presented for first-degree relatives of individuals affected by cancers of the breast, ovary, and colon. The derivation of Mendelian and Bayesian risk estimates in the setting of well-defined cancer family syndromes, and the growing role of DNA testing in more accurately assessing these risks, are discussed. Such carrier testing requires careful psychologic and ethical considerations. CONCLUSION: Multidisciplinary cancer genetic counseling is an emerging resource available to physicians who care for families with common adult malignancies.
Age Factors↗
QALYs for resource allocation: a rejoinder to a reply.
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Australia↗
Ethics in action: a young Hmong man with inoperable liver cancer.
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Cultural Characteristics↗
Studies on antigen binding by intact and hinge-deleted chimeric antibodies.
A matched set of chimeric IgG1 and IgG4 antibodies were used to investigate the role of the IgG hinge in binding to Ag with differing space between the epitopes. Antibodies bearing identical V regions and either IgG1 or IgG4 C regions were engineered with and without hinges. We measured the binding of these antibodies to the peptide CYYYEEEEY and to CYYYEEEEY-BSA conjugates with decreasing numbers of peptides per BSA molecule. We earlier showed that V region differences in antibodies could affect Ag binding patterns in solid-phase but not solution-phase assays; however, both types of assay yielded similar results for the hinge-deleted antibodies. Binding of CYYYEEEEY-BSA by hinge-deleted and intact IgG1 was similar, but intact IgG1 bound free peptide better than did hinge-deleted IgG1. Intact IgG4 antibody bound less well to CYYYEEEEY and CYYYEEEEY-BSA than did IgG1 but, surprisingly, hinge-deleted IgG4 showed better binding than did intact IgG4 and was more like the IgG1 antibodies in binding affinity. Thus, the IgG4 hinge may impart a structural constraint that prevents high affinity binding to Ag. The hinge-deleted IgG4 antibody did not activate C, although it bound Ag similarly to IgG1. This study is the first to address the effect of the IgG hinge on Ag binding by using well defined Ag with different epitope densities. Our results may provide an explanation for the apparent low affinity of IgG4 antibodies.
Amino Acid Sequence↗
Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha.
The NK-kappa B transcription factor complex is sequestered in the cytoplasm by the inhibitory protein I kappa B-alpha (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-kappa B nuclear localization and transactivation of its target genes. It is demonstrated here with human T lymphocytes and monocytes that different stimuli, including tumor necrosis factor alpha and phorbol 12-myristate 13-acetate, cause rapid degradation of I kappa B-alpha, with concomitant activation of NF-kappa B, followed by a dramatic increase in I kappa B-alpha mRNA and protein synthesis. Transfection studies reveal that the I kappa B-alpha mRNA and the encoded protein are potently induced by NF-kappa B and by homodimers of p65 and of c-Rel. We propose a model in which NF-kappa B and I kappa B-alpha mutually regulate each other in a cycle: saturating amounts of the inhibitory I kappa B-alpha protein are destroyed upon stimulation, allowing rapid activation of NF-kappa B. Subsequently, I kappa B-alpha mRNA and protein levels are quickly induced by the activated NF-kappa B. This resurgence of I kappa B-alpha protein acts to restore an equilibrium in which NF-kappa B is again inhibited.
Blotting, Northern↗
The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers.
Bcl-3 is an I kappa B-related protein with ankyrin repeat motifs. Its gene is located at a site of recurrent translocations in a subset of B cell chronic lymphocytic leukemias. Bcl-3 associates tightly with p50B (NFKB2, p52) homodimers in cells, and together these proteins form a ternary complex with DNA at kappa B sites. Such an association functionally leads to a novel and potent form of transactivation through the kappa B motif: the tethering of Bcl-3 to DNA via the p50B homodimers allows Bcl-3 to transactivate directly, while p50B homodimers alone cannot. Transactivation mediated by Bcl-3 requires two cooperating domains located amino- and carboxy-terminal to the ankyrin domain. Bcl-3 is localized to the nucleus, and a Bcl-3-p50B complex is detected in certain lymphoid cells. Our data reveal a novel role for Bcl-3, distinct from that of the inhibitor I kappa B. The results have implications for tumorigenesis.
Animals↗
Fragilitas ossium (fro/fro) in the mouse: a model for a recessively inherited type of osteogenesis imperfecta.
The fragilitas ossium (fro/fro) mutation in the mouse has been demonstrated to have clinical, radiographic and morphologic manifestations similar to those which arise in autosomal recessive forms of osteogenesis imperfecta (OI) occurring in humans. Approximately 90% of mutant offspring in the mouse were perinatally lethal with clinical and roentgenographic findings similar to those of OI type II subgroup A in humans. The 10% of mutant mice surviving follow a course very similar to severe progressively deforming OI type III. In surviving mice, there is progressive fore-limb and hind-limb bowing in the absence of a high fracture frequency.
Animals↗
Two studies of reported pretraumatic stressors' effect on posttraumatic stress disorder severity.
We contrasted in two studies the effects of military trauma on Vietnam veterans who reported high and low premilitary stress. In the first, we administered the Posttraumatic Stress Disorder Interview (PTSD-I), a premilitary modification of the Social Readjustment Rating Scale, and the Military Stress Scale to hospitalized veterans. Premilitary stress appeared to reduce the impact of combat on several trauma-reexperiencing ratings, although the relevant evidence was inconsistent. In the second study, the premilitary stress main effects and the premilitary stress/combat interactions on four PTSD-I factors were nonsignificant. Thus, the severities of most PTSD symptoms increased with trauma intensity, but not with milder premilitary stress. The inconsistent data on the impact of pretraumatic stress on the trauma severity/PTSD relationships suggest further study.
Adult↗
The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites.
Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappa B sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF-kappa B. Such homodimers are abundant for example in nuclei of unstimulated primary T cells. Here we extend the model and provide new evidence which fulfills a number of predictions. (i) Bcl-3 preferentially targets p50 homodimers over NF-kappa B heterodimers since the homodimers are completely dissociated from kappa B sites at concentrations of Bcl-3 which do not affect NF-kappa B. (ii) Select kappa B sites associate very strongly and stably with p50 homodimers, completely preventing binding by NF-kappa B. Such kappa B sites are likely candidates for regulation by p50 homodimers and Bcl-3. (iii) Bcl-3 and p50 can be co-localized in the nucleus, a requirement for active removal of homodimers from their binding sites in vivo. (iv) The ankyrin repeat domain of Bcl-3 is sufficient for the reversal of p50 homodimer-mediated inhibition, correlating with the ability of this domain alone to inhibit p50 binding to kappa B sites in vitro. Our data support the model that induction of nuclear Bcl-3 may be required during cellular stimulation to actively remove stably bound p50 homodimers from certain kappa B sites in order to allow transactivating NF-kappa B complexes to engage. This exact mechanism is demonstrated with in vitro experiments.
Animals↗