Acute angle closure in Miller Fisher syndrome.
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Acute Disease↗
Biomedical subjects
D Lake
Publications and source records attributed to D Lake.
Comparison and clinical application of frequency domain methods in analysis of neonatal heart rate time series.
The frequency content of the heart rate (HR) series contains information regarding the state of the autonomic nervous system. Of particular importance is respiratory sinus arrhythmia (RSA), the high-frequency fluctuation in HR attributable to respiration. The unevenly sampled nature of heart rate data, however, presents a problem for the discrete Fourier transform. Interpolation of the HR series allows even sampling, but filters high-frequency content. The Lomb periodogram (LP) is a regression-based method that addresses these issues. To evaluate the efficacy of the LP and Fourier techniques in detecting RSA, we compared the spectrum of intervals, the spectrum of HR samples, and the LP of simulated and clinical neonatal time series. We found the LP was superior to the spectrum of intervals and the spectrum of HR samples in analysis near the critical frequency of one half the average sampling rate. Applying the LP to clinical data, we found (1) evidence of stochastic resonance, an enhancement of periodicity with the addition of small amounts of noise, and (2) reduced power at all frequencies prior to clinical diagnosis of neonatal sepsis.
Arrhythmia, Sinus↗
Immunologic memory 5 years after meningococcal A/C conjugate vaccination in infancy.
Infant vaccination with meningococcal conjugates may provide long-term protection against disease. Antibody levels and immunologic memory were assessed in 5-year-old Gambian children who received meningococcal A/C conjugate vaccination (MenA/C) in infancy. At 2 years, they were randomized to receive a booster of MenA/C (conjugate group), meningococcal A/C polysaccharide (MPS group), or inactivated polio vaccine (IPV group). All groups were revaccinated with 10 microg MPS at 5 years of age, as were 39 previously unvaccinated age-matched control subjects. Before revaccination, titers were higher in the conjugate and MPS groups than in control subjects (P<.001); titers for the IPV group were similar to those for control subjects. Ten days after revaccination, the conjugate and IPV groups had similar serogroup C serum bactericidal antibody titers (3421 vs. 2790, respectively). These levels were significantly higher than those in the MPS (426) and control (485) groups (P<.001). Thus, immunologic memory was sustained for > or =5 years; however, MPS challenge at 2 years interfered with a subsequent memory response.
Adult↗
A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma: cancer and leukemia group B study 9181.
BACKGROUND: Megestrol acetate (MA) is a synthetic progestin with reported activity in both hormone-sensitive and hormone-refractory prostate carcinoma (HRPC). Based on limited data suggesting a possible dose-response effect, a trial was initiated to compare standard versus moderately high dose MA in HRPC. METHODS: One hundred forty-nine men with hormone-refractory prostate carcinoma were randomized to receive oral MA either at 160 mg/day (low dose) or 640 mg/day (high dose). Patients were stratified by performance status and measurable versus evaluable disease. The primary end point was tumor response. Secondary end points were survival, quality-of-life measures, and prostate specific antigen (PSA) decline. RESULTS: The median survival times of 11.2 months for patients who received the low dose and 12.1 months for patients who received the high dose therapy were not significantly different. Best response was equivalent in the 2 arms: 2 partial responses and 22 patients with stable disease for the 160 mg/day dose, and 1 partial response and 28 patients with stable disease for the 640 mg/day dose. A greater than 50% decline in PSA occurred in 13.8% and 8.8% of patients in the low and high dose treatment arms, respectively. There were no differences in the toxicity or quality-of-life outcomes between the two arms. Poorer performance status (2 vs. 0-1), greater than 5% weight loss, higher baseline PSA, and measurable disease all predicted shorter survival. CONCLUSIONS: MA has limited activity in hormone-refractory prostate carcinoma, and there is no apparent dose-response correlation.
Adenocarcinoma↗
High-dose chemotherapy and stem cell transplantation for patients with stage IV breast cancer without clinically evident disease: correlation of CD34+ selection to clinical outcome.
Forty-five patients with metastatic breast cancer without clinically evident disease were treated with thiotepa 750 mg/m2, mitoxantrone 40 mg/m2 and carboplatin 1000 mg/m2 followed by stem cell transplantation to determine the safety and efficacy of CD34+ selection of peripheral blood stem cells. Of these, 15 patients' (group I) stem cells were processed through Baxter Isolex 300 device for CD34+ selection, whereas 30 patients (group II) received unmanipulated stem cells. Toxicity, progression-free survival and survival were compared between these two groups. There was no difference in transfusion requirements, white cell count and platelet recovery and non-hematologic toxicity between the two groups. The survival of patients in group I was 27 months compared to 38 months in group II (P = 0.8). The progression-free survival was 12 months and 13.5 months for group I and group II patients, respectively (P = 0.6). Our results indicate that while there is no adverse effect, there is also no significant advantage of CD34+ selection in terms of progression-free survival and survival in patients with metastatic breast cancer without clinically evident disease. Bone Marrow Transplantation (2000).
Adult↗
Confirmation of psaA in all 90 serotypes of Streptococcus pneumoniae by PCR and potential of this assay for identification and diagnosis.
The gene encoding the pneumococcal surface adhesin A (PsaA) protein, psaA, was confirmed in all Streptococcus pneumoniae serotypes by a newly developed PCR (psaA PCR) assay. Eighty-nine of the 90 serotypes amplified produced an 838-bp fragment; the exception was a serotype 16F strain acquired from the American Type Culture Collection (ATCC). Analysis of 20 additional 16F strains from the United States and Brazil showed that the gene was amplified in all 16F strains, implying that the serotype 16F ATCC strain must be a variant. The specificity of the assay was verified by the lack of signal from analysis of heterologous bacterial species (n = 30) and genera (n = 14), including viridans group streptococci. The potential of the assay for clinical application was shown by its ability to detect pneumococci in culture-positive nasopharyngeal specimens. Demonstration of psaA in all 90 serotypes and lack of amplification of heterologous organisms suggest that this assay could be a useful tool for detection of pneumococci and diagnosis of disease.
Adhesins, Bacterial↗
Hand vein responses to noradrenaline in normotensive patients with insulin-dependent diabetes mellitus and microalbuminuria: effects of alpha-adrenoceptor blockade with doxazosin.
Nephropathy commonly develops in patients with insulin-dependent (type 1) diabetes. Administration of an antihypertensive agent to type 1 diabetes patients with microalbuminuria, the first clinically detectable stage of nephropathy, can help slow renal deterioration. It is postulated that the exaggerated vasoconstrictor response to noradrenaline seen in these patients may be relevant in the development of microalbuminuria. This open, non-comparative pilot study was designed to investigate the effects of the alpha-adrenoceptor antagonist doxazosin on noradrenaline-induced hand vein vasoconstriction and on albumin excretion in 14 normotensive type 1 diabetes patients with microalbuminuria. After a three-week placebo run-in period, patients received doxazosin (1, 2, and then 4 mg once-daily, at two-week intervals) for six weeks, followed by a two-week placebo washout period. Vasoconstrictor responses to noradrenaline were measured in dorsal hand veins at the end of each two-week period. Hand vein vasoconstrictor responses to noradrenaline decreased significantly, compared with placebo, at 4 mg/day doxazosin (p = 0.006). The mean albumin excretion rate was lower than baseline at all doses of doxazosin, but changes did not reach statistical significance. Doxazosin was generally well-tolerated; four patients (29%) reported mild-to-moderate treatment-related adverse events. This study indicates that alpha 1-adrenoceptor blockade can blunt the exaggerated vascular reactivity to noradrenaline in normotensive type 1 diabetes patients with microalbuminuria, and supports further research into a potential role for doxazosin in preventing the development of diabetic nephropathy.
Adrenergic alpha-Antagonists↗
Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia.
PURPOSE: To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients. PATIENTS AND METHODS: Fifty-three patients with acute leukemia not responsive to standard therapy were treated at eight dose levels of topotecan (2.5 mg/m2/d to 7.75 mg/m2/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m2/d, both for 5 days. Using a flow-cytometric technique, the percent apoptotic cells in blood and bone marrow samples was determined, and the cell cycle distribution of the leukemic cells studied. RESULTS: Oropharyngeal mucositis was dose-limiting. The MTD of topotecan was 4.75 mg/m2/d for 5 days in high-risk patients and 7.0 mg/m2/d for 5 days in low-risk patients. The mean percent apoptotic cells in the peripheral blood reached a peak of 18.8%, a median of 48 hours following the first dose of topotecan. Patients with higher S-phase fractions, either before treatment or following cytarabine, were more likely to achieve bone marrow aplasia than those with lower S-phase fractions (P = .01 and P < .05, respectively). Clinical responses were seen in four of 39 patients with acute myelogenous leukemia (AML; of whom 32 had received prior high-dose cytarabine), three of six with acute lymphoblastic leukemia (ALL), and one of eight with chronic myelogenous leukemia in blast phase (CML-BP). CONCLUSION: The recommended phase II dose of topotecan with intermediate-dose cytarabine is 4.75 mg/m2/d for high-risk patients and 7.0 mg/m2/d for low-risk patients. The percentage of cells in S phase was important in determining response to treatment.
Adult↗
A One-Bead One-Peptide Combinatorial Library Method for B-Cell Epitope Mapping
The one-bead one-peptide combinatorial library method represents a powerful approach to the discovery of binding peptides for various macromolecular targets. It involves the synthesis of millions of peptides on beads such that each bead displays only one peptide entity. The peptide-beads that interact with a specific macromolecular target are then isolated for structure determination. We have applied this method to discovering peptide ligands for several murine monoclonal antibodies: (i) anti-beta-endorphin (continuous epitope), (ii) anti-vmos peptide, (iii) anti-human insulin (discontinuous epitope), and (iv) surface immunoglobulins (μkappa) of two murine B-cell lymphoma cell lines (antigen unknown).
Journal Article↗
Factors influencing prognosis after dose-intensive therapy for recurrent or refractory Hodgkin's disease. Results of sequential trials: a case for treating patients with resistant disease.
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Adolescent↗
Band 3 and its peptides during aging, radiation exposure, and Alzheimer's disease: alterations and self-recognition.
An aging antigen, senescent cell antigen, resides on the 911 amino acid membrane protein band 3. It marks cells for removal by initiating specific IgG autoantibody binding. Band 3 is a ubiquitous membrane transport protein found in the plasma membrane of diverse cell types and tissues, and in nuclear, mitochondrial, and golgi membranes. Band 3 in tissues such as brain performs the same functions as it does in red blood cells forming senescent cell antigen. Oxidation is a mechanism for generating senescent cell antigen. The aging antigenic sites reside on human band 3 map residues 538-554, and 812-830. Carbohydrate moieties are not required for the antigenicity or recognition of senescent cell antigen. Anion transport site were mapped to residues 588-594, 822-839, and 869-883. The aging vulnerable site which triggers the antigenic site and the transport sites of band 3 were mapped using overlapping synthetic peptides along the molecule. Naturally occurring autoantibodies to regions of band 3 comprising both senescent cell antigen and B cells producing these antibodies were demonstrated in the sera of normal, healthy individuals. The presence of these antibodies tend to increase with age. Individuals with autoimmune diseases (rheumatoid arthritis and systemic lupus erythematosus) have increased antibodies to senescent cell antigen peptides. Radiation exposure results in an increase in antibodies to peptides 588-602 which lies in a transport region containing the aging vulnerable site. Band 3 ages as cells and tissues age. Our studies, to date, indicate, that the anion transport ability of band 3 decreases in brains and lymphocytes from old mice. This decreased transport ability precedes obvious structural changes such as band 3 degradation and generation of SCA, and is the earliest change thus far detected in band 3 function. Other changes include a decreased efficiency of anion transport (decreased Vmax) in spite of an increase in number of anion binding sites (increased Km), decreased glucose transport, increased phosphorylation, increased degradation to smaller fragments as detected by quantitative binding of antibodies to band 3 breakdown products and residue 812-830, and binding of physiologic IgG autoantibodies in situ. The latter 3 findings indicate that post-translational changes occur. In Alzheimer's Disease (AD), our results indicate that post-translational changes occur in band 3. These include decreased band 3 phosphorylation of a 25-28kD segment, increased degradation of band 3, alterations in band 3 recognized by antibodies, and decreased anion and glucose transport by blood cells. Serum autoantibodies were increased in AD patients compared to controls to band 3 peptide 822-839. This band 3 residue lies in an anion transport/binding region.
Aging↗
Marrow transplantation for Hodgkin's disease: points to ponder.
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Antineoplastic Combined Chemotherapy Protocols↗
IgG autoantibodies to "switch peptide" determinants of TCR alpha/beta in human pregnancy.
The fetus is a natural allograft that is protected from immunologic rejection by a complex set of structural and regulatory mechanisms. We determined whether healthy pregnant women differed significantly from healthy non-pregnant controls in their capacity to produce autoantibodies to defined antigenic determinants of the alpha/beta T-cell receptor. Although controls and pregnant women expressed comparable levels of autoantibodies against an intact recombinant T-cell receptor containing the complete V alpha/V beta structures, analysis of comparative reactivity against individual peptide segments of the molecules, indicated enhanced reactivity to regions corresponding to the CDR1 of the alpha chain and to the Fr3 of the variable region of the beta chain. A major difference was noted by increased reactivity of IgG autoantibodies of pregnant women to peptides corresponding to the "switch" region joining the variable and constant domains. This was noted with both the Tcr alpha and beta chains and was directed against highly conserved determinants within these molecules. Antibodies to this region are lacking in the non-pregnant controls. It is possible that autoantibodies directed against conserved regions of the T-cell receptor might function in the suppression of T-cell reactivity of fetal determinants.
Amino Acid Sequence↗
Smoking attenuates the vasoconstrictor response to noradrenaline in type I diabetic patients and normal subjects: possible relevance to diabetic nephropathy.
Exaggerated vascular reactivity has been implicated in the pathogenesis of diabetic nephropathy, and several studies suggest that smoking accelerates its progression. We therefore assessed the vasoactive effects of smoking by comparing noradrenaline-induced vasoconstriction in dorsal hand-veins between smoking and non-smoking groups of Type I diabetic patients with and without microalbuminuria and in non-diabetic subjects. Smokers had a significantly higher dose causing 50% vasoconstriction (reduced sensitivity to noradrenaline) in all three groups: microalbuminuric diabetic smokers vs. nonsmokers, 20.2(4.6) (SEM) vs. 6.6(2.3) ng min-1 (P = 0.02); normoalbuminuric, 76.9(29.4) vs. 22.8(9.1) ng min-1 (P = 0.03); non-diabetic subjects, 97.8(30.0) vs. 38.0(12.8) ng min-1 (P = 0.01). Both microalbuminuric diabetic groups showed significantly greater sensitivity to noradrenaline-induced vasoconstriction than the other smoking and non-smoking groups, respectively (P < 0.01). Vasoconstrictors responses to noradrenaline are attenuated in smokers, possibly due to alpha-adrenoceptor down-regulation. Smoking could increase urinary albumin losses and accelerate renal damage through catecholamine surges which raise systemic and, perhaps, intraglomerular blood pressure. This hypothesis deserves further consideration.
Adult↗
Synthetic autoantigens of immunoglobulins and T-cell receptors: their recognition in aging, infection, and autoimmunity.
Immunoglobulins and their close relatives, the antigen-specific T-cell receptors, are recognition proteins that express structures which readily serve as self-immunogens. Healthy humans can produce antibodies against variable region-defined recognition structures termed idiotypes, as well as against constant region structures, and the levels of these can increase markedly in autoimmune disease; e.g., rheumatoid factors are autoantibodies directed against a conformational determinant of the gamma heavy chain. More recent analyses employing synthetic peptide technologies and construction of recombinant T-cell receptors document that autoantibodies directed against both variable and constant region markers of the alpha/beta T-cell receptor occur in healthy individuals. Alterations in levels of antibody, usage of IgM or IgG isotypes, and specificity for particular peptide-defined regions vary with natural physiological processes (aging, pregnancy), with artificial allografting, with retroviral infection, and with the inception and progression of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). Two of the major autoimmunogeneic regions of the Tcr alpha/beta are "constitutive" markers inasmuch as all individuals tested produce antibodies against these regions. The most frequently observed autoantibodies are against Tcr V beta CDR1 and Fr3 markers. It is hypothesized that these are normally involved in immunoregulation. Autoantibodies usually are not detected against CDR2 region determinants, or the "private idiotypes" defined by the CDR3 region, or the highly conserved FR4 segment specified by the joining gene segment. However, autoantibodies against the CDR2 of the Tcr alpha chain occur in some SLE patients, and healthy pregnant women produce antibodies against the common peptide determinant expressed by the joining gene and the beginning of the C alpha or C beta domain. Although the precise role of the naturally occurring autoantibodies in immunoregulation remains to be determined, modification of the course of autoimmune diseases in experimental rodent models (experimental allergic encephalomyelitis) has been successfully carried out by immunization with synthetic peptides corresponding to the CDR2 and Fr3/CDR3 segments, and immunization of humans with synthetic V beta CDR2 segments may prove helpful in multiple sclerosis. Moreover, infusion of intravenous immunoglobulins has been successful in the treatment of many autoimmune diseases, including examples where levels of T cells bearing particular V beta gene subsets were elevated. The recent knowledge gained from T-cell receptor structural analysis and antigenic modeling holds promise for determining the roles of particular variable domain structures in antigen recognition MHC-restriction and immunoregulation, and in the development of synthetic and recombinant reagents for modulation of autoimmune and infectious diseases.
Aging↗
We felt safe in Iowa ... until the explosion.
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Adaptation, Psychological↗
A 38-year-old female trauma victim of a car bomb.
This case profoundly affected prehospital and hospital care providers alike. Most Midwestern areas have small cities and towns, and most of our trauma results from accidents, not deliberate, senseless human acts. There is a quality of life in our community that does not involve doing things like this to others. If our staff was this affected, it is sobering to think of the profound adjustment required of the victim.
Adult↗
In vitro efficacy of anti-HIV immunotoxins targeted by various antibodies to the envelope protein.
Six different anti-HIV envelope antibodies and one irrelevant control antibody were coupled to ricin A chain and tested for their efficacy in inhibiting HIV tissue culture infections. The anti-HIV antibodies consisted of five monoclonals, three of murine and two of human origin, and one polyclonal preparation prepared by affinity purifying pooled serum antibodies from HIV-infected humans on rgp160. The binding specificity of the antibodies was defined by ELISA by using recombinant envelope proteins and synthetic peptides, and by flow cytometry on HIV-infected cells. The in vitro efficacy of the antibodies was tested by the abilities of the immunotoxins to inhibit protein synthesis in persistently infected cell lines and by their abilities to inhibit HIV production during both acute and persistent infection as measured with an HIV-specific focal immunoassay. The immunotoxins were tested against a panel of distinctly different HIV isolates. The results indicate the following: 1) A mAb to the immunodominant neutralizing loop was highly effective against homologous strains of HIV, but had no activity against heterologous HIV. 2) The efficacy of anti-gp41 mAb varied depending upon the epitope recognized and possibly the affinity of binding to gp41. 3) The polyclonal human anti-gp160 antibodies produced the immunotoxin with the broadest specificity for different HIV strains and the greatest specific activity. This is related to the polyclonal nature of the preparation rather than an increase in relative avidity of the antibody. 4) Activity of an immunotoxin is not a direct function of the binding of the antibody to the surface of infected cells. 5) The ability of an immunotoxin to halt the spread of infection through a tissue culture cell population is dependent upon the ability of the antibody to neutralize the virus as well as the activity of the toxin. Our data suggest that efficacious immunotoxins for the treatment of AIDS may be made with polyclonal anti-envelope antibodies derived from the serum of patients who have been infected with HIV or with appropriately chosen anti-gp41 antibodies.
Acquired Immunodeficiency Syndrome↗