Novartis reclaims tk technology.
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Brain Neoplasms↗
Biomedical subjects
E Johnson
Publications and source records attributed to E Johnson.
The treatment of relapsed or refractory intermediate grade non-Hodgkin's lymphoma with autologous bone marrow transplantation followed by cyclosporine and interferon.
In an effort to decrease the relapse rate following autologous bone marrow transplantation for non-Hodgkin's lymphoma, patients were given cyclosporine and interferon following autologous marrow transplantation. Forty patients with intermediate grade non-Hodgkin's lymphoma that was relapsed or refractory to standard chemotherapy underwent autologous marrow transplantation. The preparative regimen consisted of cyclophosphamide 6.8 g/m2, etoposide 1600 mg/m2, and carmustine 400 mg/m2 over 4 days followed by reinfusion of bone marrow. Intravenous cyclosporine was started on day -1 as a 16 mg/kg loading dose followed by 3.6 mg/kg/day for 28 days after transplant. Patients were begun on alpha-interferon (starting dose, 0.5 million units s.c. every other day) following platelet engraftment (median day 24 post-transplant) and continued on 1.5 million units s.c. daily for 2 years. Regimen-related toxicities resulted in four (10%) deaths. Twenty-one (53%) patients developed marked erythema of the palms, soles, and arms. Biopsies of the erythema were consistent with grade I GVHD. Patients who did not develop rashes were not biopsied. The erythema persisted for a median of 10 days and resolved in all cases without treatment. Visceral GVHD was not apparent. All patients have been followed for a median of 24 months (range 12-54 months). To date, only five patients (13%) have relapsed after bone marrow transplant. Multivariant analysis could not identify risk factors for relapse post-transplant. Disease-free survival of all patients is 77% (95% confidence interval, 67-93%). The results of this pilot study suggest that the administration of cyclosporine and interferon may decrease the relapse rate of relapsed/refractory non-Hodgkin's lymphoma following autologous bone marrow transplantation.
Adolescent↗
Discrete expression and distribution pattern of TIMP-3 in the human retina and choroid.
PURPOSE: Extracellular matrix homeostasis is dependent in part upon a family of matrix metalloproteinases and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recently, gene defects in TIMP-3 have been identified in the affected individuals of several families with Sorsby's fundus dystrophy (SFD). Very little information is available regarding TIMP-3 function or even its existence in the retina or choroid. METHODS: We used reverse transcription-polymerase chain reaction and Northern analysis to evaluate the expression of TIMP mRNA and Western immunoblots to evaluate TIMP protein produced by select cells of the human retina and choroid. We also used these methods and immunohistochemistry to localize the TIMPs in the retina and choroid. RESULTS: TIMP-3 transcripts are found in cultured human retinal pigment epithelium (RPE), choroidal microcapillary endothelium and pericytes. RPE cells also express and secrete TIMP-3 protein, which is localized to the extracellular matrix and is not found in culture medium; TIMP-1 and -2 are found almost exclusively in the medium. Immunohistochemistry of human retina/choroid sections shows pronounced TIMP-3 immunostaining in Bruch's membrane, particularly near the surface of the RPE and endothelial cells, presumably in their basement membranes, with minimal staining in other portions of the retina. Immunostaining for TIMP-1 is absent and for TIMP-2 is much less prevalent, but detectable in Bruch's membrane. CONCLUSIONS: TIMP-1, -2 and -3 exhibit distinctive expression patterns in the retina and choroid. This distribution and expression pattern partially explains why TIMP-3 mutations result in SFD, rather than other retinal pathologies, such as those associated with proliferative diabetic retinopathy.
Cells, Cultured↗
A university-affiliated community hospital inpatient geriatrics program functioning in an administrative and educational capacity.
OBJECTIVE: To demonstrate an unusual form of inpatient geriatric assessment with unique outcomes. DESIGN: A prospective evaluation of patients admitted to a community hospital-based inpatient geriatrics unit utilizing traditional members of the assessment team along with educational assessment of nurses and satisfaction profiles of patients and/or families. SETTING: A non-profit community hospital in Northeast Washington, DC. PARTICIPANTS: All patients older than age 62 admitted to the 42-bed Geriatric Unit during a 4 1/2 year time period. MEASUREMENTS: Number of total and category recommendations taken by attending physicians from the Inpatient Geriatric Assessment Team, periodic evaluation of unit nurses' geriatric knowledge base and certification, and patient satisfaction through periodic surveys. RESULTS: More than 4500 patients have been evaluated during the past 4 1/2 years. The number of recommendations taken by attending physicians has averaged 31.3 to 50.7% during four consecutive chart reviews involving the first 25 consecutive patients for the month each performed every six months (n = 100). The average age of patients evaluated was 77.2 (minimum of 62 and maximum of 97); 67% were females and 33% males. The average number of recommendations communicated per patient was 4.1, and the average number adhered to 1.6/patient. The overall knowledge base and certification in geriatric nursing has increased significantly over a 2.5-year period. Composite monthly unit patient satisfaction survey scores increased as well. CONCLUSIONS: The program is unique in its development, limitations, and outcomes. Other than the cost of limited geriatric nurse practitioner and faculty salary support, the program has been implemented using only current hospital department personnel. The role of the assessment team is to educate attending nurses and staff physicians. It has not yet been possible to measure objective outcomes. However, the current program also serves the purpose of introducing a new medical program to a community hospital in a nonthreatening way and offers opportunities for research. In addition, the program offers further opportunity for expansion and change.
Aged↗
Termination of nontraumatic cardiac arrest resuscitative efforts in the field: a national survey.
OBJECTIVES: 1) To describe elements of adult nontraumatic cardiac arrest protocols in those U.S. cities in which resuscitative efforts are being terminated in the out-of-hospital setting. 2) To determine the prevalence and methods of on-scene family grief counseling delivered in this setting. METHODS: Emergency medical services (EMS) systems in each of the 200 largest cities in the United States were surveyed by telephone regarding the content of their adult cardiac arrest protocols. Type of arrest (medical vs trauma), final dysrhythmia, termination policies, and presence or absence of a grief counseling protocol were recorded. RESULTS: All of the target population responded to the telephone survey. Most (135; 68%) EMS systems currently have written protocols that allow in-field termination of resuscitative efforts for adult nontraumatic cardiac arrest patients who remain asystolic. Only 47 (24%) EMS systems allow cessation of efforts for patients without return of spontaneous circulation regardless of the dysrhythmia. Base station contact is required for authorization to end resuscitative efforts in 120/135 (89%) EMS systems. Only 26/135 (19%) EMS systems that cease efforts in the field have written policies concerning on-scene family grief counseling. This counseling is most likely to be conducted by the out-of-hospital providers themselves. CONCLUSION: Many U.S. urban EMS systems are terminating efforts for selected adult nontraumatic cardiac arrest patients, although few have written policies to address grief intervention for family members at the scene.
Adult↗
Clusterin and the terminal complement pathway synthesized by human umbilical vein endothelial cells are closely linked when detected on co-cultured agarose beads.
Clusterin and the terminal complement pathway synthesized by human umbilical vein endothelial cells are closely linked when detected on co-cultured agarose beads. Clusterin is a multifunctional regulatory protein rendering the terminal complement complex (TCC) soluble and unable to insert into cell membranes. The aim of the present study was to examine whether clusterin was an integral part of serum-derived TCC bound to agarose beads which activate the alternative pathway of complement. Further, we searched for evidence of clusterin synthesis in human umbilical vein endothelial cells (EC) and whether this synthesis was regulated by various proinflammatory cytokines (IL-1, IL-6, and TNF) and IFN-gamma. The clusterin and TCC on co-incubated beads were measured by radioimmunoassay based on primary anti-complement antibodies (anti-C3c, anti-TCC, anti-clusterin). We found that clusterin in serum experiments is bound to C9 in agarose bound TCC and not directly to the agarose. Addition of the protein synthesis inhibitor cycloheximide to cultured human umbilical vein cells resulted in a strong reduction (about 70%) of anti-clusterin binding to co-cultured beads, which strongly supports de novo synthesis of clusterin in EC. The results indicate that clusterin derived from the EC is linked with the TCC on the co-incubated beads for the following reasons: First, in serum experiments clusterin like vitronectin, was co-deposited with C9 in agarose-bound TCC. Second, cytokine stimulation of the EC with proinflammatory cytokines such as IL-1, IL-6 and TNF, known to increase the detection of bound TCC, also increased the amount of clusterin detected on the beads. Third, IFN-gamma, which reduces the concentration of bound TCC, exhibited the same effect on the amount of clusterin detected on such beads. There was a strong and dose-dependent reduction of anti-TCC binding from about 45% to about 95% when clusterin (5-40 micrograms/ml) was added to EC cultures. This effect was also evident (about 40-50% inhibition of bound TCC) using human serum as complement source. These results are probably mainly caused by clusterin binding to C5b-7, making this complex soluble without the capacity to bind to the agarose surface. This study supports the view that clusterin is a potent regulator of TCC at the levels of C5b-7 and C9.
Cells, Cultured↗
Single case evaluation of the effects of aromatherapy and massage on disturbed behaviour in severe dementia.
Aromatherapy and massage could provide a useful addition to psychological therapeutic interventions with clients suffering from dementia. The effects of aromatherapy and massage on disturbed behaviour in four individuals with severe dementia were evaluated using a single-case research design. Each participant received 10 treatment sessions of aromatherapy, aromatherapy and massage combined, and massage alone. The effects on each individual's behaviour in the hour following treatment were assessed against 10 'no treatment' control sessions. Reliable individualized disturbed behaviour scales were designed. The effects of the treatments were mixed. The opinion of the staff providing treatment was that all participants benefited. On close scrutiny, only one of the participants benefited from the aromatherapy and massage to a degree that reached statistical significance. In two of the cases aromatherapy and massage led to an increase in agitated behaviour. The importance of the single case study approach with this client group is discussed.
Aged↗
The prevalence of shedding of Cryptosporidium and Giardia spp. based on a single fecal sample collection from each of 91 horses used for backcountry recreation.
Cryptosporidium parvum and Giardia duodenalis are now recognized as primary enteric pathogens in animals and humans. Regulatory agencies, such as the Environmental Protection Agency are under increasing pressure to reduce the concentration of these protozoa in surface waters. Given the popularity of recreational riding of horses on public land in California backcountry, concerns have been raised by various regulatory agencies as to whether horses used for backcountry recreation are a significant source of C. parvum and G. duodenalis for the environment. The prevalence of fecal shedding of Cryptosporidium and Giardia in horses with a history of being ridden in California backcountry during 1993 and 1994 was estimated. Using both direct fluorescent antibody and levitation centrifugation tests, none of 91 single-collection fecal samples from throughout California had Cryptosporidium oocysts or Giardia cysts. Horses ranged from 4 to 24 years of age. Because none of the 91 samples, collected 1 time from each horse, were positive and assuming that the sensitivity and specificity of the test methods employed were 100%, the highest probable prevalence of shedding for either protozoal pathogen was < 3.2% for the cohort of horses studied.
Age Factors↗
Icebox, a recessive X-linked mutation in Drosophila causing low sexual receptivity.
The X-linked recessive mutation icebox (ibx; 1-23, 7F1) of Drosophila melanogaster lowers the sexual receptivity of females. The probability of mating with mature wild-type males is reduced in ibx homozygotes, and the frequency of rejection behavior (rate per minute) towards courting males is increased. ibx fails to complement In(1)RA35, which is a lethal allele of Neuroglian (Nrg, which encodes a transmembrane protein found in embryonic tissues including the nervous system) due to a breakpoint in that gene; however, both l(1)B4 and l(1)VA142, other lethal mutations of Nrg, do complement ibx. 12-h ibx embryos exhibit a normal pattern of staining for the Neuroglian-specific antibody, Mab BP104. Males and females mutant for ibx have normal egg-to-adult survival and appear normal in several "general" behavioral traits including olfaction, phototaxis, locomotor activity, and heartbeat. ibx males court normally, and are successful in mating. These characteristics suggest that ibx does not cause sensory or motor defects. Ovarian growth and sperm storage are wild-type in ibx/ibx females. Treatment with the JH analog methoprene increases the receptivity of ibx/ibx females.
Animals↗
Feet are for life. An interdisciplinary approach to foot and leg ulcer management.
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Community Health Nursing↗
Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer: a phase I study.
PURPOSE: Selective high-dose radiation of solid tumors has been a goal of radiation oncology. The physiological barriers of solid tumors (high interstitial tumor pressure, reduced tumor vascularity, and poor perfusion) have been major barriers in achieving significant tumor dose of systemically infused radioconjugates. Direct tumor infusional brachytherapy overcomes these barriers and leads to selective high tumor doses. METHODS AND MATERIALS: The development of interstitial tumor infusion of macroaggregated albumin (MAA) followed by colloidal chromic phosphate 32P has overcome solid tumor obstacles in 47 patients with nonresectable pancreatic cancer in a Phase I dose escalation study. The colloidal 32P infusion was followed by external radiation and five fluorouracil. RESULTS: Of the 28 patients with cancer limited to the pancreas, 15 of 16 patients retained 86-100% (mean 96%) of the infused colloidal 32P isotope. While the other 12 patients had partial shunting to the liver, shunting to the liver was due to high interstitial resistance with tumor dose deposition of 17-88% (mean 52 %). Of the 19 patients with metastatic pancreas cancer, colloidal 32P tumor deposition ranged from 22 to 100% of the infused dose (mean 79%). The less than optimal tumor deposition led to our increasing the MAA from 600,000 to 1.5-2.5 million particles. Interstitial dexamethasone 2 mg and later 4 mg was infused first and prevented liver shunting by somehow reducing tumor resistance. The median survival in 28 Phase I patients with nonresectable pancreas cancer without metastasis, was 12 months. No significant toxicity occurred when treatment was limited to two infusions with as much as 30 mCi each. The maximum tumor dose was 17,000 Gy (1.700,000 cGy). In 19 nonresectable pancreatic cancer patients with metastasis, a 6.9 months median survival was observed. CONCLUSIONS: Infusional brachytherapy is an outpatient procedure that delivers high-dose radiation selectively to pancreatic cancer. Results of the Phase I study in nonresectable pancreas cancer has led to a national multiinstitutional Phase II trial.
Adult↗
Search for Nonresonant B+-->h+h-h+ Decays.
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Journal Article↗
Toward quality assurance for metaphase FISH: a multicenter experience.
Although fluorescent in situ hybridization (FISH) is rapidly becoming a part of clinical cytogenetics, no organization sponsors multicenter determinations of the efficacy of probes. We report on 23 laboratories that volunteered to provide slides and to use a probe for small nuclear ribonucleoprotein polypeptide N (SNRPN) and a control locus. Experiences with FISH for these laboratories during 1994 ranged from 0 to 645 utilizations (median = 84) involving blood, amniotic fluid, and bone marrow. In an initial study of hybridization efficiency, the median percentage of metaphases from normal individuals showing two SNRPN and two control signals for slides prepared at each site was 97.0 (range = 74-100); for slides prepared by a central laboratory, it was 97.8 (range = 81.6-100). In a subsequent blind study, each laboratory attempted to score 5 metaphases from each of 23 specimens [8 with del(15)(q11.2-->q12) and 15 with normal #15 chromosomes]. Of 529 challenges, the correct SNRPN pattern was found in 5 of 5 metaphases in 457 (86%) and in 4 of 5 in 33 (6%). Ambiguous, incomplete, or no results were reported for 32 (6%) challenges. Seven (1%) diagnostic errors were made, including 6 false positives and 1 false negative: 1 laboratory made 3 errors, 1 made 2, and 2 made 1 each. Most errors and inconsistencies seemed due to inexperience with FISH. The working time to process and analyze slides singly averaged 49.5 min; slides processed in batches of 4 and analyzed singly required 36.9 min. We conclude that proficiency testing for FISH by using an extensive array of challenges is possible and that multiple centers can collaborate to test probes and to evaluate costs.
Autoantigens↗
Foreign glycoproteins expressed from recombinant vesicular stomatitis viruses are incorporated efficiently into virus particles.
In a previous study we demonstrated that vesicular stomatitis virus (VSV) can be used as a vector to express a soluble protein in mammalian cells. Here we have generated VSV recombinants that express four different membrane proteins: the cellular CD4 protein, a CD4-G hybrid protein containing the ectodomain of CD4 and the transmembrane and cytoplasmic tail of the VSV glycoprotein (G), the measles virus hemagglutinin, or the measles virus fusion protein. The proteins were expressed at levels ranging from 23-62% that of VSV G protein and all were transported to the cell surface. In addition we found that all four proteins were incorporated into the membrane envelope of VSV along with the VSV G protein. The levels of incorporation of these proteins varied from 6-31% of that observed for VSV G. These results suggest that many different membrane proteins may be co-incorporated quite efficiently with VSV G protein into budding VSV virus particles and that specific signals are not required for this co-incorporation process. In fact, the CD4-G protein was incorporated with the same efficiency as wild type CD4. Electron microscopy of virions containing CD4 revealed that the CD4 molecules were dispersed throughout the virion envelope among the trimeric viral spike glycoproteins. The recombinant VSV-CD4 virus particles were about 18% longer than wild type virions, reflecting the additional length of the helical nucleocapsid containing the extra gene. Recombinant VSVs carrying foreign antigens on the surface of the virus particle may be useful for viral targeting, membrane protein purification, and for generation of immune responses.
Animals↗
Toward quality assurance for metaphase FISH: a multi-center experience.
Although fluorescent in situ hybridization (FISH) is rapidly becoming a part of clinical cytogenetics, no organization sponsors multi-center determinations of the efficacy of probes. We report on 23 laboratories that volunteered to provide slides and to use a probe for SNRPN and a control locus. Experiences with FISH for these laboratories during 1994 ranged from 0 to 645 utilizations (median = 84) involving blood, amniotic fluid and bone marrow. In an initial study of hybridization efficiency, the median percentage of metaphases from normal individuals showing two SNRPN and 2 control signals for slides prepared at each site was 97.0 (range = 74-100); for slides prepared by a central laboratory, it was 97.8 (range = 81.6-100). In a subsequent blind study, each laboratory attempted to score 5 metaphases from each of 23 specimens [8 with del(15) (q11.2-->q12) and 15 with normal 15 chromosomes]. Of 529 challenges, the correct SNRPN pattern was found in 5 of 5 metaphases in 457 (86%) and in 4 of 5 in 33 (6%). Ambiguous, incomplete or no results were reported for 32 (6%) challenges. Seven (1%) diagnostic errors were made including 6 false positives and 1 false negative: 1 laboratory made 3 errors, 1 made 2, and 2 made 1 each. Most errors and inconsistencies seemed due to inexperience with FISH. The working time to process and analyze slides singly averaged 49.5 minutes; slides processed in batches of 4 and analyzed singly required 36.9 minutes. We conclude that proficiency testing for FISH using an extensive array of challenges is possible and that multiple centers can collaborate to test probes and to evaluate costs.
Humans↗
Structural determinants of the specificity for synaptic vesicle-associated membrane protein/synaptobrevin of tetanus and botulinum type B and G neurotoxins.
Tetanus and botulinum neurotoxins type B and G are zinc-endopeptidases of remarkable specificity. They recognize and cleave a synaptic vesicle-associated membrane protein (VAMP)/synaptobrevin, an essential protein component of the vesicle docking and fusion apparatus. VAMP contains two copies of a nine-residue motif, also present in SNAP-25 (synaptosomal-associated protein of 25 kDa) and syntaxin, the two other substrates of clostridial neurotoxins. This motif was suggested to be a determinant of the target specificity of neurotoxins. Antibodies raised against this motif cross-react among VAMP, SNAP-25, and syntaxin and inhibit the proteolytic activity of the neurotoxins. Moreover, the various neurotoxins cross-inhibit each other's proteolytic action. The role of the three negatively charged residues of the motif in neurotoxin recognition was probed by site-directed mutagenesis. Substitution of acidic residues in both copies of the VAMP motif indicate that the first one is involved in tetanus neurotoxin recognition, whereas the second one is implicated in binding botulinum B and G neurotoxins. These results suggest that the two copies of the motif have a tandem association in the VAMP molecule.
Amino Acid Sequence↗
A nurse practitioner's experience in bush Alaska.
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Alaska↗
Lack of independent relationships between left ventricular mass and cardiovascular reactivity to physical and psychological stress in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
The objective of this study was to determine whether exaggerated blood pressure (BP) reactivity to stress and psychosocial characteristics are related to left ventricular mass (LVM) in a large cohort of young adults. Analyses were conducted with 3,742 participants of the CARDIA study (945 white men, 1,024 white women, 781 black men, and 992 black women), evaluated in 1990 to 1091 with echocardiographic measurement of LVM. Analyses were stratified by gender and race. The relationships of LVM/height2.7 and cardiovascular reactivity to physical and psychological stressors (treadmill exercise, cold pressor, video game, and star-tracing tasks), were examined in both univariate and multivariate analyses adjusting for baseline BP, weight, and other relevant biobehavioral variables. The relationships between LVM and several psychosocial characteristics (hostility, anger suppression, anxiety, depressive symptoms, and education) were also assessed. Systolic blood pressure (SBP) reactivity to exercise was significantly related to LVM in black and white men; LVM was 10% greater among white men with exaggerated (upper quintile) peak exercise SBP than among other white men. SBP reactivity to the cold pressor test was related to LVM in all race/gender groups, although the relationship remained significant only among white men and women in the multivariate analysis. Diastolic blood pressure (DBP) reactivity to the video game was related to LVM only among black men in adjusted analyses. After adjusting for resting BP, weight, and other covariates in linear multiple regression models, SBP reactivity to exercise explained only 3% of the variance in LVM among white men. Otherwise, reactivity to other stressors or psychosocial variables accounted for no more than 1% of the variance in LVM. It was concluded that among a cohort of young adults, blood pressure reactivity to physical and mental stressors did not add substantially to the prediction of LVM when resting BP, weight, and other covariates were taken into account.
Adolescent↗