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Biomedical subjects

S Anderson

Publications and source records attributed to S Anderson.

At least 361 records · Page 20Linked to original sources

Dysfunctional grieving.

Dysfunctional grieving represents a failure to follow the predictable course of normal grieving to resolution (Lindemann, 1944). When the process deviates from the norm, the individual becomes overwhelmed and resorts to maladaptive coping. The process implies movement toward assimilation to or accommodation of the loss, resulting in progression toward social, psychological, and medical morbidity. Nurses will better assess the needs of the client with adequate information about the client's recent losses and perception of those losses. Such an assessment, in conjunction with an understanding of the signs, symptoms, and predisposing factors of complicated bereavement, will enable the nurse to develop a plan of effective intervention. Both case examples illustrate unresolved grief. In Case Example 1, the patient denied the importance of the relationship, which became masked with displaced anger and therefore delayed the grieving process. In Case Example 2, the patient's attempts at grieving over the loss of her son were complicated by her long-standing struggle with her husband's infidelity at the time of her pregnancy. The revelation of secondary loss is common in dysfunctional grieving. Resolution of grief encompasses not only accommodation to object loss, but also change in the pathological behaviors incorporated into the patient's self-image as a result of the loss (Lazare, 1979). The maladaptive operations employed by these patients to preserve self-image were discarded as the grief resolved. The focus of therapy included the loss of those behaviors as they were relinquished to prevent the patient from experiencing further anxiety and sense of loss (Zisook, 1987).(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Psychological↗

Relationship of changes in helplessness and depression to disease activity in rheumatoid arthritis.

We investigated the relationship between changes in helplessness and depression to disease activity in rheumatoid arthritis (RA). Sixty-three men with RA were examined at baseline, 3 months, and 6 months. Joint counts, immunophenotypic analyses of peripheral blood lymphocytes, and measures of psychological status were obtained at each examination. Zero-order correlations between psychological change and disease activity change from baseline to 6 months were not significant, but hierarchical multiple regression analyses revealed that changes in affective state were significantly related to joint counts at 6 months. Additionally, changes in absolute numbers of HLA-DR+ (human leukocyte antigen DR type) cells were significantly related to joint counts at 6 months. When absolute numbers of HLA-DR+ cells were entered prior to affective state in a hierarchical multiple regression, affective state was only marginally statistically significant. The study shows that longitudinal relationships between affective changes and disease activity are moderated by intervening variables such as immunologic activation.

Aged↗

Effect of changing the bioequivalence range from (0.80, 1.20) to (0.80, 1.25) on the power and sample size.

International harmonization of guidelines for bioequivalence assessment has led to a wide acceptance of the multiplicative model for the extent and rate characteristics AUC and Cmax and--in consistency with this--of the bioequivalence range (0.80, 1.25). The effect of this change from (0.80, 1.20) on the power of the two one-sided test procedure and the sample sizes based thereon is investigated as a function of the within-subject coefficient of variation (CV) and the ratio mu T/mu R of expected medians for test and reference. The relative reduction in sample size is practically zero for mu T/mu R < or = 0.9 and then gradually increases as mu T/mu R approaches 1.2. At mu T/mu R = 1, the reduction is up to 20%. For a fixed ratio mu T/mu R this reduction increases with the coefficient of variation, reaching a plateau at a CV of about 25%.

Models, Statistical↗

The relationship between neonatal mortality and hospital level.

BACKGROUND: The relative safety of the small obstetrics unit compared with that of the larger or more technologically sophisticated units remains controversial. The purpose of this study was to examine the relationship between neonatal mortality and the level of perinatal services present in the hospital of birth. METHODS: Logistic regression was used to model neonatal mortality as a function of race, weight, and hospital level. Hospitals were classified into five categories using the volume of deliveries and the level of perinatal services available. RESULTS: Both black and white infants born at Level I-A hospitals who weighed less than 2250 (5 lb) fared worse than those born at Level III hospitals. There were no other statistically significant differences between the remaining hospital levels at any weight, although there was a trend toward improved mortality for white babies weighing less than 1500 g (3 lb, 5 oz) born at Level III centers. Level II-B hospitals, which also had neonatal intensive care available, did not demonstrate this trend. RESULTS: The results of this study support the safety of facilities with lower levels of care for delivery of normal birthweight infants and the need for continued centralized delivery of higher levels of care for high-risk patients.

Black or African American↗

Types of bioequivalence and related statistical considerations.

Approval of a generic alternative to an existing formulation carries the implication that the two formulations are "equivalent". However, there are many notions of equivalent. Current practice in bioequivalence studies defines equivalence solely in terms of average (or median) measures of bioavailability. Current methods for this average bioequivalence approach are commonly based on the two one-sided tests principle. Average bioequivalence is the special case of population bioequivalence, where the entire distribution of bioavailabilities is considered. Statistical approaches for population bioequivalence are suggested. Population bioequivalence is an improvement over average bioequivalence, because average bioequivalence does not consider the variabilities of the formulations. However, population bioequivalence is still not sufficient to ensure that an individual will respond similarly to the two formulations; that requires individual bioequivalence. Again, statistical approaches are suggested, one of which, a tolerance interval approach, appears to directly address the clinical question of switchability of formulations. We conclude that population bioequivalence is sufficient for marketing approval, but that individual bioequivalence is necessary for switchability.

Biological Availability↗

The effects of ice massage, ice massage with exercise, and exercise on the prevention and treatment of delayed onset muscle soreness.

We investigated the effects of ice massage, ice massage with exercise, and exercise on the prevention and treatment of delayed onset muscle soreness (DOMS). Twenty-two subjects were randomly assigned to one of four groups. Preexercise measures were recorded for range of motion (ROM), strength, perceived soreness, and serum creatine kinase (CK) levels. Subjects performed up to 300 concentric/eccentric contractions of the elbow flexors with 90% of their 10 repetition maximum to induce muscle soreness. Dependent variables were assessed at 2, 4, 6, 24, 48, 72, 96, and 120 hours postexercise. Significant differences occurred in all variables with respect to time (ANOVA(p<.05)). However, no significant mode of treatment, or mode of treatment/assessment time interaction was present. Decreases in range of motion and flexion strength correspond with increases in perceived soreness. The nonsignificant mode of treatment/assessment time interaction suggests that the use of ice massage, ice massage with exercise, or exercise alone is not effective in significantly reducing the symptoms of delayed onset muscle soreness. In fact, though not statistically significant, the pattern of the data suggested the use of ice in the treatment of DOMS may be contraindicated. Further investigation is recommended.

Journal Article↗

Mechanism of target cell recognition by natural killer cells: characterization of a novel triggering molecule restricted to CD3- large granular lymphocytes.

In an attempt to identify a molecule in target recognition by CD3- large granular lymphocytes (LGL), we have generated a rabbit antiidiotypic (anti-ID) serum against a monoclonal antibody (mAb 36) that reacted with the cell membrane of K562. Flow cytometry analysis demonstrated that the anti-ID serum bound selectively to CD3- LGL and that F(ab')2 fragments of the anti-ID serum blocked both target cell binding and lysis by NK cells. Stimulation of CD3- LGL with F(ab')2 fragments resulted in the release of serine esterases and the secretion of interferon gamma. Furthermore, anti-ID F(ab')2 antibodies crosslinked to anti-DNP F(ab')2 mediated directed cytotoxicity of a non-natural killer (NK)-susceptible mouse target (YAC-1) via this surface ligand. These functional reactivities were only removed by adsorption with the specific idiotype. Protein analysis showed that the anti-ID serum immunoprecipitated 80-, 110-, and 150-kD proteins. Using this anti-ID, a partial cDNA was cloned and an antipeptide antiserum was made against the portion of the predicted amino acid sequence that corresponded to a portion of the ID binding region. This antipeptide serum exhibited similar functional and biochemical reactivities to those observed with the anti-ID serum. These data suggest that the cell surface moiety recognized by the anti-ID and anti-p104 is novel and is selectively involved in both recognition and triggering of NK-mediated lytic function.

Amino Acid Sequence↗

Significance of ipsilateral breast tumour recurrence after lumpectomy.

Breast cancer treatment trials from the US National Surgical Adjuvant Breast and Bowel Project have established breast-conserving operations as a replacement for radical mastectomy (NSABP B-04), and have shown that in terms of survival free from distant disease there was no significant difference between lumpectomy, lumpectomy plus breast irradiation, and total mastectomy (NSABP B-06). 9-year follow-up data from B-06 are used here to address the issue of ipsilateral breast tumour recurrence (IBTR) and the development of distant disease, a question with important clinical and biological implications. A Cox regression model on fixed co-variates (ie, features such as tumour type or size present at surgery and not subsequently alterable) and on IBTR, which is time dependent and not fixed, revealed that the risk of distant disease was 3.41 times greater after adjustment for co-variates in patients in whom an IBTR developed. IBTR proved to be a powerful independent predictor of distant disease. However, it is a marker of risk for, not a cause of, distant metastasis. While mastectomy or breast irradiation following lumpectomy prevent expression of the marker they do not lower the risk of distant disease. These findings further justify the use of lumpectomy.

Breast Neoplasms↗

Induction of antibodies to the envelope protein of the human immunodeficiency virus by immunization with monoclonal anti-idiotypes.

Anti-idiotypes that possess the internal image of antigen can induce protective humoral immunity toward microbes. Herein we demonstrate antigen mimicry by monoclonal anti-idiotypes of a distinct epitope of the human immunodeficiency virus (HIV) envelope protein that is defined by a synthetic peptide. This peptide, corresponding to amino acid residues 503-535 (peptide 503-535) of HIV-1 IIIB gp160, induced antibodies in three mammalian species that interacted with HIV-1 gp120 and inhibited in vitro syncytium formation caused by HIV-1, IIIB and MN isolates. Three monoclonal anti-idiotypes were generated against rabbit anti-gp120 antibodies specific for peptide 503-535. These anti-idiotypes recognize an interspecies cross-reactive idiotype expressed on mouse, chimpanzee, baboon, rabbit, and human anti-gp120 antibodies specific for peptide 503-535. The interaction with the cross-reactive idiotype is inhibited by synthetic peptide and HIV-1 gp160. Furthermore, rabbits immunized with the monoclonal anti-idiotypes produced antibodies that also bind HIV-1 gp120 and gp160 and recognized the epitope defined by peptide 503-535.

Amino Acid Sequence↗

Self-assembled B19 parvovirus capsids, produced in a baculovirus system, are antigenically and immunogenically similar to native virions.

B19 parvovirus is pathogenic in humans, causing fifth disease, transient aplastic crisis, some cases of hydrops fetalis, and acquired pure red cell aplasia. Efforts to develop serologic assays and vaccine development have been hampered by the virus's extreme tropism for human bone marrow and the absence of a convenient culture system. We constructed recombinants containing either the major (VP2) or minor (VP1) structural proteins of B19 in a baculovirus-based plasmid, from which the polyhedrin gene had been deleted; these recombinant plasmids were used to generate recombinant infectious baculovirus. Subsequent infection of insect cells in vitro resulted in high-level expression of either B19VP1 or VP2. Parvovirus capsids were obtained by self-assembly in cell cultures coinfected with either VP1- and VP2-containing baculoviruses or, surprisingly, VP2-containing baculoviruses alone. Empty B19 capsids composed of VP1 and VP2 could replace serum virus as a source of antigen in a conventional immunoassay for detection of either IgG or IgM antiparvovirus antibodies in human serum. Immunization of rabbits with capsids composed of VP1 and VP2 resulted in production of antisera that recognized serum parvovirus on immunoblot and neutralized parvovirus infectivity for human erythroid progenitor cells. Baculovirus-derived parvovirus antigen can substitute for scarce viral antigen in immunoassays and should be suitable as a human vaccine.

Amino Acid Sequence↗

Secretion incompetence of bovine pancreatic trypsin inhibitor expressed in Escherichia coli.

There is increasing evidence that protein folding and protein export are competing processes in prokaryotic cells. Virtually all secretion studies reported to date, however, have employed proteins that are relatively uncharacterized in terms of their folding behavior and three-dimensional structure. In contrast, the structural and biochemical parameters governing the folding of bovine pancreatic trypsin inhibitor (BPTI) and several of its mutants have been studied intensively. We therefore undertook a study of the secretion behavior in Escherichia coli of recombinant BPTI and its mutants. Wild-type BPTI and two well-characterized folding mutants (C14A, C38A)BPTI and (C30A, C51A)BPTI (missing the 14-38 and 30-51 disulfide bonds, respectively), were investigated by analyzing their expression fused to an E. coli signal sequence or to two synthetic IgG-binding domains of staphylococcal protein A. Both disulfide mutants are destabilized relative to wild-type BPTI and exhibit markedly altered folding kinetics: one (C14A, C38A) folds more slowly than wild-type BPTI and the other (C30A, C51A) unfolds more rapidly. Both mutants were observed to be exported 3-10 times more efficiently than the wild-type molecule. Moreover, the levels of unprocessed preprotein in the cytoplasm were severalfold higher for the wild-type fusion than for the fusion to the two folding mutants. Intracellular degradation of the BPTI moiety was also observed. These results are consistent with traffic of intracellular BPTI preproteins on at least three routes along the secretory pathway: (a) facile secretion of unfolded material, (b) intracellular folding leading to secretion blockage, and (c) degradation followed by export of truncated molecules. A novel feature of these findings is the implication that disulfide bonds can form in the bacterial cytoplasm and lead to secretion incompetence.

Amino Acid Sequence↗

Conservative management of intraductal carcinoma (DCIS) of the breast. Collaborating NSABP investigators.

Seventy-six patients with intraductal carcinoma (DCIS) of the breast have been observed for 83 months (range 50-141) following treatment by lumpectomy (L) only (21), L and breast irradiation (XRT) (27), or mastectomy (28). All represented examples of DCIS retrieved after pathologic examination of a much larger cohort of patients with stage I and II invasive breast cancer enrolled in NSABP protocol 6. Local breast recurrences were similar for women with DCIS and those from this cohort at a similar period of follow-up with invasive cancer treated by L only (43% vs. 39%) and L + XRT (7% vs. 10%). The presence of moderate/marked comedonecrosis was suggestively related to local breast recurrence (P = .07). This latter was significantly reduced for patients receiving post L XRT (P = .01). All local breast recurrences in this study and 29 of 31 recorded by others occurred at or close to the site of extirpation of the index cancer minimizing multicentricity as a contraindication for the conservative surgical treatment of DCIS. Survival rates which were similar for patients with DCIS regardless of form of local treatment were better than that observed for negative node patients with invasive cancer enrolled in protocol 6. Thus, DCIS is a less, not more, ominous disease than invasive cancer. This and other features of its natural history indicate that it would be a contradiction to treat invasive cancer but not DCIS conservatively.

Adult↗

Individual bioequivalence: what matters to the patient.

Current procedures for assessing the bioequivalence of two formulations are based on the concept of average bioequivalence. That is, they assess whether the average responses between individuals on the two formulations are similar. We show first that average bioequivalence is not sufficient to assure that an individual patient could be expected to respond similarly to the two formulations. To have such reasonable assurance requires a different notion of bioequivalence; individual (or within-subject) bioequivalence. Second, we propose a simple statistical procedure for assessing individual bioequivalence. This decision rule, TIER (test of individual equivalence ratios) requires the specification of the minimum proportion of subjects in the applicable population for which the two formulations being tested must be bioequivalent (a regulatory decision). The TIER rule is summarized in terms of the minimum number of subjects with bioavailability ratios falling within the specified equivalence interval necessary to be able to claim bioequivalence for given sample size and type I error. We recommend that the corresponding lower bounds (one-sided confidence intervals) for the proportion of bioequivalent subjects be calculated.

Chemistry, Pharmaceutical↗

Cytomegalovirus infection in AIDS. Patterns of disease, response to therapy and trends in survival.

Among 347 AIDS patients seen at St Mary's Hospital, London between 1983 and 1989, cytomegalovirus (CMV) disease was observed in 75 (22%). Of these, 58 (77%) had CMV retinitis, 26 (35%) CMV colitis, and 12 (16%) had CMV infection diagnosed at other sites. Relapse occurred in 71%. A favourable response to the use of ganciclovir as induction therapy for CMV retinitis was observed in 92%. Relapse of CMV retinitis occurred in 54% at a median time of 97 days. Neutropenia was the most frequent and serious side-effect of ganciclovir, 76% patients having neutrophil counts less than 1.0 x 10(9)/l and 48% less than 0.5 x 10(9)/l at some stage of therapy. Thrombocytopenia was also common, and platelet counts of less than 50 x 10(9)/l occurred in 43% patients on ganciclovir. The concurrent use of zidovudine made the development of severe neutropenia and thrombocytopenia more likely. Median survival following the diagnosis of CMV disease increased from 5-8 months between 1984 and 1987, to over 12 months in 1988. Patients with CMV colitis had a worse prognosis than patients with CMV retinitis, with median survival of 4.5 and 7 months respectively. In conclusion, CMV is an important opportunist infection in AIDS and both the disease and its treatment cause considerable morbidity. Hence, it is important to develop more effective and less toxic forms of therapy for CMV infection.

Acquired Immunodeficiency Syndrome↗

A consequence of omitted covariates when estimating odds ratios.

In the epidemiologic literature, one finds three criteria for confounding, which we will call the classical (marginal), operational (change-in-estimate) and conditional criteria. We define mavericks to be covariates that satisfy the operational criterion, but not the classical criterion. We present what is known about the problems of mavericks for estimating odds ratios and clarify the interpretation of odds ratios. Key results are: (1) omitting mavericks biases odds ratios towards 1; (2) omitting mavericks cannot artificially introduce an effect in contrast to omitting classical confounders; (3) the operational criterion for confounding corresponds to the conditional criterion when estimating odds ratios, but for relative risks, there are no mavericks (i.e. the classical and operational criterion correspond); and (4) the interpretation of odds ratios obtained from standard methods is that of comparing proportions, not of individual risk.

Confounding Factors, Epidemiologic↗

Confirmation of the predicted source of a slow folding reaction: proline 8 of bovine pancreatic trypsin inhibitor.

A major question in protein structural analysis concerns the applicability of results from model systems to other proteins. Theoretical approaches seem the best manner of transferring information from one system to another, but their accuracy in the model systems must first be tested with results from experiment. Since bovine pancreatic trypsin inhibitor (BPTI) is a model system for the evaluation of energy minimization and molecular dynamics routines, we can use folding and stability measurements to examine the reliability of these methods. All two-disulfide mutants of BPTI investigated thus far have two very slow folding reactions which have characteristics of proline isomerization. These reactions may occur because the non-native cis form of two of the four prolines in BPTI significantly destabilizes the folded state of the protein. Previous energy minimization studies of wild-type BPTI suggested that the cis form of Pro8 was the most destabilizing of the four prolines [Levitt,M. (1981) J. Mol. Biol., 145, 251-263]. In this paper, we show that mutation of Pro8----Gln in the two-disulfide bond mutant Val30/Ala51 results in a loss of the slowest folding reaction, consistent with Levitt's prediction.

Animals↗

Intracellular expression of BPTI fusion proteins and single column cleavage/affinity purification by chymotrypsin.

The novel and efficient expression system described here produces formerly poorly expressed, proteolytically unstable mutants of bovine pancreatic trypsin inhibitor (BPTI). A new, single column method for the cleavage of a recombinant fusion to BPTI and affinity purification of the BPTI moiety by immobilized chymotrypsin is an integral part of the system. Wild-type and mutant BPTI molecules are expressed in Escherichia coli as fusion proteins forming intracellular inclusion bodies. Transcription initiation is under the control of the E. coli trp promoter. The expressed protein is tripartite fusion comprising (i) a portion of the TrpLE leader peptide, (ii) a synthetic IgG binding domain derived from protein A and (iii) the BPTI variant. Solubilization of the inclusion bodies and refolding of the fusion proteins in a thiol-disulfide shuffling system yields correctly folded inhibitor molecules. In the single column purification and cleavage procedure, immobilized chymotrypsin cleaves the refolded fusion protein and releases affinity purified active BPTI mutants with correct N-termini. Mutant BPTI molecules which do not fold into active inhibitors are also stably expressed in inclusion bodies but cannot be purified by this method. Unlike previously described secretion systems for the production of BPTI, expression levels in this system appear to be independent of both the mutation in the BPTI gene and the activity of the expressed protein. Mutants poorly expressed in secretion systems can now be produced in sufficient quantities for protein folding studies and structural analysis using X-ray crystallography and NMR spectroscopy.

Amino Acid Sequence↗