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Biomedical subjects

S Jacobs

Publications and source records attributed to S Jacobs.

At least 73 records · Page 4Linked to original sources
PubMed1997

Validation parameters for a novel biosensor assay which simultaneously measures serum concentrations of a humanized monoclonal antibody and detects induced antibodies.

This report documents the validation of an assay using BIAcore 2000 that, with a single injection of mouse serum, allows the quantitation of a humanized monoclonal antibody and can also detect the presence of antibodies directed against this humanized antibody. The important components required for the validation of biosensor assays including precision, accuracy, linearity, stability of the immobilized ligand, specificity and sensitivity are addressed. The tandem assay that is used as a model for biosensor validations is accomplished by flowing each sample across the surface of two flowcells in sequence. The first flowcell has the antigen that the humanized mAb was generated against immobilized while the humanized mAb itself is immobilized on the second flowcell. The quantitation component of this assay is precise and accurate with a limit of quantitation of 1 microg/ml in mouse serum samples. Any antibodies directed against the humanized mAb can be detected and also characterized as to isotype. This unique assay can be performed with as little as 10 microl of serum which is then diluted ten-fold prior to analysis. The small sample requirement allows analysis of individual mouse serum samples rather than requiring the use of pooled samples from multiple mice. A further advantage of this assay is the automation capability which allows unattended operation.

Animals↗
PubMed1997

Assessment of the agreement between cardiac output measured by bolus thermodilution and continuous methods, with particular reference to the effect of heart rhythm.

Cardiac output (CO) is a fundamentally important haemodynamic parameter and its continuous measurement has the potential to enable early recognition of haemodynamic trends and earlier therapeutic response. A method of continuous cardiac output (CCO) monitoring is now available for clinical use. The accuracy and reliability of this method has been confirmed in clinical trials but not, to our knowledge, in the presence of abnormal heart rhythms. A comparison was made between CCO and bolus thermodilution methods, to determine if there is a greater difference between their respective determinations of CO when heart rhythm is abnormal. A convenience sample of 38 intensive care patients was used to obtain 410 comparisons of CCO and bolus CO determinations. Heart rhythm associated with each comparison was determined. The comparison produced a measurement bias of -0.07 l/min and limits of agreement of -1.77 to 1.63 l/min. The bias of the two measurements was -0.35 l/min for sinus rhythm, -0.19 l/min for sinus tachycardia and -0.12 l/min for atrial flutter/fibrillation. Increased temperature and heart rate did not affect measurement agreement. In conclusion, the agreement between the bolus and continuous methods is clinically acceptable and is unaffected by the heart rhythms of sinus rhythm, sinus tachycardia and atrial flutter/fibrillation.

Arrhythmias, Cardiac↗
PubMed1997

Comparison of open and laparoscopic live donor nephrectomy.

OBJECTIVE: This study compares an initial group of patients undergoing laparoscopic live donor nephrectomy to a group of patients undergoing open donor nephrectomy to assess the efficacy, morbidity, and patient recovery after the laparoscopic technique. SUMMARY BACKGROUND DATA: Recent data have shown the technical feasibility of harvesting live renal allografts using a laparoscopic approach. However, comparison of donor recovery, morbidity, and short-term graft function to open donor nephrectomy has not been performed previously. METHODS: An initial series of patients undergoing laparoscopic live donor nephrectomy were compared to historic control subjects undergoing open donor nephrectomy. The groups were matched for age, gender, race, and comorbidity. Graft function, intraoperative variables, and clinical outcome of the two groups were compared. RESULTS: Laparoscopic donor nephrectomy was attempted in 70 patients and completed successfully in 94% of cases. Graft survival was 97% versus 98% (p = 0.6191), and immediate graft function occurred in 97% versus 100% in the laparoscopic and open groups, respectively (p = 0.4961). Blood loss, length of stay, parenteral narcotic requirements, resumption of diet, and return to normal activity were significantly less in the laparoscopic group. Mean warm ischemia time was 3 minutes after laparoscopic harvest. Morbidity was 14% in the laparoscopic group and 35% in the open group. There was no mortality in either group. CONCLUSIONS: Laparoscopic live donor nephrectomy can be performed with morbidity and mortality comparable to open donor nephrectomy, with substantial improvements in patient recovery after the laparoscopic approach. Initial graft survival and function rates are equal to those of open donor nephrectomy, but longer follow-up is necessary to confirm these observations.

Adult↗
PubMed1997

Traumatic grief as a risk factor for mental and physical morbidity.

OBJECTIVE: The aim of this study was to confirm and extend the authors' previous work indicating that symptoms of traumatic grief are predictors of future physical and mental health outcomes. METHOD: The study group consisted of 150 future widows and widowers interviewed at the time of their spouse's hospital admission and at 6-week and 6-, 13-, and 25- month follow-ups. Traumatic grief was measured with a modified version of the Grief Measurement Scale. Mental and physical health outcomes were assessed by self-report and interviewer evaluation. Survival analysis and linear and logistic regressions were used to determine the risk for adverse mental and physical health outcomes posed by traumatic grief. RESULTS: Survival and regression analyses indicated that the presence of traumatic grief symptoms approximately 6 months after the death of the spouse predicted such negative health outcomes as cancer, heart trouble, high blood pressure, suicidal ideation, and changes in eating habits at 13- or 25-month follow-up. CONCLUSIONS: The results suggest that it may not be the stress of bereavement, per se, that puts individuals at risk for long-term mental and physical health impairments and adverse health behaviors. Rather, it appears that psychiatric sequelae such as traumatic grief are of critical importance in determining which bereaved individuals will be at risk for long-term dysfunction.

Anxiety Disorders↗
PubMed1996

The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6.

Interleukin 6 (IL-6) is considered an important mediator of acute inflammatory responses. Moreover, IL-6 functions as a differentiation and growth factor of hematopoietic precursor cells, B cells, T cells, keratinocytes, neuronal cells, osteoclasts, and endothelial cells. IL-6 exhibits its action via a receptor complex consisting of a specific IL-6 receptor (IL-6R) and a signal transducing subunit (gp130). Soluble forms of both receptor components are generated by shedding and are found in patients with various diseases such as acquired immune deficiency syndrome, rheumatoid arthritis, and others. The function of the soluble (s)IL-6R in vivo is unknown. Since human (h)IL-6 acts on human and murine target cells, but murine IL-6 on murine cells only, we constructed transgenic mice expressing the hsIL-6R. We report here that in the presence of hsIL-6R, mice are hypersensitized towards hIL-6, mounting an acute phase protein gene induction at significantly lower IL-6 dosages compared to control animals. Furthermore, in hsIL-6R transgenic mice, the detected acute phase response persists for a longer period of time. The IL-6/IL-6R complex prolongs markedly the Il-6 plasma half-life. Our results reinforce the role of the hsIL-6R as an agonistic protein, help to understand the function of the hsIL-6R in vivo, and highlight the significance of the receptor in the induction of the acute phase response.

Acute-Phase Reaction↗
PubMed1996

Monoclonal antibody alpha IR-3 inhibits non-small cell lung cancer growth in vitro and in vivo.

The ability of monoclonal antibody (mAb) alpha IR-3 to interact with non-small cell lung cancer (NSCLC) cells was investigated. MAb alpha IR-3 inhibited specific binding of 125I-IGF-I and 125I-alpha IR-3 to a panel of 8 NSCLC cell lines with high affinity (IC50 = 200 and 50 ng/ml, respectively). 125I-alpha IR-3 bound with high affinity (Kd = 40 ng/ml) to a single class of sites (Bmax = 8,000/cell) using NCI-H838 cells. 125I-alpha IR-3 was internalized when exposed to NCI-H838 or H1299 cells at 37 degrees C but not 4 degrees C. alpha IR-3 immunoprecipitated major 90 and 130 kD proteins. IGF-I stimulated and alpha IR-3 inhibited the clonal growth of NCI-H1299 cells. alpha IR-3 slowed the growth of NCI-H157 and H838 xenografts in nude mice. In a biodistribution study 125I-alpha IR-3 was preferentially localized to the tumor as opposed to other organs. These data suggest that IGF-I may be a regulatory agent in NSCLC.

Animals↗
PubMed1996

Pseudomonas aeruginosa outbreak associated with a contaminated blood-gas analyser in a neonatal intensive care unit.

Over a 10 month period in a neonatal intensive care unit there was an outbreak of infection caused by Pseudomonas aeruginosa (resistant to ticarcillin, timentin) which involved 24 newborns. There was extensive morbidity and mortality (38%) associated with the infections, which presented as septicaemia (N = 6) (five succumbed and four had coexisting pneumonia), pneumonia (N = 6), meningitis (one, died), conjunctivitis (N = 1), otitis externa (N = 1), conjunctivitis plus otitis externa (N = 1). In addition there were two pseudosepticaemias and six colonized infants, three of whom were treated for the presence of P. aeruginosa in endotracheal aspirates. There was always at least one baby colonized or infected with P. aeruginosa during the outbreak. Environmental surveillance and genomic DNA fingerprinting of isolates identified the blood gas analyzer port as the likely reservoir for the outbreak. Further spread of the organism did not occur after commencement of staff education on vigilant and careful handwashing, especially after use of the blood-gas analyser.

Blood Gas Analysis↗
PubMed1996

Isolation and characterization of a monomethioninesulfoxide variant of interferon alpha-2b.

PURPOSE: To isolate and characterize a monomethioninesulfoxide variant of the commercially available therapeutic protein interferon alpha-2b. METHODS: The methionine (Met)-oxidized variant was isolated by reverse-phase high performance liquid chromatography and characterized by SDS-PAGE, peptide mapping and mass spectrometric analysis of the trypsin/V8-generated peptide fragments. The biological and immunological activities of the isolated variant were also evaluated. RESULTS: The rHuIFN alpha-2b variant was found to contain a Met sulfoxide residue at position 111 of the rHuIFN alpha-2b molecule. The far-UV CD spectra showed a slight loss of alpha-helical content and an increase in the beta-sheet contribution. The CD spectra indicate that both chromatographic conditions and Met oxidation contribute to the observed secondary structure changes. Both interferon alpha-2b main component and its methionine-oxidized variant showed different reactivity to monoclonal antibodies employed in immunoassays for the protein. CONCLUSIONS: A monomethioninesulfoxide rHuIFN alpha-2b variant was found to be present in the rHuIFN alpha-2b bulk drug substance in solution. The Met(111) residue was identified as Met sulfoxide by comparative tryptic/V8 mapping and mass spectrometric analysis. Nevertheless, the oxidation of the Met(111) residue did not seem to have a detectable effect on the biological activity of the molecule.

Amino Acid Sequence↗
PubMed1996

Complicated grief as a disorder distinct from bereavement-related depression and anxiety: a replication study.

OBJECTIVE: This study sought to confirm in an independent, nonclinical study group previous work which demonstrated that the symptoms of complicated grief were distinct from the symptoms of bereavement related depression and anxiety. METHOD: Data used in the analyses were derived from a group of 150 widowed individuals who were interviewed 6 months after their deceased spouses' hospital admission (study entry). Complicated grief was measured with a modified version of the Grief Measurement Scale. Principal axis factoring was used to determine the distinctiveness of complicated grief, depression, and anxiety. RESULTS: The principal axis factoring showed that the symptoms of complicated grief loaded quite highly on the first (complicated grief) factor and loaded very poorly on the anxiety and depression factors. CONCLUSIONS: The results confirmed the authors' previous findings demonstrating the distinction between symptoms of complicated grief and symptoms of bereavement-related depression and anxiety.

Anxiety Disorders↗
PubMed1996

Hormone replacement therapy in the aged. A state of the art review.

The use of hormone replacement therapy (HRT) in the immediate postmenopause for the relief of menopausal symptoms and for the prevention of osteoporosis and cardiovascular disease is well established. The continuation of treatment beyond the age of 60 years is likely to maximise these long term benefits and there is now increasing evidence to suggest that commencing treatment de novo in women of this age is likely to be beneficial. Many women remain symptomatic well into their sixties and the introduction of HRT at this stage will not only relieve these symptoms but will also conserve bone density and reduce future osteoporotic fracture risk. Furthermore, HRT appears to reduce the risk of cardiovascular disease, even in those women with pre-existing heart disease. The possible association between HRT and breast cancer remains controversial. Overall, there seems to be a slight increase in risk with long term HRT usage (longer than 10 years) but certain subgroups of women may be more at risk. This review discusses the merits and potential problems of prescribing HRT to the elderly and gives some guidance on the type, dose and route of administration of estrogen and progestogen to be used. Poor compliance with HRT is a major problem and the more widespread use of pretreatment counselling together with a wider range of products should have a positive impact in this area. The final decision about whether to continue or commence HRT in the elderly should be an informed one made by the woman and her clinician together.

Administration, Oral↗
PubMed1996

Using research for successful Medicare and Medicaid risk marketing.

Medicare/Medicaid risk marketing is a vital business challenge, one that countless managed care organizations are facing right now. Early entry into new markets and aggressive participation in existing markets are essential to meet competitive pressures. Health plans intent on success in government risk programs should conduct research to learn the medical needs, wants, and desires of older persons in the geographic area they serve. Original, market-specific research yields critical marketing and clinical data that can be used to improve care and member satisfaction along with customer loyalty and retention.

Aged↗
PubMed1996

Cerebral SPECT imaging: effect on clinical management.

This study, performed in 94 consecutive patients referred for evaluation, demonstrates the clinical utility of cerebral SPECT imaging. In a significant percentage of patients (47%), the additional information provided by SPECT resulted in an alteration in clinical management. Long-term follow-up will be necessary to determine the effect of these management decisions on patient outcome.

Brain↗
PubMed1995

Activity of melphalan in combination with the glutathione transferase inhibitor sulfasalazine.

Glutathione (GSH) transferases (GST), a family of detoxification enzyme proteins, are suggested to play an important role in tumor cell resistance to melphalan. The GST-activity inhibitor ethacrynic acid has been shown to increase the antitumor activity of melphalan in vitro as well as in vivo. In this study we determined the activity and toxicity of melphalan in combination with another GST-activity inhibitor, sulfasalazine, an agent used to treat ulcerative colitis. We entered 37 previously treated patients with advanced cancer of different histologies on sulfasalazine given at the individually calculated maximum tolerated dose (MTD) and melphalan given at doses beginning at 20 mg/m2. The main toxicity arising from this combination was nausea and vomiting, whereas increased myelosuppression was not observed. A partial response was seen in 2/4 of the ovarian cancer patients only. Plasma sulfasalazine levels varied between 2.5 and 47.1 micrograms/ml. Although reductions in GSH/GST levels were observed in peripheral mononuclear cells of certain patients following sulfasalazine treatment, there was no correlation between the extent of reduction and the plasma sulfasalazine level. A larger patient population must be studied to determine the usefulness of this combination.

Drug Administration Schedule↗
PubMed1995

The effects of oral 4-hydroxyandrostenedione on peripheral aromatisation in post-menopausal breast cancer patients.

This study investigated the influence of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA, formestane), given orally, on peripheral aromatase activity and plasma oestradiol (E2) levels in post-menopausal women with advanced breast cancer. The aim was to establish whether an optimal dose could be identified that had a pharmacological effectiveness comparable with that of parenteral 4OHA. A total of 13 post-menopausal women were studied before treatment and after a minimum of 4 weeks on treatment with one or more of the following doses: 125 mg once daily (od), 125 mg b.i.d. (bd) and 250 mg od. In all, seven aromatase studied were performed at 125 mg od; four, at 125 mg bd; and ten, at 250 mg od. Three patients were studied at all doses. E2 was measured concurrently and was available at all dose increments for seven patients. Given at doses of 125 mg od, 125 mg bd and 250 mg od, treatment with formestane inhibited in vivo aromatisation by 62.3% +/- 9.5%, 70.0% +/- 5.1% and 57.3% +/- 5.3%, respectively (mean +/- SEM). Corresponding values for plasma E2 suppression were 30.7% +/- 6.5%, 43.4% +/- 4.5% and 42.9% +/- 6.7%, respectively. Thus, apart from a somewhat better suppression of plasma E2 levels by the two higher doses as compared with 125 mg od, no significant difference in the degree of aromatase inhibition or plasma E2 suppression was observed. The suppression of E2 by oral 4OHA at 125 mg bd or 250 mg od approaches that achieved by the recommended parenteral schedule of 250 mg fortnightly, but inhibition of aromatase at this dose was substantially inferior. The findings are consistent with a hypothesis that 4OHA given orally may cause substantial plasma oestrogen suppression during part of the day, but neither the od nor the bd regimens investigated in the present study were capable of producing optimal aromatase inhibition.

Administration, Oral↗