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Biomedical subjects

S Fisher

Publications and source records attributed to S Fisher.

At least 145 records · Page 8Linked to original sources
PubMed1989

Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease.

Amyloid deposition in senile plaques and the cerebral vasculature is a marker of Alzheimer's disease. Whether amyloid itself contributes to the neurodegenerative process or is simply a by-product of that process is unknown. Pheochromocytoma (PC12) and fibroblast (NIH 3T3) cell lines were transfected with portions of the gene for the human amyloid precursor protein. Stable PC12 cell transfectants expressing a specific amyloid-containing fragment of the precursor protein gradually degenerated when induced to differentiate into neuronal cells with nerve growth factor. Conditioned medium from these cells was toxic to neurons in primary hippocampal cultures, and the toxic agent could be removed by immunoabsorption with an antibody directed against the amyloid polypeptide. Thus, a peptide derived from the amyloid precursor may be neurotoxic.

Alzheimer Disease↗
PubMed1989

Asparagine-linked glycosylation of the scrapie and cellular prion proteins.

Post-translational modification of the scrapie prion protein (PrP) is thought to account for the unusual features of this protein. Molecular cloning of a PrP cDNA identified two potential Asn-linked glycosylation sites. Both the scrapie (PrPSc) and cellular (PrPC) isoforms were susceptible to digestion by peptide N-glycosidase F (PNGase F) but resistant to endoglycosidase H as measured by migration in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. PNGase F digestion of PrPC yielded two proteins of Mr26K and 28K; however, the 26-k species was only a minor component. In contrast, PNGase F digestion of PrPSc yielded equimolar amounts of two proteins of Mr26K and 28K. The significance of this altered stoichiometry between the 26- and 28-kDa deglycosylated forms of PrP during scrapie infection remains to be established. Both isoforms as well as PrP 27-30, which is produced by limited proteolysis of PrPSc, exhibited a reduced number of charge isomers after PNGase F digestion. The molecular weight of PrP 27-30 was reduced from 27K-30K by PNGase F digestion to 20K-22K while anhydrous hydrogen fluoride or trifluoromethanesulfonic acid treatment reduced the molecular weight to 19K-21K and 20K-22K, respectively. Denatured PrP 27-30 was radioiodinated and then assessed for its binding to lectin columns. PrP 27-30 was bound to wheat germ agglutinin (WGA) or lentil lectins and eluted with N-acetylglucosamine or alpha-methyl-mannoside, respectively. Digestion of PrP 27-30 with sialidase prevented its binding to WGA but enhanced its binding to Ricinus communis lectin. These findings argue that PrP 27-30 probably possesses Asn-linked, complex oligosaccharides with terminal sialic acids, penultimate galactoses, and fucose residues attached to the innermost N-acetyl-glucosamine. Whether differences in Asn-linked oligosaccharide structure between PrPC and PrPSc exist and are responsible for the distinct properties displayed by these two isoforms remain to be established.

Animals↗
PubMed1988

Primary radiation therapy for stage I and II breast cancer.

In 1987 there were estimated to be approximately 130,000 new cases of breast cancer diagnosed in the United States. Presently, about 20-30,000 of these cases are treated with primary radiotherapy, although many more of the 90,000 stage I and II breast cancer cases are eligible for this form of treatment. Appropriate selection must be employed, including the size and site of the primary tumor, the size of the breast, the potential for multifocal disease, and the age of the patient. When proper selection is used, primary radiotherapy for stage I and II disease yields equivalent overall survival and NED survival when compared to traditional mastectomy. The benefit is preservation of the breast with good to excellent cosmesis in the vast majority of patients.

Breast Neoplasms↗
PubMed1988

The intraperitoneal delivery of radiolabeled monoclonal antibodies: studies on the regional delivery advantage.

The i.p. delivery of murine monoclonal antibody was compared with i.v. delivery in normal mice and rats, in normal nude mice and in those with i.p. human ovarian carcinoma xenografts. In normal rats, all classes of antibodies and antibody fragments evaluated were cleared from the peritoneal cavity at comparable rates. The regional delivery (Rd1) advantage to the peritoneal cavity following i.p. delivery was thus most dependent on the rate of clearance of the antibody or fragment from the blood stream. Determining the exact i.p. delivery advantage was problematic due to the difficulty in reliably obtaining peritoneal fluid later than 9-10 h after i.p. injection in normal animals. During the first 9 h following i.p. injection, the Rd(0-9/0-9) was, for a murine IgG2ak Fab greater than F(ab')2 greater than IgG (at 13.6 greater than 10 greater than 7.9). Two murine IgMs evaluated differed in Rd(0-9) at 27.1 and 9.2 respectively. When blood levels were extrapolated to infinity, these Rd (0-9/affinity) values were considerably lower with the Fab having the highest Rd at 4.67. The i.p. Rd advantage was almost solely due to the i.p. antibody levels seen in the first 24 h after injection, as after that time, blood levels become comparable to those seen following i.v. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. or i.v. injection in rats showed comparable levels of radioantibody activity, whether the injection was i.p. or i.v. (except for higher diaphragmatic levels following i.p. delivery). In nude mice with i.p. human-derived ovarian tumors, intact IgG clearance from the peritoneal cavity to the blood was considerably slower than in normal animals, and early i.p. tumor uptake of specific antibody was significantly higher than that following i.v. antibody delivery. With higher early tumor uptake and lower systemic exposure, early tumor/nontumor ratios were significantly greater than those for i.v. delivery, though not beyond 48 h after i.p. injection. This study demonstrates the pharmacokinetic rationale for i.p. monoclonal antibody delivery, especially for agents cleared rapidly from the blood, such as antibody fragments. In addition, definite i.p. delivery benefit for antibody specific to i.p. tumors in the i.p. ovarian cancer system was shown soon after injection. These data regarding i.p. antibody delivery should be useful in rationally planning diagnostic and therapeutic studies involving the i.p. delivery of unmodified and immunoconjugated monoclonal antibodies.

Animals↗
PubMed1988

Improved radioimmunolocalization of human tumor xenografts following subcutaneous delivery of monoclonal antibodies.

The localization of a radiolabeled murine monoclonal antibody reactive with choriocarcinomas to human choriocarcinoma xenografts following intravenous and subcutaneous injection was evaluated by gamma scanning and tissue sampling. Tumor xenografts were established in the popliteal node region of athymic nude mice after repeated innoculations of the hind foot pads with BEWO choriocarcinoma cells. In dual label specific antibody studies, tumor/non tumor uptake ratios following subcutaneous (resulting in considerable intralymphatic uptake) injection of 131I-5F9.3 were significantly higher than those achieved post simultaneous intravenous injection of 125I-5F9.3. Double label experiments with 131I-5F9.3 and a nonspecific antibody, 125I-UPC-10, following subcutaneous injection, demonstrated that the high localization to popliteal region tumors was largely due to antibody specificity. Gamma scans following subcutaneous antibody administration of specific antibody to tumor bearing animals showed tumors soon after subcutaneous injection, at times earlier than those typically seen following intravenous delivery. Similar subcutaneous injections showed little normal nodal uptake in BALB/c control animals on gamma scans. No correlation was seen between tumor localization by specific antibody between the intravenous and intralymphatic routes, implying a difference in the mechanisms of tumor uptake of antibody by these two routes. The subcutaneous approach to antibody delivery offers advantages over intravenous delivery in tumors of human origin, including higher tumor/non tumor ratios and earlier imaging times. This was true even though these tumors were many times larger than normal lymph nodes. This subcutaneous delivery advantage should be exploitable in imaging nodal metastases of human tumors.

Animals↗
PubMed1988

Vulnerability factors in the transition to university: self-reported mobility history and sex differences as factors in psychological disturbance.

A study was conducted on the psychological reaction to the transition to university in 198 first year residential students. Female subjects had higher levels of psychological disturbance and cognitive failure. Thirty-one per cent of the subjects reported experiencing homesickness. These subjects had higher levels of psychological disturbance and cognitive failure than non-homesick subjects. There were no sex differences in homesickness reporting. The non-homesick group were found to be more likely to have been away from home before either to attend boarding school or to take holidays. This suggests either that selective aspects of previous mobility experience are beneficial or that self-selection factors operate in that those who do not feel distress at leaving home are more likely to acquire mobility experience.

Adolescent↗
PubMed1988

Plasma and tissue concentrations of ceforanide and cefazolin in women undergoing hysterectomy.

Thirty-four women who underwent vaginal hysterectomy received either ceforanide or cefazolin as perioperative antimicrobial prophylaxis. Samples of plasma, myometrium, endometrium and fallopian tubes were obtained at various intervals after injection and were assayed for cephalosporin concentration. Following intramuscular injection approximately 1 h prior to surgery, both drugs provided adequate tissue levels at the time of the procedure. Although both antimicrobials achieved similar tissue concentrations, all tissue samples for ceforanide exceeded the MIC90 for Escherichia coli while in the cefazolin group 9/18 myometrial samples and 10/15 endometrial samples fell below the MIC90 for this organism.

Adult↗
PubMed1988

Short- and long-term effects of auxiliary labels on patient knowledge of precautionary drug information.

The purpose of this study was to determine the efficacy of auxiliary prescription labels in educating outpatients about medicines at two different time periods. Five hundred fifty-nine patients were randomly assigned either to an experimental group or a control group; each person in the experimental group received a prescription bottle to which one study auxiliary label ("sticker") had been affixed, and those in the control group received bottles with no study sticker attached. Patients were interviewed by telephone approximately one week or two months after prescription pick up. Patients who had the study sticker affixed to their prescription bottle were significantly more knowledgeable after one week about precautionary information than those patients who did not receive stickers; however, sticker-group patients receiving the delayed interview incorrectly attributed many precautions to their medication. This is the first controlled study to document that auxiliary labels increase short-term knowledge about medications, and to suggest that the same labels may result in an inappropriate generalization over time.

Drug Labeling↗
PubMed1988

Lipoprotein changes in familial hypercholesterolemia after extracorporeal immunoadsorption of low density lipoproteins.

The effects of extracorporeal immunoadsorption of LDL on the lipoprotein metabolism in two patients with familial hypercholesterolemia are reported. The immunoadsorbent consisted of F(ab')2 fragments of sheep anti-LDL antibodies, which had been coupled to Sepharose CL 4B. Within a time period of 3 to 3.5 hours a mean reduction of the level of total cholesterol by 76 +/- 4 p. cent could be obtained. The level of LDL cholesterol was reduced by 78 +/- 4 p. cent and the level of apo. B by 84 +/- 5 p. cent. Both LDL and VLDL were bound to the immunoadsorbent, while HDL was predominantly lowered by the plasma-dilution, which was in the order of 20 p. cent. The same was true for other serum proteins, not related to LDL or VLDL. The relative distribution of the different lipoprotein classes was again reached 3 days after the treatment, the initial lipid and apolipoprotein levels two to three weeks after the treatment. In a long-term therapy consisting of 45 treatments with a mean interval of 18 days between two treatments a mean cholesterol lowering of 42 p. cent could be achieved. No adverse effects and no sensitization to be heterologous protein were observed.

Adult↗
PubMed1987

5-Fluorouracil, cyclophosphamide, and vincristine for adenoid cystic carcinoma of the head and neck.

Twenty-one patients with adenoid cystic carcinoma of the head and neck were treated with intravenous boluses of cyclophosphamide and vincristine and 5-day continuous intravenous infusions of 5-fluorouracil (CVF) every 4 weeks. Eight patients received CVF as palliation for recurrent or metastatic disease. A sustained complete response (107+ months) was observed in one patient; one partial response and one mixed response each also were observed. In four patients disease stabilized, and in one disease progressed. Thirteen patients received six courses of CVF in the adjuvant setting after surgery and radiation for either primary or locoregional recurrent disease. Recurrences developed in two of seven patients with primary disease and three of six patients with recurrent disease with a median follow-up 45 months (range, 20-108+). Recurrence rate and time interval to recurrence were comparable to those of well-matched historical controls. Distant metastases have not developed in patients treated with CVF in the adjuvant setting, whereas distant metastases had developed in historical controls within comparable periods of follow-up. Serious toxicities were not encountered in any patient. The authors conclude that CVF is a well-tolerated combination chemotherapy program with activity in adenoid cystic carcinoma of the head and neck. This regimen, however, has not had a major impact in the adjuvant setting in preventing recurrent disease.

Adult↗
PubMed1987

Patient-initiated postmarketing surveillance: a validation study.

A new patient-initiated, pharmacy-based postmarketing surveillance system is described. At the time a new prescription for a targeted drug was filled, 2705 outpatients (experimentals) randomly assigned to the new system had a printed notice attached to their medication bags: the information requested them to report any "new or unusual symptoms" during the next 2 weeks by a toll-free telephone number to a trained nonprofessional who conducted a standardized adverse drug reaction (ADR) interview. To help validate the new system, another sample of 1109 patients (controls) did not receive a request for self-monitoring but were interviewed by telephone 2 weeks later. Target drugs were chosen from two classes for which side effect profiles are well identified: oral antibiotics and tricyclic antidepressants. Results show that within both drug classes, all patient-initiated reports closely matched those obtained from controls; the experimental and control groups also reported predictably high relative frequencies for the most commonly expected ADRs. Additional analyses suggest that a patient-initiated monitoring system could prove to be a promising complement to existing physician-based surveillance systems.

Adult↗
PubMed1987

Increased frequency of doxycycline side effects.

As part of a study investigating new methods of detecting adverse drug reactions, adult outpatients receiving new prescriptions for 1 of 4 antibiotics (doxycycline, penicillin VK, ampicillin, or tetracycline) were assigned to 1 of 2 methods of monitoring adverse drug reactions. Data were collected from a total of 457 staff-initiated interviews and from 1467 patients who were asked to telephone to report possible adverse effects. Doxycycline is considered by authoritative sources to be generally comparable in side effects to other tetracyclines and penicillins, with the exception that it increases photosensitivity. Results from both monitoring methods consistently indicated at least a 3-fold higher frequency of nausea or vomiting with doxycycline relative to the other antibiotics. Complaints of skin rash also were at least 4 times more frequent with doxycycline, depending on the particular sample.

Adult↗
PubMed1987

Intraperitoneal delivery of monoclonal antibodies: enhanced regional delivery advantage using intravenous unlabeled anti-mouse antibody.

Radiolabeled monoclonal antibodies (MAb) delivered intraperitoneally expose cells in contact with peritoneal fluid to considerably higher levels of MAb than if the MAb dose were given intravenously. This regional delivery advantage for intact MAb is present mainly due to the relatively slow exit of MAb from the peritoneal fluid to the blood. Eventually, following i.p. injection, blood levels of MAb rise resulting in exposure of the animal to high systemic MAb levels and potential toxicity. In this series of experiments, systemic exposure was minimized by the administration of unlabeled goat polyclonal anti-mouse antibody intravenously from 1 1/2 to 6 h following i.p. MAb injection. This maneuver results in the formation of immune complexes with their subsequent clearance and dehalogenation by the reticuloendothelial system, thus minimizing systemic MAb exposure. This approach, of increasing systemic clearance of MAb, did not alter intraperitoneal MAb levels and thus significantly increased the regional delivery advantage to the peritoneal cavity by 70-100%. This approach provides an immunologic rationale for the further enhancement of MAb delivery to i.p. foci of malignant disease and may have diagnostic and therapeutic utility.

Animals↗
PubMed1987

Pathologic findings related to the lead system and repeated defibrillations in patients with the automatic implantable cardioverter-defibrillator.

The purpose of the present study was to examine at autopsy the effect of multiple defibrillations on the myocardium and the pathologic consequences of short- and long-term placement of the intravascular and interpericardial leads of the automatic implantable cardioverter-defibrillator. Twenty-five patients were examined at autopsy; 8 of them underwent lead implantation only and 17 received both leads and the automatic implantable cardioverter-defibrillator. Twelve patients (48%) died of ventricular tachycardia or ventricular fibrillation; seven (28%) died of other causes. Acute pericarditis occurred in all patients, resulting in a localized, progressive fibrosis around the apical patch lead without giving rise to pericardial restriction. Thrombus formation was associated with the superior vena cava spring electrode in four patients (17%) and the right ventricular rate-sensing electrode in one patient (4%). Asymptomatic pulmonary emboli occurred in two patients (8%). In one patient who underwent defibrillation 59 times, superior vena cava changes consisted of vein wall destruction, fibrosis and thrombus formation. Pathologic changes under the apical patch related to defibrillation were observed in seven patients; two of these had fewer than 5 defibrillations, one had 8 defibrillations and four had 21 to 74 defibrillations. These changes consisted of contraction band necrosis in four patients, vacuolar cytoplasmic clearing and loss of myocytes confined to the myocardium under the patch electrode in five patients who had multiple defibrillations. The observed pathologic changes were estimated to affect less than 2% of the total myocardial mass. Thus, the automatic implantable cardioverter-defibrillator lead system and multiple defibrillations result in localized myocardial injury confined to the tissue under the patch electrode.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

99Tcm-MDP uptake by lymph nodes following tracer infiltration: clinical and laboratory evaluation.

Uptake of bone scanning agents in non-osseous sites has been described in a variety of pathologic conditions including tumor metastases. We have seen several patients in which such uptake was proximal and ipsilateral to the injection site of 99Tcm-methylene diphosphonate, apparently in normal lymph nodes. To further investigate this phenomenon, it was studied in a rat model. Activity in popliteal nodes ipsilateral to the injection site was over 60-fold greater in the animals that received subcutaneous (s.q.) footpad injection compared to femoral IV injection. Ipsilateral popliteal node activity in the s.q. group was 159 times that of contralateral popliteal nodes, with an ipsilateral node to liver ratio of 184:1. In summary, dramatically increased uptake of 99Tcm-MDP in normal lymph nodes ipsilateral and proximal to an extravasated injection has been demonstrated. An awareness of this phenomenon in the clinical setting can avoid confusion with pathologic forms of soft tissue uptake.

Aged↗
PubMed1987

The relationship between cognitive failures, psychoneurotic symptoms and sex.

As Broadbent et al's (1) original analysis of the relationship between the Cognitive Failures Questionnaire (CFQ) and the Middlesex Hospital Questionnaire (MHQ) was conducted on an altered version of the MHQ, the present study undertook this same analysis using the full MHQ. In addition, the relationship was examined to see if it was mediated by the differences in the scoring of males and females on each questionnaire. Our results support and strengthen Broadbent et al's conclusion that high rates of cognitive failure are associated with psychoneurotic symptoms. The sex difference on the CFQ is discussed in terms of vulnerability to stress to account for the higher incidence of psychoneurotic symptoms in females.

Adolescent↗
PubMed1987

The stress of the transition to university: a longitudinal study of psychological disturbance, absent-mindedness and vulnerability to homesickness.

A longitudinal study was conducted to examine the effects of the transition to university in residential and home-based students. All students showed evidence of raised psychological disturbance and absent-mindedness following the transition. Although there were no differences between resident and home-based students in this respect, those who reported homesickness were distinguished from the remainder in terms of higher levels of psychological disturbance and cognitive failure following the transition to university. Covariate analysis established that the gain in psychological disturbance following the transition was greater for the homesick group. The results are discussed in terms of the effects of stressful transitions on psychological state and the concept of personal vulnerability.

Adjustment Disorders↗