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Biomedical subjects

R M Dunn

Publications and source records attributed to R M Dunn.

36 records · Page 2Linked to original sources
PubMed1996

Thyroid radiation doses during radioimmunotherapy of CEA-expressing tumours with 131I-labelled monoclonal antibodies.

A number of radioimmunotherapy (RAIT) trials with iodinated antibodies have shown a high variability in the radiation doses to the thyroid. Therefore, the aim of this study was to evaluate which factors influence these thyroid doses during RAIT with 131iodinated monoclonal anti-carcinoembryonic antigen (CEA) antibodies. Data from 36 patients with CEA-expressing tumours were analysed. The patients underwent RAIT with the 131I-labelled IgG1 anti-CEA antibody, MN-14 (Ka = 10(9) l mol-1) or its F(ab')2 fragment (activity range 45.8-220.0 mCi). The thyroid was blocked with 120 mg iodine (lugol's orSSKI solution) and 400 mg perchlorate per day, starting 1 day prior to the first study. Blood clearance and molecular composition of labelled plasma compounds were determined by blood sampling and size-exclusion high-performance liquid chromatography analysis. The cumulated activities of tissues were determined from daily imaging and blood clearance data. Doses were derived from the MIRD scheme. Thyroid radiation doses showed a high variability, between 1.2 and 37.7 cGy mCi-1 (mean +/- S.D.: 11.1 +/- 8.3 cGy mCi-1), corresponding to absolute doses between 2.5 and 43.6 Gy. However, the maximal iodine uptake in the thyroid was 2.4 +/- 1.9 microCi mCi-1 (range 0.2-10.0 microCi mCi-1), which was less than 1% of the injected activity, indicating that more than 99% of the thyroid was blocked in all cases. No correlation was found between these thyroid doses and conditions leading to an enhanced exposure to free radioiodine, such as unbound I- in the mAb preparation, rapid metabolic breakdown of the labelled antibody due to human anti-mouse antibodies (HAMA), or immune complex formation with circulating antigen. However, a relationship between the thyroid doses and the patients' compliance in taking their Lugol's and perchlorate blocking medications, as well as to a relatively high variability in the biological half-life of the iodine in the thyroid (range from 31.1 h to virtual infinity), is indicated. No rising TSH titres or other signs of (latent) hypothyroidism were seen in these patients during a 2 year follow-up period. Longer follow-up was not possible because of the terminal condition of most of the patients. These data show that thyroid doses in an appropriately blocked individual given a standard, non-myeloablative dose of RAIT, are generally lower than those assumed to be required to cause late hypothyroidism. Even if higher activities are used, potential hypothyroidism may be overcome easily by hormone replacement. Thyroid doses are independent of parameters leading to an enhanced exposure of the thyroid to free radioiodine, suggesting that patient compliance in taking their blocking medication may be the most crucial factor for reducing thyroid doses in RAIT with 131I-labelled antibodies.

Adenocarcinoma↗
PubMed1996

Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion.

UNLABELLED: The renal uptake of radiolabeled antibody fragments and peptides presents a problem in radioimmunodetection and therapy, compromising lesion sensitivity, especially with intracellularly-retained isotopes. Previously, we showed that cationic amino acids and their derivatives are capable of significantly reducing kidney uptake in animals. We report our initial clinical results of successful renal uptake reduction in five patients who underwent cancer radioimmunodetection with 99mTc-anti-CEA Fab' fragments. METHODS: The patients were infused with two liters of a commercially-available nutritive amino acid solution (containing approximately 2.25 g/liter lysine-glutamate and 2.50 g/liter arginine), whereas 75 control patients received the same volume of saline (quantification of organ and tumor kinetics from conjugate whole-body views by ROI technique). RESULTS: The renal uptake in the amino acid group was significantly lower (p<0.05) than in the control group (11.1 +/- 2.0% injected dose versus 17.7 +/- 7.0% injected dose at 24 hr postinjection), whereas the uptake of all other organs remained unaffected. Gel filtration chromatography of the urine taken from amino-acid-treated patients showed that a significantly higher amount of excreted activity was bound to intact Fab' (53% of excreted activity) in contrast to only less than 10% in the control group. CONCLUSION: The renal uptake of monoclonal antibody fragments in patients can be reduced significantly by amino acid infusion, even at considerably lower doses than those that were safe and effective in animals. As was found in animals, the mechanism seems to rely on an inhibition of the re-absorption of tubularly-filtered proteins by the proximal tubule cells. These results encourage further clinical trials to lower the renal uptake experienced in radioimmunodetection, as well as in therapeutic trials with antibody fragments and peptides.

Aged↗
PubMed1995

Reduction of the renal uptake of radiolabeled monoclonal antibody fragments by cationic amino acids and their derivatives.

The renal uptake of radiolabeled antibody fragments and peptides is a problem in radioimmunodetection and radioimmunotherapy, especially with intracellular retained radiometals. The aim of this study was to develop suitable methods to reduce this kidney uptake. BALB/c mice or nude mice bearing the human GW-39 colon carcinoma xenograft were given i.p. injections of basic amino acids or a range of different basic amino acid derivatives, amino sugars, as well as cationic peptides. The effect of these agents on the biodistribution of Fab' and F(ab')2 fragments of different mAbs radiolabeled with 99mTc, 188Re, 111In, 88Y, or 125I was studied. Tumor and organ uptake was determined and compared to untreated mice. The kidney uptake of Fab' fragments was reduced 5-6-fold in a dose-dependent manner as compared to untreated controls. The uptake in all other organs, as well as the tumor, was unaffected. A similar reduction in renal retention was seen for all other intracellularly retained isotopes, as well as for F(ab')2 fragments. D- and L-isomers of lysine were equally effective whether given i.p. or p.o. D-glucosamine was effective, but its N-acetyl derivative was not. Basic polypeptides (e.g., poly-L-lysine) were also effective; their potency increased with increasing molecular weight. HPLC of the urine taken from treated animals showed the excretion of intact Fab', in contrast to mostly low-molecular-weight metabolites in the control group. These studies indicate that a variety of basic compounds is capable of inhibiting the tubular reabsorption of peptides and proteins, thus lowering the kidney uptake of antibody fragments significantly. On a molecular basis, the effect seems to essentially rely on the presence of a positively charged amino group. By reducing renal retention of antibody fragments, their role as imaging and therapeutic agents may be expanded.

Animals↗
PubMed1994

Nitrogen limitation induces expression of the avirulence gene avr9 in the tomato pathogen Cladosporium fulvum.

The avirulence gene avr9 of the fungal tomato pathogen Cladosporium fulvum encodes a race-specific peptide elicitor that induces the hypersensitive response in tomato plants carrying the complementary resistance gene Cf9. The avr9 gene is not expressed under optimal growth conditions in vitro, but is highly expressed when the fungus grows inside the tomato leaf. In this paper we present evidence for the induction of avr9 gene expression in C. fulvum grown in vitro under conditions of nitrogen limitation. Only growth medium with very low amounts of nitrogen (nitrate, ammonium, glutamate or glutamine) induced the expression of avr9. Limitation of other macronutrients or the addition of plant factors did not induce the expression of avr9. The induced expression of avr9 is possibly mediated by a positive-acting nitrogen regulatory protein, homologous to the Neurospora crassa NIT2 protein, which induces the expression of many genes under conditions of nitrogen limitation. The avr9 promoter contains several putative NIT2 binding sites. The expression of avr9 during the infection process was explored cytologically using transformants of C. fulvum carrying an avr9 promoter-beta-glucuronidase reporter gene fusion. The possibility that expression of avr9 in C. fulvum growing in planta is caused by nitrogen limitation in the apoplast of the tomato leaf is discussed.

Base Sequence↗
PubMed1994

Free flap valvular transplantation for refractory venous ulceration.

PURPOSE: Nonoperative therapeutic approaches to chronic venous ulceration, although effective, often require prolonged dressing care and immobilization with leg elevation. Results of skin grafting, perforator ligation, and valve interpositions and reconstructions improve results of ulcer healing but have not uniformly prevented ulcer recurrence. Our hypothesis is that reconstruction of chronic venous ulcers by excision of the diseased tissue bed and replacement with a free flap containing multiple competent microvenous valves and a normal tissue microcirculation will result in long-term cure of these debilitated patients. METHODS: Six patients with chronic venous insufficiency and recurrent ulceration (class 3) underwent excision of ulcers and surrounding liposclerotic tissue beds and reconstruction with fasciocutaneous free flaps (two bilateral). Preoperative and postoperative photoplethysmography was used to assess venous refilling times. Duplex scanning was performed to assess deep venous reflux. RESULTS: There were no flap failures. Photoplethysmographic venous refilling times measured on flaps demonstrated significant immediate and long-term increases from preoperative values (all results +3 by Society of Vascular Surgery outcome grading). Long-term maintenance of tissue integrity is shown by absence of recurrent ulceration and no evidence of recurrent tissue lipodermatosclerosis in all flaps at follow-up (8 months to 7.5 years; mean 24 months). No recurrent lipodermatosclerosis was seen on flap biopsy at 2 and 7 years. Separate cadaveric injection studies, including scanning electron microscopy, revealed numerous microvenous valves directed toward the draining pedicle in the flaps used for reconstruction. CONCLUSIONS: This is the first comprehensive report providing combined laboratory and clinical evaluation, anatomic rationale, and long-term outcome of surgical rehabilitation of patients with chronic venous ulceration who have undergone microsurgical flap reconstruction.

Adult↗
PubMed1993

The rat rectus abdominis myocutaneous flap: a true myocutaneous flap model.

UNLABELLED: Investigations of experimental flaps in lower-order animals have concluded that the cutaneous vascular anatomy of "loose-skinned" animals is not analogous to that of humans. This is particularly relevant with respect to myocutaneous flaps. The interpretation of results of studies in lower-order animals raises questions as to the applicability of these data to the human condition. OBJECTIVES: To establish a true myocutaneous flap model in the rat, to define the microvascular anatomy and the cutaneous vascular territory of the rat rectus abdominis myocutaneous flap, and to determine its suitability for additional investigative study of myocutaneous flaps. METHODS: Forty-two Sprague-Dawley rats weighing 300 to 400 gm were divided into the following six experimental groups: Group 1 (microvascular anatomy, n = 5), microfil injection and microdissection; Group 2 (n = 5), India ink injection of an isolated superior or inferior epigastric artery pedicle; Group 3, flap control (n = 6); Group 4, superior epigastric (n = 17); Group 5, deep inferior epigastric (n = 16); and Group 6, bipedicle deep inferior epigastric (n = 3). Rectus abdominis myocutaneous flaps based on a single superior or inferior vascular pedicle, or on a double inferior vascular pedicle with an overlying cutaneous island extending from the costal margin to the pubis and anterior to the anterior axillary line, were raised and replaced. Control flap vascular pedicles were transected. Assessment of viability was performed at 7 days using two-dimensional planimetry, tetrazolium, and hematoxylin and eosin stain. RESULTS: Injection studies revealed large (0.1 mm), direct, perforating vessels from the rectus abdominis muscle to the overlying cutaneous island. The cutaneous territory was defined by isolated pedicle india ink injection extended over the vertical muscle axis to the anterior axillary line and for a variable distance across the midline. All controls flaps were nonviable at 7 days. Superiorly based single-pedicle, and double-pedicle inferiorly based, flaps had 97% (SD, 0.03) survival of the cutaneous island. Single inferior pedicle flaps had 77% (SD, 0.07) survival of the cutaneous island with necrosis of the contralateral distal skin island. All flaps had 100% muscle survival. CONCLUSION: The rat rectus abdominis muscle and overlying cutaneous island constitutes a true myocutaneous territory. This has not been described in a low-order laboratory animal. The flap can be based on single or double, superior or inferior, epigastric vessels with predictable flap survival. The superiorly based and double pedicle flap demonstrates nearly complete viability. This model should serve as a useful investigational tool in the laboratory study of myocutaneous flaps.

Animals↗
PubMed1993

Experimental and clinical use of pH monitoring of free tissue transfers.

No current method of flap monitoring is ideal for use in all types of free tissue transfers. No method provides objective, easily communicated data that is identical in all types of transfers. In particular, reliable monitoring of buried transfers has proved difficult with available methods. The rat anterior thigh flap based on the external iliac vascular pedicle was introduced by us as a model of deep free tissue transfer. Four sets of 10 flaps were raised in the following groups: Group A (control), Group B (arterial occlusion), Group C (venous occlusion), and Group D (arterial and venous occlusion). Postoperative muscle flap pH was measured with a micro-pH electrode (1.2 mm) and correlated with arterial blood gas. Results showed excellent correlation of flap and serum pH over time (mean flap pH, 7.28; mean serum pH, 7.30). Arterial occlusion produced a rapid drop in flap pH of 0.66 pH units at 1 hour. Venous occlusion pH drop was 0.27 pH units at 1 hour, 0.53 pH units at 3 hours. Arterial and venous occlusion produced a pH drop of 0.55 pH units at 1 hour. The most rapid rate of pH drop occurred immediately after vessel occlusion. We have used continuous pH monitoring in 21 free tissue transfers for up to 84 hours after surgery. PH values remained constant in each transfer (range, 7.20-7.50; grand mean, 7.35). There was one flap failure among the monitored group of flaps, which was predicted by pH drop before loss of Doppler pulse.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Flap models in the rat: a review and reappraisal.

The laboratory rat has long provided plastic surgical investigators a model to study many aspects of flap physiology. Clinical advances in reconstructive surgery have succeeded or preceded experimental work, setting the stage for further advances. We have critically reviewed all reports of flap models in the laboratory rat. This has begun with simple skin flaps designed on various areas of the body and continued with a review of free-tissue transfer models. Because of the multitude of as yet unanswered questions remaining, the laboratory rat will invariably continue to be widely used as an investigatory source in this area. This report should allow investigators to select more easily reliable, reproducible experimental models, and, one hopes, to streamline their investigative efforts.

Animals↗
PubMed1987

Expression of capsular polysaccharide during experimental focal infection with Staphylococcus aureus.

In vivo expression of the type 8 capsular polysaccharide (CP) of Staphylococcus aureus was studied by using the Becker strain, the prototype type 8 strain, in a guinea pig model of persistent subcutaneous infection. At 24 hr after infection, supernatants of aspirates from the site of infection contained low levels of CP (median, 0.53 ng/ml; range, less than 0.16-6.30 ng/ml). CP levels increased at day 3 to a geometric mean level of 47 ng/ml, at day 6 to 389 ng/ml, at day 8 to 537 ng/ml, and thereafter persisted in that range. On days 1, 3, and 6, CP was not detectable (less than 0.16 ng/ml) in the serum, but on days 8, 10, or 13, CP was present in 15 (58%) of 26 animals; the median peak level of serum CP among these animals was 2.00 ng/ml (range, 0.31-5.90 ng/ml). These studies document that the type 8 CP of S. aureus is produced and released during a focal, suppurative infection and can be detected in the serum of infected animals.

Animals↗
PubMed1982

Choice, relative reinforcer duration, and the changeover ratio.

Relative reinforcer duration was varied in concurrent schedules with a fixed-ratio four changeover requirement. The schedule in effect after each reinforcer was randomly chosen. For all three pigeons, relative response rates overmatched relative reinforcer durations. Time allocation was less extreme and, on the average, matched relative reinforcer duration. In a subsequent manipulation, the level of preference was shown to depend on the size of the changeover requirement. These results are similar to those from related unequal reinforcement-frequency procedures.

Journal Article↗
PubMedDate not supplied

In-vitro and in-vivo comparative analysis of four tissue pH monitoring systems.

The purpose of this investigation was to identify the type of pH-reference electrode combination that is the most suitable and reliable in clinical applications involving long-term postoperative monitoring of microvascular reconstructive transplants and diagnosis of compartment syndrome. Four types of pH-sensing devices were chosen for the study: a standard glass pH electrode, a polymer-based pH electrode, an ISFET pH sensor, and a fiberoptic pH sensor. Various combinations of electrodes were tested in vitro for typically four days. The glass and polymer electrodes maintained stable pH readings, averaging drifts of 0.14 +/- 0.07 and 0.14 +/- 0.08 pH units per 96 hours, respectively. The fiberoptic sensors displayed an average drift of 0.20 +/- 0.15 pH units per 96 hours. ISFET sensors displayed nearly linear drifts, averaging 1.36 +/- 0.54 pH units per 96 hours. When placed in healthy animal tissue, glass and polymer electrode pH readings followed the arterial blood pH values, measured by a blood gas analyzer. In compromised tissue, both glass and polymer electrodes recorded falling pH levels correctly, indicating ischemic conditions. Generally, ISFET sensors in healthy tissue produced pH readings that did not correlate well with arterial blood pH values. Fiberoptic sensors monitored healthy-tissue pH correctly; however, mechanical disturbances of the fiberoptic sensor and occasional discontinuation of computer operation would shift the pH output significantly (at times by 0.2 pH units), resulting in subsequent inaccurate pH readings. The glass electrode was the only sensor evaluated clinically. It correctly indicated tissue viability in all clinical cases, involving both healthy and ischemic tissue. The authors conclude that the glass pH electrode has the best combination of characteristics for clinical tissue pH measurements.

Animals↗