Biomedical subjects
Publications and source records attributed to D L Larson.
Osteoradionecrosis (ORN) of the mandible is a severe complication that follows ionizing radiation therapy in patients undergoing treatment for head and neck cancers. The occurrence of ORN usually implies other coexisting problems and should not be thought of as a "bone only" defect. For treatment to be effective, all tissues involved must be addressed.
Irradiation-associated chest wall lesions pose a significant health hazard to the patient. The principles of management include (1) biopsy of any open wounds to rule out the recurrence or persistence of tumor, (2) aggressive debridement of all offending tissues, and (3) reconstruction with well-vascularized flap tissue. Numerous questions arise regarding the practical management of these patients. The controversies that have arisen during our management of more than 100 of these patients have been discussed. It is appropriate to perform reconstruction following nonhealing of a superficial ulcer or immediately following the excision of a full-thickness chest wall defect. Hyperbaric oxygen can serve as a useful adjunct. It is rarely necessary to use a prosthetic material for the purpose of chest wall stabilization during the reconstruction of full-thickness defects. Paradoxic chest wall movement in the postoperative period does not significantly affect pulmonary function tests and is generally a transient problem. Subtotal excisions are frequently necessary. As long as all of the necrotic or tumor-bearing tissue has been fully removed, these wounds can be expected to heal in most instances by placing vascularized tissue into the defect. Operative sites in previously irradiated chest wall tissue can be expected to heal if proper and careful surgical technique is employed. Nevertheless, there is a risk of wound breakdown following any surgery in irradiated tissue. Finally, we believe it is appropriate to proceed with aesthetic recontouring of chest wall deformities associated with irradiation exposure.
Radiation-associated pelvic wounds should be managed by complete excision of all affected tissues and reconstruction with a vascularized flap. The complex anatomy and function of the perineum and pelvis create a variety of reconstructive demands. This article attempts to demonstrate the diversity of the problems that can occur in this region as well as to describe the varied options for reconstruction.
A series of naltrindole-related ligands (4-10) with an N-methyl,N-phenethyl,N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via delta opioid receptors. However, two of these ligands (4 and 5) appeared to be delta-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to delta opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of delta agonist selectivity in vivo may be due to a number of factors, including a basic difference between the delta receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize delta receptors in the brain in antagonist state.
Acute toxic shock syndrome (TSS) not related to menstruation has comprised an increasing proportion of cases reported to the Center for Disease Control in recent years. We report a patient with TSS resulting from a postoperative donor site infection after bilateral breast reconstruction with latissimus dorsi musculocutaneous flaps. The diagnosis, management, and outcome of TSS are reviewed. The plastic surgeon should be aware of TSS as a potential postoperative complication of routine procedures in plastic surgery.
We describe a technique to eliminate the vertical portion of the inverted-T incision in patients who have combined enlargement of the breasts and moderate to severe ptosis. Initial preoperative markings are made, placing the new nipple site at the level of the transposed inframammary crease. The nipple-areola complex is then retained on a vascularized pedicle, with major reduction of the breast tissue being done in the medial and lateral quadrants. The nipple and breast tissue are then tucked underneath the superior skin segment and placed in this new position as one would do with the umbilicus in an abdominoplasty. Excess vertical skin is removed, and horizontal excess is collected at the midline as a small dog-ear. We have found that this dog-ear reduces markedly with time, rounding out the inferior portion of the breasts. The remaining small amount of excess skin can then be removed under local anesthetic at a later date. We have performed this procedure on 20 patients, with follow-up from 6 to 24 months.
A series of fatty acid derivatives of naltrexamine and naltrexhydrazine were synthesized and evaluated for their persistent binding to opioid receptors. Members of this series were found to require greater than five washes for removal from mouse brain membranes when the fatty acyl chain was saturated. The presence of unsaturation in the fatty acyl groups enhanced the persistent binding. In this regard the persistent binding increased as a function of the number of double bonds, with the unsaturated congeners requiring greater than 10 washes for removal of the ligand from the membranes. The results of this study are consistent with the apparently important role of polyunsaturated fatty acids in the binding of ligands to opioid receptors.
The most important effects of hyperbaric oxygen (HBO), for the surgeon, are the stimulation of leukocyte microbial killing, the enhancement of fibroblast replication, and increased collagen formation and neovascularization of ischemic tissue. Preoperative hyperbaric oxygen induces neovascularization in tissue with radionecrosis. Refractory osteomyelitis and necrotizing fasciitis appear to respond to adjunctive hyperbaric oxygen. Crush injury and compartment syndrome appear to benefit through preservation of ATP in cell membranes, which limits edema. Hyperbaric oxygen in burn injury permits shorter hospital stays, a reduced number of surgeries, and less fluid replacement. Skin grafts and flaps are reported to take more completely and more rapidly. The same mechanisms may apply in ischemic problem wounds such as infected diabetic extremities. Contraindications and side effects are described. Hyperbaric oxygen will not heal normal wounds more rapidly but may, under certain circumstances, induce problem wounds to heal more like normal ones.
A series of naltrexamine bivalent ligands, compounds with two naltrexamine pharmacophores separated by a spacer which contains a variable number of glycyl units flanking a succinyl group, were synthesized and evaluated in vivo in mice. These compounds possessed long-acting agonist and especially antagonist activities. The bivalent ligands, 2 and 3 displayed antinociceptive activity that lasted greater than 4 h. Compound 1, a bivalent ligand and 4, the monomer, antagonized the antinociceptive effect of morphine for a week after a single injection i.c.v. The long duration of action may be due to entrapment of these ligands in the central nervous system. These compounds may give future insights into the design of long-acting agonists and antagonists.
The records of 50 selected pediatric patients who were treated and followed at M. D. Anderson Cancer Center were reviewed to study the late effects of nonsurgical treatment of cancer in children. There were 26 girls and 24 boys ranging in age between 2 months and 16 years. Patients with head and neck cancer received chemotherapy and radiotherapy for rhabdomyosarcoma (n = 27), retinoblastoma (n = 8), or nasopharynx cancer (n = 2). Median follow-up was 13 years. The most severe side effects were noted in the fields of radiation and included hypoplasia of the jaw, orbit, or hemi-face with varying degrees of atrophy of the overlying soft tissues. A wide range of endocrine, dental, and psychologic abnormalities was also documented. Since 1 in every 1,000 adults older than 20 years today is likely to be a survivor of childhood cancer, recommendations are made for this "new" class of patients whom the head and neck surgeon will be seeing in the future.
Reconstruction of chest-wall defects with musculocutaneous flaps permits resection of advanced chest-wall tumors and of tissues severely damaged by radiotherapy in patients who in a previous era were not surgically treatable. To determine the long-term outcome from this surgery, the records of 96 patients who had undergone chest-wall resection with musculocutaneous flap reconstruction were reviewed. Median survival for the entire group was 20.5 months, but a more accurate prediction of outcome could be obtained by dividing the patients into three groups. In group I, patients free of known malignancy and undergoing resection of radionecrotic tissues, median survival was 60.0 months. In group II, patients with resectable disease and free of tumor following surgery, median survival was 31.1 months. In group III, patients incompletely resected or known to have metastatic disease following surgery, median survival was only 12.5 months. Even in group III, however, some individuals achieved prolonged survival and lasting benefits from the surgery, so these data should not be used to exclude patients from undergoing necessary palliative procedures.
Though uncommon, the occurrence of an extravasation of a tissue-toxic drug can be a very disconcerting event in the physician's practice. A wound specialist, such as a plastic surgeon, is frequently consulted. The author reviews the "state of the art" approach to these challenging wounds.
The 1982-1984 Hispanic Health and Nutrition Examination Survey used ultrasonography to investigate the epidemiology of gallstone disease. Mexican American, Cuban American, and Puerto Rican men and women, aged 20-74 yr, were selected from household samples in Texas, New Mexico, Arizona, Colorado, California, Connecticut, New Jersey, New York, and Florida. Ultrasonography was performed on 2299 persons. The age-adjusted prevalence of gallstone disease (gallstones + cholecystectomy) among Mexican American men (7.2%) was 1.7 times that of Cuban American men and 1.8 times that of Puerto Rican men. The prevalence for Mexican American women (23.2%) was 1.5 times that of Cuban American women and 1.7 times that of Puerto Rican women. Rates were about three times higher among women than men and increased with age in both sexes and all ethnic groups except older Puerto Rican women. Among Mexican American women aged 60-74 yr, the prevalence of gallstone disease reached 44.1%. These results support the hypothesis that Mexican Americans are at increased risk of gallstone disease.
The relative reactivities of a number of alpha, beta-unsaturated ketones used as flavourings were determined using glutathione as the nucleophile. Monosubstitution at the beta-position of the alpha, beta-unsaturated system impeded nucleophilic addition by approximately 1000 times. Beta-Disubstitution reduced reactivity by more than 100,000 times. Endocyclic alpha, beta-unsaturated ketones were generally less reactive than alicyclic analogues. By way of comparison, the most reactive flavouring investigated, 2-octene-4-one, was consumed by glutathione about 700 times less rapidly than was methylvinyl ketone. Methylvinyl ketone was found to condense with guanylic acid 240,000 times more slowly than with glutathione. It is concluded that alpha, beta-unsaturated ketones used as flavourings generally possess low electrophilicity.
A series of beta-naltrexamine and beta-oxymorphamine derivatives that contain ionizable moieties coupled to the 6 beta-amino group were synthesized in an effort to develop antagonists and agonists that have negligible access into the central nervous system (CNS). Among the beta-naltrexamine derivatives 1-7, all displayed partial agonism on the guinea pig ileal longitudinal muscle preparation except for aspartyl derivative 6, which was a full agonist with activity in the range of morphine. The beta-oxymorphamine derivatives 8-12 were all full agonists with potencies ranging from 1.5 to 6.1 times that of morphine. Among the compounds evaluated in mice for antinociceptive or opioid antagonist activities, aspartyl derivative 6 possessed the greatest difference between peripheral (po or iv) and icv equiactive antagonist doses. Compared to naltrexone, 6 was greater than 100 times more potent by the icv route, but 6000-10,000 times less potent when administered po or icv. The present study suggests that zwitterionic groups are highly effective in preventing penetration of ligands into the CNS. Such ligands may be useful pharmacologic tools for investigation of peripheral opioid mechanisms. Moreover, they could find clinical applications when the central actions are unwanted.
Restoration of mandibular continuity after trauma or cancer by means of vascularized bone grafts, as described by Taylor and coworkers in 1979, has become an established method of oral rehabilitation. Still considered by some an endpoint in reconstruction, we have found that the judicious application of newly described dental prosthetic materials can provide the patient with improved appearance and function associated with a fully restored mandible. Twelve patients who underwent vascularized bone grafting for mandibular reconstruction had adjunctive implantation to improve either dentition or to reconstruct the temporomandibular joint. Nine patients had dental implants to restore permanent stable dentition either by placement of the mandibular bone staple plate or osseointegrated implants. Three additional patients underwent placement of metallic condylar head prostheses placed on the vascularized bone graft at the time of transfer. These patients demonstrated good mastication and an excellent incisal opening which was maintained in the late postoperative period. Vascularized bone transfer for restoration of continuity of the mandible should not be considered an endpoint in and of itself. By using implantable dental devices to restore dentition and condylar head prostheses to improve both the aesthetic result and function of the mandible to complement the vascularized osteocutaneous flap, we can bring our patients closer to the goal of total rehabilitation. The majority of these patients would otherwise never have been offered a chance at restoration of dentition. All had beneficial effects with regard to mastication and the majority also had improved speech.
In an effort to develop selective antagonists for kappa opioid receptors, bivalent ligands that contain opioid antagonist pharmacophores derived from naltrexone or other morphinans were synthesized and tested on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. The minimum requirements for kappa selectivity are at least one free phenolic OH group and one N-cyclopropyl or N-ally substituent. Several compounds (3, 8, 10) with kappa selectivity as good as or better than norbinaltorphimine (nor-BNI, 2) were discovered. The structure-activity relationship revealed that the pyrrole ring functions strictly as a spacer and does not contribute to kappa selectivity. The pharmacologic data suggest that only one antagonist pharmacophore may be required for kappa selectivity and that the other morphinan portion of the molecule confers selectivity by interacting with a unique subsite proximal to the antagonist pharmacophore recognition locus.
We evaluated the treatment and results of 46 patients with lip cancer of commissure origin or extension. The patients were evaluated by clinical stage and pathologic findings. Treatment was predominantly by surgery for T1 and T2 lesions (31 of 37 patients), whereas combined resection and radiation therapy was used for larger tumors. The results showed control of both very large and very small lesions, but T2 lesions had repeated recurrences. We therefore recommended aggressive therapy for T2 and higher classifications of lip cancer with commissure involvement.