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Biomedical subjects

R L Goode

Publications and source records attributed to R L Goode.

At least 73 records · Page 4Linked to original sources

Tobramycin-impregnated methylmethacrylate for mandible reconstruction.

Reconstruction of the mandible to restore continuity following resection is described in four cases using a tobramycin-impregnated methylmethacrylate implant fabricated at the time of surgery. Methylmethacrylate has excellent biocompatibility and strength and has been used in surgery for over 20 years. The technique uses readily available materials and is similar in concept to reconstruction with a metal plate. Potential advantages are: (1) the presence of a potent antibiotic within the implant that is released over a period of months to minimize postoperative infection and (2) the capability of the material to accurately fit any defect, either when used alone or in combination with a plate or rod. Three of the four patients whom we present are doing well; one implant became exposed following postoperative radiotherapy and had to be removed.

Adolescent↗

Inhibition of PAIII rat prostatic adenocarcinoma growth and metastasis by a new diarylsulfonylurea antitumor agent, LY181984.

LY181984 is a compound in a series of orally active diarylsulfonylureas with broad spectrum in vivo activity against syngeneic rodent and human xenograft tumor models. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this antitumor agent on the lymphatic and pulmonary metastasis of the tumor in male Lobund Wistar rats. LY181984 was inactive against the proliferation of PAIII cells in vitro. Following subcutaneous implantation of 10(6) PAIII cells in the tail, oral administration of LY181984 (25.0, 50.0, or 100.0 mg./kg./day) for 30 days had no significant effects on body weight gain. LY181984 treatment produced significant (p less than 0.05) dose-dependent inhibition of primary tumor growth in the tail (max. inhibition = 46% from untreated control levels). In these same animals, LY181984 administration produced significant (p less than 0.05) dose-dependent inhibiton of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 79% and 80% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by oral LY181984 treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (p less than 0.05) reduced by LY181984 administration in a dose-dependent manner (maximal reduction = 78% from control values). While the non-toxic doses (less than 100.0 mg./kg./day for 28 days) of LY181984 produced marked decreases in tumor growth and metastasis, administration of the compound had no effect on the survival of PAIII-bearing rats. These data support the contention that LY181984 represents a new class of orally active antitumor and antimetastatic agents with potential efficacy in the treatment of hormone-insensitive prostatic cancer. Further studies are needed to define maximal efficacy of LY181984 and other sulfonylurea agents in urogenital solid tumor animal models.

Adenocarcinoma↗

Androgens lower prostaglandin E2 levels in neonatal mouse bulbourethral gland in in vitro cultures.

The neonatal mouse bulbourethral gland (BUG) in vitro culture model is useful to study hormone-induced genitourinary (GU) tract growth and differentiation. Like the prostate, the BUG is a derivative of the urogenital sinus and may have relevance to understanding growth processes involved in normal and pathological GU tract development. Previous studies have reported androgen-induced elevation of prostaglandin E2 (PgE2) levels in mouse GU tract in vivo. PgE2 has been proposed to mediate neonatal GU tract masculinization. In our studies, tissues were obtained from neonatal male mice and cultured in serum-free Dulbecco's Modified Eagle's Medium-Ham's F-12 Medium (1:1) supplemented with varying concentrations of androgen. PgE2 levels were measured by RIA in the medium, and tissue specimens were cultured for 7 days or less. During this period, androgens induced proliferation and glandular morphogenesis in the BUGs. In the absence of androgen, tissue and medium PgE2 levels increased over 7 days. Significant (P < 0.05) PgE2 increases over day 1 control values were observed from days 5-7 in tissues and on day 7 in media. During this same time period, androgen supplementation decreased PgE2 levels. Significant (P < 0.05) PgE2 decreases from day 1 cultures were observed from days 3-7 in tissues and on day 7 in media. PgE2 was decreased significantly (P < 0.05) by androgen compared to control values from days 3-7 in tissues and from days 5-7 in media. On day 7 of culture, PgE2 levels were significantly (P < 0.05) inhibited by androgen in a concentration-dependent fashion in tissues and media. Maximal androgen-induced inhibition of PgE2 levels was 96% and 99% in tissues and media, respectively. Although the addition of indomethacin to control cultures markedly inhibited PgE2 production, BUG morphology was unaffected. In addition, the morphology of androgen-stimulated BUGs does not appear to be affected by the addition of exogenous PgE2. We conclude that although androgens induce development and decrease PgE2 levels, PgE2 does not appear to play a major role in in vitro BUG postnatal growth and morphogenesis. The BUG in vitro culture model may mimic growth and morphogenetic processes occurring in the human GU tract. Further understanding of the role of steroid hormones and PG metabolism may yield additional insight into developmental and proliferative GU tract disorders.

Androgens↗

In vivo assay for conversion of testosterone to dihydrotestosterone by rat prostatic steroid 5 alpha-reductase and comparison of two inhibitors.

An in vivo assay for steroid 5 alpha-reductase in rat ventral prostate has been developed and used to compare the inhibitory activity of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) and 6-methylene-4-pregnene-3,20-dione (LY207320). Immature rats (70-80 g) received test compounds 30 min prior to s.c. injection of [3H]-T. The rats were sacrificed 30 min later and the ventral prostates were analyzed for [3H]-T metabolites. Intraprostatic [3H]-T and [3H]-DHT reached peak levels within 5 min after injection of [3H]-T and declined to about 25% of peak levels after 2 hr. 4-MA was a very potent inhibitor of [3H]-DHT formation with an estimated IC50 of 0.2 mg/kg. LY207320, an inhibitor of 5 alpha-reductase in vitro, was weakly active in vivo and did not achieve greater than 45% inhibition at high doses (greater than 200 mg/kg, s.c.). Tissue uptake of [3H]-T was also inhibited by LY207320, which may contribute to its inhibitory activity on accessory sex organ growth in the rat.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Esophagography and esophagoscopy. Comparison in the examination of patients with head and neck carcinoma.

We carried out a prospective, double-blind study at three institutions, comparing esophagography with esophagoscopy for the detection of simultaneous cancer of the esophagus in patients with other squamous cell cancers of the head and neck. The goal was to determine whether esophagography and esophagoscopy are necessary for the examination of patients before treatment. One hundred eighty-two patients were studied; both examinations were done in 148 patients. Twenty-one patients could not undergo esophagoscopy; esophagography was inadequate in 9 patients; 4 patients could have neither examination. Concordance was noted between the two procedures in 86.5% of patients. Sixty-five percent were normal, and 21.5% were abnormal. One esophageal cancer was found in this series that was diagnosed by both methods. Our data suggest that esophagoscopy and esophagography may be complementary in evaluating squamous cell carcinoma of the head and neck in patients before treatment. Esophagography alone was useful in patients in whom esophagoscopy could not be performed.

Adult↗

Endocrine effects of a new histamine H2-receptor antagonist, nizatidine (LY139037), in the male rat.

A new orally active histamine H2-receptor antagonist, nizatidine (LY139037), was evaluated in male rats for effects on mechanisms regulating accessory sex organ growth and function. Cimetidine antagonized androgen binding to cytosolic receptors in vitro while nizatidine had no effect. Nizatidine and cimetidine were administered at the ED50, 5 X ED50, or 10 X ED50 doses for inhibition of gastric acid secretion previously determined using in vivo dog and rat models. The relative potencies of both agents to antagonize histamine H2-receptor-mediated gastric acid secretory responses have been confirmed in human clinical trials. Neither nizatidine nor cimetidine antagonized the in vivo uptake or nuclear translocation of radiolabeled androgen into the hypothalamic-preoptic-amygdala, pituitary, or ventral prostate. Nizatidine, given at doses equal to and 10 X the ED50 gastric acid secretion inhibitory values, and cimetidine (10 X ED50 value) had no effect on the response of male accessory sex organs to a submaximally stimulating dose of androgen in castrated rats. High doses of dietary nizatidine (greater than 500 mg/kg-day) administered for 6 months did not alter intact rat male accessory sex organ weights or circulating androgen levels relative to untreated controls. Acute administration of either nizatidine or cimetidine produced transient elevations in plasma prolactin (PRL) levels. Cimetidine was more potent and consistent than nizatidine in producing these increases in circulating PRL. The data described herein support the contention that unlike cimetidine, nizatidine is not a pharmacological antagonist of androgen action and has less of a stimulatory effect upon plasma prolactin. Taken together, these studies indicate that in the male rat, nizatidine exhibits a large therapeutic index between its gastric antisecretory activity and potential endocrinological effects.

Androgens↗

Antagonism of androgen and estrogen effects in guinea pig seminal vesicle epithelium and fibromuscular stroma by keoxifene (LY156758).

Using separated epithelium (SVE) and fibromuscular stroma (SVM) of guinea pig seminal vesicle, the antihormonal effects of daily subcutaneous administration (14 and 28 days) of the benzothiophene keoxifene (LY156758; [6-hydroxy-2-(4-hydroxyphenyl)benzo(b) thien-3-yl] [4-(2-1-piperidinyl) ethoxyl] phenyl) methanone hydrochloride) in intact, castrate, and androgen/estrogen-maintained castrate animals was evaluated. The compound was devoid of agonist activity in castrated males, in that the compound had no stimulatory effect on SVM wet weight or DNA content. In vitro cytosolic binding of [3H]estradiol (E2) in the SVM was decreased in a concentration-dependent manner by keoxifene, but the compound did not perturb the binding of [3H]dihydrotestosterone (DHT) in the SVM or SVE. Likewise, keoxifene administration to castrated males treated with exogenous steroids antagonized the estrogen-induced hyperplastic response of the SVM, whereas no interference with androgen-induced growth of the SVM or SVE was observed. Keoxifene treatment of intact male guinea pigs produced regression of the androgen-sensitive SVE as well as the androgen/estrogen-sensitive SVM. Keoxifene-induced decreases in guinea pig serum testosterone levels were associated with this activity. Histological analysis of the seminal vesicle under these conditions suggests androgen deprivation. These findings indicate that keoxifene is a physiological antagonist of androgen action in the intact male guinea pig. The pure estrogen antagonist properties of keoxifene and its ability to decrease accessory sex organ epithelium and fibromuscular stroma in vivo suggest potential applications of the benzothiophenes in the medical management of prostatic neoplasia.

Androgen Antagonists↗

Comments on "Acoustic Transfer Characteristics in Human Middle Ears Studied by a SQUID Magnetometer Method" [J. Acoust. Soc. Am. 82, 1646-1654 (1987)].

The study by Brenkman et al. [J. Acoust. Soc. Am. 82, 1646-1654 (1987)] of malleus umbo and anterior crus of stapes displacement in 14 human temporal bones shows a mean -7.3-dB/oct slope above 1.0 kHz for stapes displacement in response to a 80-dB SPL input at the eardrum. The slope they obtained for midfrequency (1.0-4.0 kHz) stapes displacement is significantly flatter than what was found previously [Gyo et al., Acta Otolaryngol. 103, 87-95 (1987); Gundersen, Prostheses in the Ossicular Chain (University Park, Baltimore, MD, 1971); Kringlebotn and Gundersen, J. Acoust. Soc. Am. 77, 159-164 (1985); Vlaming and Feenstra, Clin. Otolaryngol. 11, 353-363 (1986a)]; in these studies, stapes displacement rolled off at -12.0 to -14.9 dB/oct above 1.0 kHz. It appears that their mean midfrequency stapes displacement slope has been flattened by some unusual results in a small number of ears. Possible reasons for these results are discussed.

Acoustic Stimulation↗

Correlation of the in vivo anticoagulant, antithrombotic, and antimetastatic efficacy of warfarin in the rat.

Fibrin formation has been hypothesized to be an element of the metastatic process in cancer, and pharmacological interference with such fibrin formation has been proposed as a means of antimetastatic therapy. We have tested this hypothesis through an in vivo study of warfarin in two independent rat disease models--a model of chemical-injury-induced arterial thrombosis, and a model of spontaneous metastasis. We found 0.50 mg/kg-day warfarin to be uniformly lethal after two weeks treatment. The chronic dose of 0.25 mg/kg-day was non-toxic and produced effective anticoagulation and marked antithrombotic and antimetastatic activity. The 0.125 mg/kg-day dose produced a reduction in factor IIc (50%) and factor VIIc (70%), and resulted in statistically significant antithrombotic and antimetastatic activity. The 0.0625 mg/kg-day dose failed to reduce the vitamin K-dependent clotting factors, and failed to produce any antithrombotic or antimetastatic effects. The substantial correlation (very similar dose-response effects) among the anticoagulant, antithrombotic and antimetastatic efficacies of warfarin in the rat suggests that anticoagulation provides the pharmacological mechanism underlying both the antithrombotic and the antimetastatic effects. The poor therapeutic index we observed in the rat may be the attribute which limits the efficacy of warfarin in the treatment of human cancer.

Animals↗

Wound tension in rhytidectomy. A preliminary report.

In superficial musculoaponeurotic system (SMAs) suspension procedures in rhytidectomy, skin closing tension seems to be lower at the main anchor points than with non-SMAS procedures. To evaluate this clinical impression, a preliminary investigation into the effect of SMAS suspension on wound closing tension was undertaken. Intraoperatively, skin closing tension was compared with and without SMAS plication sutures at the two key anterior and posterior skin anchor points. Results confirmed decreased tension with SMAS plication. Anteriorly in the temporal part of the scalp, a significant difference of 87 g was demonstrated. Posteriorly in the occipital hairline, a significant difference of 96 g was demonstrated. Individual differences in tension were more pronounced in patients with prominent SMAS laxity than in those patients with mild laxity.

Aged↗

The role of pars flaccida in human middle ear sound transmission.

The role of the pars flaccida in middle ear sound transmission was studied with the use of twelve otoscopically normal, fresh, human temporal bones. Peak-to-peak umbo displacement in response to a constant sound pressure level at the tympanic membrane was measured with a noncontacting video measuring system capable of repeatable measurements down to 0.2 micron. Measurements were made before and after pars flaccida modifications at 18 frequencies between 100 and 4000 Hz. Four pars flaccida modifications were studied: (1) acoustic insulation of the pars flaccida to the ear canal with a silicone rubber baffle, (2) stiffening the pars flaccida with cyanoacrylate cement, (3) decreasing the tension of the pars flaccida with a nonperforating incision, and (4) perforation of the pars flaccida. All of the modifications (except the perforation) had a minimal effect on umbo displacement; this seems to imply that the pars flaccida has a minor acoustic role in human beings.

Acoustic Stimulation↗

Modification of the deltopectoral flap for pharyngoesophageal reconstruction.

These modifications minimize flap loss, fistulae, and stenosis, and make the final stage easier to perform. The need for periodic dilation with Maloney dilators may be required; however, we do not consider this a significant complication. The goal is a predictable result with a low complication rate so that oral feedings can begin 5 weeks after laryngopharyngectomy, and postoperative radiotherapy may be started at 6 weeks. The need for three stages may appear excessive; however, three planned stages are better than three or more unplanned stages that result in flap loss or dehiscence.

Esophagus↗

Pharmacologic enhancement of composite graft survival.

The use of composite grafts in facial reconstruction has been limited by a history of unpredictable survival beyond a radius of 1 cm. Numerous pharmacologic agents have been employed to improve the survival of random skin flaps but, to our knowledge, have not been studied in composite grafts. Three agents that have demonstrated efficacy in random skin flap survival, intravenous heparin sodium, topical nitroglycerin, and intramuscular methylprednisolone sodium succinate, were investigated for their effect on composite graft survival. Using a rabbit model, full-thickness auricular composite grafts were created, rotated 180 degrees, and reattached. At 21 days, all grafts were assessed for area of survival and postexcisional weight. Animals receiving 30 mg/kg of intramuscular methylprednisolone sodium succinate daily, during the first four postoperative days, demonstrated a significant increase in graft survival compared with controls. Heparin and nitroglycerin produced no change compared with controls. Furthermore, the only grafts to achieve 100% survival were found in the group treated with methylprednisolone.

Animals↗

Stapes vibration produced by the output transducer of an implantable hearing aid. Experimental study.

The function of the output transducer of an implantable hearing aid was assessed by applying it to the stapes head in seven fresh human cadaver temporal bones while observing vibration of the stapes under a microscope with the use of a stroboscope and a video measuring system. The transducer was a 5 X 1.2 X 0.6-mm piezoelectric ceramic bimorph with attached metal holder. Transmission changed with the amount of force holding the transducer tip on the head of the stapes. An optimal connection between the vibrator and stapes produced better transmission than a tight or loose connection. Gluing the connection with cyanoacrylate cement decreased transmission in the optimal connection, produced no change in the tight connection, and improved transmission in the loose connection. Comparison of stapes displacement produced by the vibrator at 1 kHz with that produced by normal middle-ear sound transmission revealed that the vibrator-induced stapes displacement for a 1 V peak-to-peak input was equivalent to that produced by a sound stimulus of 90-dB sound pressure level at the tympanic membrane.

Ear Ossicles↗