Biomedical subjects
Publications and source records attributed to C D Wright.
This report describes the clinical, radiographic, and surgical findings in a patient with a rare postoperative complication, the postpneumonectomy syndrome. To our knowledge, it is the first reported case of postpneumonectomy syndrome after left pneumonectomy in a patient with a left-sided aortic arch.
We report a case of testicular carcinoma invading the inferior vena cava. Tumor invasion was diagnosed via endovascular biopsy. This is the first known report of a diagnosis of this entity using endovascular biopsy. We also review the literature on diagnosis and management of inferior vena caval involvement by testicular cancer.
We recently reported that GS-X pump activity, as assessed by ATP-dependent transport of the glutathione-platinum complex and leukotriene C4, and intracellular glutathione (GSH) levels were remarkably enhanced in cis-diamminedichloroplatinum(II) (cisplatin)-resistant human leukemia HL-60 cells (Ishikawa, T., Wright, C. D., and Ishizuka, H. (1994) J. Biol. Chem. 269, 29085-29093). Now, using Northern hybridization and RNase protection assay, we provide evidence that the multidrug resistance-associated protein (MRP) gene, which encodes a human GS-X pump, is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells, whereas amplification of the MRP gene is not detected by Southern hybridization. Culturing HL-60/R-CP cells in cisplatin-free medium resulted in reduced MRP mRNA levels, but these levels could be induced to rise within 30 h by cisplatin and heavy metals such as arsenite, cadmium, and zinc. The increased levels of MRP mRNA were closely related with enhanced activities of ATP-dependent transport of leukotriene C4 (LTC4) in plasma membrane vesicles. The glutathione-platinum (GS-Pt) complex, but not cisplatin, inhibited ATP-dependent LTC4 transport, suggesting that the MRP/GS-X pump transports both LTC4 and the GS-Pt complex. Expression of gamma-glutamylcysteine synthetase in the cisplatin-resistant cells was also co-induced within 24 h in response to cisplatin exposure, resulting in a significant increase in cellular GSH level. The resistant cells exposed to cisplatin were cross-resistant to melphalan, chlorambucil, arsenite, and cadmium. These observations suggest that elevated expression of the MRP/GS-X pump and increased GSH biosynthesis together may be important factors in the cellular metabolism and disposition of cisplatin, alkylating agents, and heavy metals.
BACKGROUND: Parenchyma-sparing bronchoplastic procedures have altered the management of benign bronchial stenoses and low-grade neoplasms of the airway. Reliable techniques are available to allow sleeve resection of any lobe or the main bronchus and thus maximize preservation of lung parenchyma. METHODS: Between 1972 and 1995 we performed 100 bronchoplastic procedures on 99 patients. Seventy-eight patients had low-grade or benign tumors including carcinoid, mucoepidermoid, and fibrous histiocytomas. Seven patients had inflammatory lesions including histoplasmosis and tuberculosis. Two patients had idiopathic stenosis. Thirteen patients had stenoses due to prior trauma or previous operation. Resection involved the bronchus alone in 51 cases. Sleeve lobectomies were done in 49 patients. RESULTS: There were two postoperative deaths in complicated patients. Major complications occurred in 3 patients. Sixteen patients presented preoperatively with postobstructive pneumonia but had no major postoperative complications. Long-term follow-up (mean, 88 months) reveals only one instance of tumor recurrence (adenoidcystic carcinoma) and progressive stenosis in 1 patient with idiopathic stenosis. CONCLUSIONS: Lung-sparing bronchoplastic operations are the procedures of choice in anatomically suited patients with low-grade malignant tumors of the airway and benign bronchial stenosis.
OBJECTIVE: Postpneumonectomy bronchopleural fistula remains a morbid complication after pneumonectomy. The incidence, risk factors, and management of postpneumonectomy bronchopleural fistula were evaluated in 256 consecutive patients who underwent pneumonectomy with a standardized suture closure of the bronchus. METHODS: Pneumonectomy was performed for lung cancer in 198 cases, for other malignancy in 20 cases, and for benign causes in 38 cases. The bronchial stump was closed with interrupted simple sutures to emphasize a long, membranous wall flap. All stumps were covered by autologous tissue. RESULTS: The incidence of postpneumonectomy bronchopleural fistula was 3.1%. Risk factors for bronchopleural fistula were the need for postoperative ventilation (p = 0.0001) and right pneumonectomy (p = 0.04). Five patients had bronchopleural fistulas as a result of pulmonary complications necessitating ventilation; the cause in the remaining three cases appeared to be technical. Reclosure was successful in five cases (mean postoperative day 12); in one case a pinhole fistula was healed by drainage alone. Two (25%) of the eight patients who had bronchopleural fistulas died. CONCLUSIONS: Careful, sutured closure of the main bronchus with a tissue buttress after pneumonectomy yields excellent results. The most significant risk factor for bronchopleural fistula is a pulmonary complication necessitating ventilation. Contrary to previous reports, reclosure is usually successful even if performed late.
TIF is a rare and often fatal complication of tracheostomy. Bleeding from the trachea after tracheostomy demands urgent investigation. Bronchoscopy is the diagnostic procedure of choice. Bedside control of hemorrhage by cuff overinflation or digital arterial compression can be lifesaving. Prompt operation with division of the innominate artery and separation of the trachea from the divided artery by viable tissue is indicated. Neurologic complications are rare.
It was previously reported that 3-alkoxybenzo[b]thiophene-2-carboxamides exemplified by 1, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide, decreased the adherence of neutrophils to activated endothelial cells by inhibiting the upregulation of the adhesion molecules E-selectin and ICAM-1 on the surface of the endothelium. This finding is extended here to a series of 3-thiobenzo[b]thiophene-2-carboxamides and also heterocyclic analogs of 1, including benzofurans, indoles, and napthalenes. The compounds that inhibited the expression of E-selectin and ICAM-1 had the same effect on the expression of VCAM-1. PD 144795, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide 1-oxide (44), the sulfoxide analog of 1, was orally active in several models of inflammation. The in vitro and in vivo activity of PD 144795 resided predominately in the S-enantiomer.
CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3, 4-thiadizole-2(3H)-thione, choline salt) was evaluated for its effect on arachidonic acid metabolism by human neutrophils in response to different stimuli. Leukotriene B4 (LTB4) release in response to calcium ionophore A23187 was 15 to 35 fold greater than the responses to N-formyl-methionyl-leucyl-phenylalanine (FMLP) or serum-opsonized zymosan (SOZ), respectively, while the thromboxane B2 (TXB2) release response was similar for the three stimuli tested. CI-986 inhibited the release of LTB4 and TXB2 in response to A23187 with IC50s of 63.4 and 1.6 microM, respectively. In comparison, the compound inhibited SOZ-stimulated LTB4 release with an IC50 of 11.2 microM, while having no effect on TXB2 at concentrations up to 100 microM. Conversely, CI-986 inhibited FMLP-stimulated LTB4 release by 42% at 100 microM, while inhibiting TXB2 release with an IC50 of 0.13 microM. These results demonstrate a stimulus-dependent inhibitory effect of CI-986 on human neutrophil eicosanoid metabolism.
BACKGROUND: Treatment of esophageal perforation, especially when diagnosed late, remains controversial. METHODS: Twenty-eight patients were treated for thoracic esophageal perforation with reinforced primary repair regardless of time of presentation. RESULTS: Fifteen patients were treated early (< 24 hours) with no deaths. Two had contained postoperative leaks, which healed. Thirteen were treated late (mean, 5.5 days) with four deaths (3 with healed repairs). Postoperative leaks occurred in 7 patients; of the leaks, 4 healed, 2 became a controlled fistula, and 1 required reoperation. Primary healing with preservation of the native esophagus was achieved in 25 patients (89%). Among the 18 patients without evidence of sepsis preoperatively, post-operative leaks developed in 2 (11%). Ten patients had evidence of sepsis preoperatively, and postoperative leaks developed in 7 (70%). CONCLUSIONS: Patients who present with sepsis have an increased risk of postoperative leak and therefore should have the repair buttressed. Overall mortality was 14% and no deaths were due to persistent leaks or mediastinal sepsis. Reinforced primary repair retains the native esophagus and avoids the need for later reconstructive operations. In the absence of a nondilatable stricture or cancer, reinforced primary repair should be performed for most thoracic esophageal perforations, early or late.
Electron paramagnetic resonance (EPR) studies were conducted to examine oxygen radical generation following PMN activation by N-formyl-1-methionyl-1-leucyl-1-phenylalanine (fMLP) in the presence or absence of phalloidin and cytochalasin B (CB), agents which stabilize or disrupt f-actin, or taxol and colchicine which stabilize and disrupt microtubule cytoskeletal structures respectively. PMN oxyradical production was monitored using the spin trap 5,5-dimethyl-1-pyrroline n-oxide (DMPO). PMN when unstimulated, treated with phalloidin (10(-6)-10(-8)M), CB (10(-6)-10(-8)M), taxol (10(-6)-10(-8)M), or colchicine (10(-6)-10(-8)M), did not produce a detectable DMPO signal. Stimulation with fMLP (10(-6)M), however, resulted in a significant hydroxyl radical signal which was augmented by PMN treatment with CB (10(-6)-10(-7)M, p < 0.05) and attenuated following PMN treatment with phalloidin (10(-6)-10(-7)M, p < 0.05). Interestingly, colchicine treatment (10(-6)-10(-8)M) significantly attenuated fMLP-mediated oxyradical production, whereas taxol (10(-6)-10(-7)M) significantly increased PMN oxyradical production. These data suggest that stabilization of f-actin and disruption of microtubules attenuates the PMN oxidative burst, whereas disruption of f-actin and stabilization of microtubules increases radical production. These findings suggest cytoskeletal domain-specific contributions to PMN oxidative activity.
The preparation of hydroxylamine analogs of 2,6-di-tert-butylphenols (DTBP) and the inhibition of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) by these compounds is discussed.
A total of 503 patients underwent 521 tracheal resections and reconstructions for postintubation stenosis from 1965 through 1992. Fifty-three had had prior attempts at surgical resection, 51 others had undergone various forms of tracheal or laryngeal repair, and 45 had had laser treatment. There were 251 cuff lesions, 178 stomal lesions, 38 at both levels, and 36 of indeterminate origin. Sixty-two patients with major laryngeal injuries required complete resection of anterior cricoid cartilage and anastomosis of trachea to thyroid cartilage, and 117 had tracheal anastomosis to the cricoid. A cervical approach was used in 350, cervicomediastinal in 145, and transthoracic in 8. Length of resection was 1.0 to 7.5 cm. Forty-nine had laryngeal release to reduce anastomotic tension. A total of 471 patients (93.7%) had good (87.5%) or satisfactory (6.2%) results. Eighteen of 37 whose operation failed underwent a second reconstruction. Eighteen required postoperative tracheostomy or T-tube insertion for extensive or multilevel disease. Twelve died (2.4%). The most common complication, suture line granulations (9.7%), has almost vanished with the use of absorbable sutures. Wound infection occurred in 15 (3%) and glottic dysfunction in 11 (2.2%). Five had postoperative innominate artery hemorrhage. Resection and reconstruction offer optimal treatment for postintubation tracheal stenosis.
Successful management of chronic postoperative bronchopleural fistula remains a challenge for thoracic surgeons. Forty-two patients (33 referred from other institutions) were treated for major postoperative bronchopleural fistula since 1978. Factors associated with bronchopleural fistula included right pneumonectomy (n = 23), left pneumonectomy (n = 8), long bronchial stump (n = 16), pneumonia (n = 13), radiation therapy (n = 12), stapled bronchial closure (n = 8), prolonged mechanical ventilation (n = 7), recurrent carcinoma (n = 6), and tuberculosis (n = 2). Patients had undergone an average of 3.3 surgical procedures to correct their bronchopleural fistulas during a mean interval of 24 months before our treatment. Bronchopleural fistulas were located in the right main bronchial stump (n = 23), left main bronchial stump (n = 8), right lobar bronchial stumps (n = 10), and tracheobronchial anastomosis (n = 1). Thirty-five patients were treated by suture closure of the bronchial stump, buttressed with vascularized pedicle flaps of omentum (n = 19), muscle (n = 13), or pleura (n = 2). In seven cases, direct suture closure was not possible, and omental (n = 6) or muscle (n = 1) flaps were sutured over the bronchopleural fistula. Suture closure without pedicle coverage was performed successfully in one case. Initial repair of the fistula was successful in 23 of 25 patients treated with omentum, in nine of 14 patients treated with muscle and in neither of two patients treated with pleural flaps. In nine patients with persistent or recurrent bronchopleural fistula after our initial repair, four underwent a second procedure (three successful) and five were managed with drainage only. The fistula was successfully closed in 11 of 12 patients who had received high-dose radiation therapy (nine with omentum). Overall, successful closure of bronchopleural fistula was achieved in 36 of 42 patients (86%). Four in-hospital deaths resulted from pneumonia and sepsis, two in patients with recurrent bronchopleural fistula after pleural flap closure. In 16 patients the empyema cavity was obliterated during definitive repair of the fistula. The cavity resolved with drainage in four others, nine had draining cavities at follow-up, and one was lost to follow-up. Ten patients required a total of 17 Clagett procedures and one had a delayed myoplasty. Direct surgical repair of chronic bronchopleural fistula may be achieved in most patients after adequate pleural drainage by suture closure and aggressive transposition of vascularized pedicle flaps. Omentum is particularly effective in buttressing the closure of bronchopleural fistulas.
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The ATP-dependent glutathione S-conjugate export pump, named GS-X pump, has been shown to eliminate a potentially cytotoxic glutathione-platinum (GS.Pt) complex from tumor cells, thereby modulating glutathione (GSH)-associated resistance to cis-diamminedichloroplatinum(II) (cisplatin) (Ishikawa, T., and Ali-Osman, F. (1993) J. Biol. Chem. 268, 20116-20125). The present study provides evidence that the GS-X pump is functionally overexpressed in cisplatin-resistant human promyelocytic leukemia HL-60 (HL-60/R-CP) cells, in which the cellular GSH level was substantially enhanced. Indeed, the rate of ATP-dependent transport of the GS.Pt complex, measured with plasma membrane vesicles, was about 4-fold greater in HL-60/R-CP cells than in HL-60 cells. Three membrane proteins with apparent molecular masses of 200, 110, and 70 kDa were overexpressed in HL-60/R-CP cells, whereas P-glycoprotein (MDR1) was not immunologically detected in the membrane preparations from resistant and sensitive cells. Unlike in HL-60 cells, increased numbers of intracellular vesicles were observed in the cytoplasm of HL-60/R-CP cells. Fluorescence microscopy with syn-(CICH2,CH3)-1,5-diazabicyclo-[3.3.0]-octa-3,6-dione-2,8-dione (monochlorobimane) revealed that the fluorescent glutathione S-conjugate accumulated in intracellular vesicles of the cisplatin-resistant cells in an energy-dependent manner. The GS-X pump is suggested to contribute to vesicle-mediated excretion of GSH-drug conjugates from cells. In addition, both HL-60 and HL-60/R-CP cells underwent cell differentiation in response to 12-O-tetradecanoylphorbol-13-acetate, retinoic acid, and dimethyl sulfoxide, resulting in proliferation arrest as well as a remarkable decrease in the c-myc mRNA levels. After cell differentiation, a significant decrease was observed in the activity of ATP-dependent transport of the GS.Pt complex in membrane vesicles prepared from both HL-60/R-CP and HL-60 cells. These results suggest that the expression of the GS-X pump in both cisplatin-resistant and -sensitive cells is related to cell proliferation.
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A variety of benzylideneoxazoles, -thiazoles, and -imidazoles derived from 2,6-di-tert-butylphenol were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. The target compounds exhibit varying degrees of selectivity toward the two enzymes. Several compounds are orally active in the rat carageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models. Structure-activity relationships are discussed. From this work, (Z)-5-[[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-methylene]-2-imino-4-thiazolidinone methanesulfonate salt (CI-1004) was identified as a potent dual inhibitor of 5-lipoxygenase (IC50 = 0.77 microM) and cyclooxygenase (IC50 = 0.39 microM), with oral activity (ID40 = 0.6 mg/kg) in the rat MFE model of inflammation.
The effects of long-term tamoxifen therapy on bone remodeling were studied in 41 women with breast cancer, 22 treated with tamoxifen for a minimum of 15 months (mean 33) and 19 untreated. Transiliac crest bone biopsies were obtained and a comprehensive histomorphometric analysis performed using a semiautomatic image analysis system. There were no statistically significant differences between the two groups in bone area, osteoid perimeter and area, or osteoid width. Mineral appositional rate, adjusted appositional rate, and mineralization lag time were also similar in the two groups; however, tissue-based bone formation rate was significantly lower in the tamoxifen-treated women (p = 0.05) and the remodeling period significantly longer (p < 0.05). Mean and maximum resorption cavity depth and cavity area were significantly reduced in the tamoxifen-treated patients compared to the untreated patients (p < 0.01, p < 0.01, and p < 0.03, respectively). Calculated and directly measured indices of cancellous bone structure were similar in the two groups, although the data indicated a trend toward greater connectedness in the tamoxifen-treated group. These data indicate that tamoxifen does not exert an antiestrogenic effect on bone remodeling in the human and are consistent with a weak estrogenic effect.