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M J Lee

Publications and source records attributed to M J Lee.

At least 19 recordsLinked to original sources
PubMed1995

Physicochemical, pharmacokinetic and pharmacodynamic evaluation of liposomal tacrolimus (FK 506) in rats.

PURPOSE: Tacrolimus (FK 506) is a new potent immunosuppressant. Because of poor water solubility, the conventional intravenous dosage forms of FK 506 (C-FK 506) contain surfactants such as HCO-60 which may cause adverse effects. We sought a liposomal formulation of FK 506 (L-FK 506) containing endogenous phospholipids to target drug to the spleen, a major organ controlling the immune system. METHODS: L-FK 506, consisting of 0.1 micron diameter vesicles of phosphatidylcholine and phosphatidylglycerol (molar ratio 9:1) and 7.5 mole% drug, was evaluated for in vitro stability. The intravenous disposition profile, spleen distribution, and immunosuppression of L-FK 506 was compared with that of C-FK 506 in the rat after single doses of 0.3 mg/kg. RESULTS: The L-FK 506 showed good in vitro stability. L-FK 506 exhibited an increased volume of distribution at steady-state (Vss) (from 3.41 to 14.71 L/kg) and increased mean residence time (MRT) (from 2.83 to 16.07 hr). FK 506 concentrations in spleen were increased by 40% at 10 hr after administration of the liposomal formulation. The pharmacodynamics of L-FK 506, evaluated by the extent of inhibition of splenocyte proliferation, was comparable to that of C-FK 506. CONCLUSIONS: Liposomal FK 506 may be an improved dosage form for parenteral use.

Animals↗
PubMed1995

An imaging algorithm for the differential diagnosis of adrenal adenomas and metastases.

OBJECTIVE: The purpose of this study was to develop an algorithm using CT and chemical-shift MR imaging for the characterization of adrenal masses in patients with a primary cancer and no other evidence of metastatic disease. SUBJECTS AND METHODS: Thirty-three patients with 37 adrenal masses (19 metastases, 18 adenomas), all of whom had a known primary cancer, were studied with noncontrast CT and chemical-shift MR imaging (1.5 T). Lesion size and density in Hounsfield units (H) were determined by CT. Adrenal signal intensity normalized to that of spleen was used to calculate adrenal-spleen ratio (ASR), defined as the percentage of signal remaining in the opposed-phase image relative to the in-phase image. Lesions less than or equal to 0 H were classified as benign, lesions greater than 20 H were regarded as malignant, and lesions between 0 and 20 H were regarded as indeterminate. Diagnoses were confirmed by biopsy (for 19 lesions) or by follow-up imaging (for 18 lesions). An imaging algorithm was derived by determining the relative value of CT and MR imaging for diagnosing the lesions. The reimbursement rates for CT-guided biopsy and MR imaging of the abdomen were obtained from Medicare. RESULTS: All 13 lesions of 0 or less H were correctly classified as benign by CT. ASR was less than 70 in 10 of these 13. In another 13 lesions, H was greater than 20; all were malignant and all had an ASR greater than 80. Of 11 CT-indeterminate lesions, four of five adenomas had an ASR less than 70, and four of six metastases had an ASR greater than 80. Two malignant lesions had ASRs between 70 and 80 and were diagnosed by biopsy findings. One CT-indeterminate adenoma had an ASR of 84 and was diagnosed by biopsy findings. The reimbursement rate by Medicare is similar for CT-guided biopsy with pathologic interpretation and for MR imaging of the abdomen. CONCLUSION: An algorithm was developed for diagnosis of adrenal lesions that uses the density reading on noncontrast CT as the first step, with chemical-shift MR imaging for CT-indeterminate lesions. In this algorithm, lesions of 0 H or less may be regarded as benign and further work-up is not required. Lesions with a density greater than 20 H are likely malignant and should be biopsied when the result will influence management. For CT-indeterminate lesions, we recommend chemical-shift MR imaging. An ASR threshold of 70 indicates a benign lesion, and no further workup is required in these patients. Lesions with an ASR greater than 70 should have a biopsy performed, depending on the clinical situation. The above algorithm is cost-effective and reduces the number of biopsies required without reducing the sensitivity of detecting malignant lesions.

Adrenal Cortex↗
PubMed1992

Statin, a protein specifically present in nonproliferating cells, is a phosphoprotein and forms a complex with a 45-kilodalton serine/threonine kinase.

The protein statin is found in nuclei of nonproliferating cells. Here we report that statin is a phosphoprotein, phosphorylated at serine residues in cultured cells. During immunoprecipitation with anti-statin (S44) antibody, a 45-kDa protein co-precipitates with the 57-kDa statin. In vitro kinase assays demonstrate that the S44 immunoprecipitates can phosphorylate, besides statin, immunoglobulins, enolase, and casein, at either serine or serine/threonine residues. Kinase assays with immunoprecipitated proteins performed on casein- or enolase-impregnated gels show that these substrates are phosphorylated by the 45-kDa (p45) protein. When the S44 immunoprecipitates from human cultured fibroblasts with different in vitro life-spans were compared, the p45 kinase activity was present only in young nongrowing and senescent cells, but not in young growing ones. In other cell cultures, the kinase is detected only in protein complexes precipitated from quiescent 3T3 cells, but not from cycling 3T3 cells or from transformed human glioma (U251-4) cells. Cell fractionation studies, indicating that the phosphorylating activity of S44 immunoprecipitates correlates both qualitatively and quantitatively with the amount of statin present, provide strong evidence that in vivo statin is specifically associated with the p45 kinase. These results suggest that the nonproliferation-specific nature of statin is indeed related to the phosphorylated property of this protein and maybe contributed by the associated kinase.

3T3 Cells↗
PubMed1992

N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo.

Certain (arylsulfonyl)urea hypoglycemic drugs exemplified by chlorpropamide (CP) are known to interact pharmacologically with alcohol (ethanol) to elicit a chlorpropamide-alcohol flushing (CPAF) reaction that is reminiscent of the disulfiram-ethanol reaction (DER). In the present structure-activity study, designed to elucidate the mechanism of inhibition of aldehyde dehydrogenase (AlDH) by CP, we discovered that the N1-methoxy derivative of CP 2a was a potent inhibitor of AlDH in vivo similar in activity to that of the N1-ethyl derivative 2b. Both 2a and 2b can release n-propyl isocyanate, a known inhibitor of AlDH, nonenzymatically. However, (arylsulfonyl)carbamates that are structurally analogous to 2a were also active inhibitors of AlDH, whereas the corresponding (arylsulfonyl)carbamate analogs of 2b were uniformly without activity. We propose a mechanism of bioactivation of 2a and its analogs that involves initial O-demethylation followed by disproportionation and solvolysis of the intermediate formed to release nitroxyl, the putative inhibitor of AlDH.

Aldehyde Dehydrogenase↗
PubMed1992

Prodrugs of nitroxyl as inhibitors of aldehyde dehydrogenase.

In the preceding paper, analogs of chlorpropamide with an OMe substituent on the sulfonamide nitrogen were shown to inhibit aldehyde dehydrogenase (AlDH), and it was postulated that these compounds were bioactivated by O-demethylation to release nitroxyl (HN = O, nitrosyl hydride), which is an inhibitor of AlDH. Further evidence for the production of nitroxyl from compounds with O-acyl instead of OMe on the sulfonamide nitrogen is now presented. Thus, nitrous oxide (N2O), the end product of nitroxyl dimerization and disproportionation, was found to be generated on alkaline or enzymatic hydrolysis of N,O-diacylated N-hydroxyarylsulfonamides. Since the latter compounds strongly inhibit yeast AlDH in vitro after bioactivation by an esterase intrinsic to this enzyme, nitroxyl generated from these compounds must be the common intermediate that inhibits AlDH.

Aldehyde Dehydrogenase↗
PubMed1992

Expression of the non-proliferation-specific protein, statin, in grey matter neuroglia of the aging rat brain.

The monoclonal antibody, S-44, identifies statin, a 57 kDa nuclear protein which appears to be expressed exclusively in non-proliferating cells. We previously demonstrated that in the aging rat corpus callosum approximately one third of neuroglia are statin-negative, suggesting the existence of an unexpectedly large cycling glial compartment. In the present study, double-labeling of individual cultured astroglia with [3H]thymidine and the S-44 antibody provided direct evidence for the non-proliferative status of statin-positive cells. The S-44 antibody was used to immuno-localize statin and thereby determine growth fractions for neuroglia in various grey matter regions of 3-, 18-, and 33-month-old rats. The proportion of statin-negative (cycling) cells for the three ages combined ranged from about 24% in the molecular layer of the dentate gyrus to 38% in the molecular layer of the parietal cortex. In most regions surveyed total glial counts and proportions of statin-positive and -negative cells did not vary significantly as a function of advancing age. These results suggest that (i) as in corpus callosum, pools of cycling neuroglia in various grey matter regions are far in excess of those previously predicted by S-phase labeling with [3H]thymidine or BUdR, and (ii) ratios of proliferating-to-quiescent neuroglia are tightly regulated over much of the animal's adult life span. These conserved ratios may be used as markers of normal CNS senescence, and deviations thereof may indicate the presence and extent of intervening neuropathologic processes.

Aging↗
PubMed1992

Modulation of the levels of cytochromes P450 in rat liver and lung by dietary lipid.

This study was undertaken to investigate the effect of dietary lipid on the regulation of several constitutive P450 isozymes. Male Sprague-Dawley rats with body weights of 130-140 g were fed either a 20% corn oil (CO) diet or a fat-free (FF) diet for 4 days following 2 days of fasting. Using liver microsomes, the catalytic activities and immunochemically detectable protein levels of P450s 1A1 and 2, 2A1, 2B1 and 2, 2C11, 2E1, and 3A were determined. The microsomes from rats fed the 20% CO diet exhibited 2-fold higher levels in N-nitrosodimethylamine demethylase activity and P450 2E1 protein than those from rats fed the FF diet. The CO group also showed 2.5-fold higher levels in 6 beta-hydroxylation of testosterone and P450 3A protein than the FF group. In contrast, the CO diet did not affect the immunodetectable level of P450 2C11 protein and its catalytic activities such as benzphetamine demethylase activity and 2 alpha-hydroxylation of testosterone. P450 1A1 was not detectable in either group, but 1A2 was 2.5-fold higher in the CO group than in the FF group. In the liver, the P450 2B1 level was very low in both groups as measured by pentoxyresorufin dealkylase activity and the protein level, whereas 2B2 was 2.5-fold higher in the CO diet group. In lung microsomes from rats fed different amounts of CO, an inverse relationship was observed between the P450 2B1 level and the dietary CO level. The results suggest that the constitutive levels of P450 isozymes are modulated by dietary lipid in a selective manner; the levels of hepatic P450s 1A2, 2B2, 2E1, and 3A were regulated positively but the level of pulmonary P450 2B1 was suppressed by dietary lipid.

Animals↗
PubMed1992

The ultrastructural immunolocalization of gamma-glutamyltranspeptidase in rat lung: correlation with the histochemical demonstration of enzyme activity.

gamma-Glutamyltranspeptidase (gamma-GT) was localized in slices of rat lung, at the ultrastructural level, by pre-embedding immunogold labelling. Antiserum was raised against the protein purified from rat kidney. The enzyme was found to be concentrated on the lumenal surface of the non-ciliated ("Clara") cells of the bronchiolar epithelium and, to a lesser degree, on the surface of type II alveolar pneumocytes. This immunological localization was consistent with the distribution of reaction product, in both slices and resin sections incubated to demonstrate gamma-GT activity. gamma-GT is probably involved in the utilization of reduced glutathione (GSH) present in the fluid lining the airway epithelium.

Animals↗
PubMed1992

Primary retroperitoneal neoplasms: how close can we come in making the correct diagnosis.

The primary retroperitoneal tumors form a rare and diverse group of neoplasms, the origin of which is independent of the various retroperitoneal organs and unrelated to systemic diseases, such as lymphomas, lymphadenopathy, or metastases. Radiologic investigation, mainly cross-sectional imaging and, to a lesser extent, angiography is essential in the diagnosis and management of these tumors. The radiologist often is challenged to identify the origin and specific tissue composition of the imaged neoplasms. When the radiologic findings are combined with patient information and clinical data, the correct diagnosis may be made in many cases. Imaging-guided percutaneous needle biopsy further enhances the diagnostic yield of the various imaging modalities by establishing the diagnosis without the need for exploration.

Adolescent↗
PubMed1992

Early surgical débridement of symptomatic pancreatic necrosis is beneficial irrespective of infection.

In order to assess the recent trend of nonoperative management of pancreatic necrosis, we reviewed 82 variables in 73 consecutive patients with symptomatic necrotizing pancreatitis. The mortality rate for the series was 25% (18 of 73). The only preintervention variables that correlated with mortality were APACHE II score greater than 15 (p = 0.01), preintervention blood transfusion (p less than 0.001), respiratory failure (p less than 0.001), and shock (p less than 0.01). Patients who developed recurrent sepsis following the initial intervention had a significantly higher mortality rate (17 of 34) than those who did not (1 of 39) (p less than 0.001). The rate of recurrent sepsis varied widely among individual surgeons and correlated with APACHE II score. The presence of infected versus noninfected necrosis did not correlate significantly with outcome. When percutaneous radiologically guided drainage was the initial therapeutic modality (n = 6), recurrent sepsis requiring surgical drainage inevitably occurred. Patients treated with percutaneous drainage (often in combination with surgical drainage) had a longer hospital stay (82 versus 42 days, p less than 0.001), spent more days in the intensive care unit (31 versus 6 days, p less than 0.001), and required more days of total parenteral nutrition (57 versus 27 days, p less than 0.001) than those treated solely by surgical means. We conclude that aggressive initial surgical débridement should be the first step in managing symptomatic pancreatic necrosis and that the presence of infection should not be the sole determinant of intervention.

Bacterial Infections↗
PubMed1992

Massive ascites after leuprolide acetate administration for the treatment of leiomyomata uteri.

The administration of GnRH-a for decreasing the size of uterine leiomyomata is tolerated by most of our patients with a minimum of side effects and difficulty. An unusual case of pseudo-Meigs' syndrome developed after a single dose of depot LA that resulted in an emergent operation in this young woman. The treatment of large leiomyomata uteri with GnRH-a warrants careful clinical surveillance.

Adult↗
PubMed1992

Palliation of malignant bile duct obstruction with metallic biliary endoprostheses: technique, results, and complications.

Expandable metallic stents were placed in 34 patients with pathologically proved malignant bile duct obstruction to determine ease of insertion, benefits of a one-stage insertion, and cost-effectiveness relative to conventional plastic stents. Thirty-eight strictures, ranging in length from 1 to 7 cm (mean, 3.2 cm), were present in the 34 patients. Strictures were located in the lower common bile duct (n = 22), middle of the common bile duct (n = 6), and hilar confluence (n = 10). In 13 patients (38%) metallic stents were placed at the time of initial biliary drainage (one-stage procedure), while the remaining patients underwent stent placement within 1-7 days of biliary drainage (two-stage procedure). Biliary obstruction was relieved in 31 of 34 patients (91%). Three patients died within 14 days of stent insertion of unrelated causes, without any change in biliary status. Mean duration of follow-up for all patients was 5.3 months (range, 0.5-14 months). Four episodes of stent occlusion occurred in three patients (12% occlusion rate); each episode was treated successfully. The average length of hospital stay for patients who underwent a one-stage procedure was 13 days (range, 3-33 days) and was 20 days (range, 9-42 days) for patients who underwent a two-stage procedure. The facility of one-step insertion, low occlusion rate, and the many strategies available for treatment of occluded stents make metallic stents an attractive alternative to conventional plastic stents in palliating patients with malignant biliary obstruction.

Adenoma, Bile Duct↗
PubMed1992

Acute complicated pancreatitis: redefining the role of interventional radiology.

Computed tomographic (CT) scans in 30 patients who had undergone percutaneous drainage for acute complicated pancreatitis were retrospectively studied to determine the role of percutaneous drainage. Fifty-nine collections were percutaneously drained in these 30 patients. Eighty-one catheters were placed in the 59 collections (average, 1.4 catheters per patient). Patients required an average of three catheter manipulations, seven abdominal CT scans, 5 weeks of catheter drainage, a mean hospital stay of 82 days (range, 42-122 days), and a mean intensive care unit stay of 31 days (range, 1-62 days). Percutaneous intervention was successful in 14 patients, partially successful in four, and unsuccessful in eight. A temporizing effect was seen in four patients. Percutaneous intervention was successful in one of 10 central (pancreas and lesser sac areas) collections and 28 of 49 peripheral collections. Surgical debridement was necessary in 16 patients because of failed or incomplete percutaneous drainage. Complications occurred in five patients, and the mortality rate was 33%. Drainage of central areas should initially be performed by a surgeon, while peripheral collections should be drained percutaneously as they develop.

Acute Disease↗
PubMed1992

Measurement of tissue carcinoembryonic antigen levels from fine-needle biopsy specimens: technique and clinical usefulness.

Levels of tissue carcinoembryonic antigen (CEA) in 54 abdominal fine-needle biopsy specimens from 50 patients were measured to ascertain the use of tissue CEA levels in diagnosis of malignancy. Biopsy was performed in the following sites: liver (n = 34), retroperitoneum (n = 8), adrenal gland (n = 3), pancreas (n = 2), omentum (n = 2), pelvis (n = 2), spleen (n = 2), and stomach (n = 1). Histologic findings proved malignancy in 39 patients and benign disease in 11 patients. In these 11 patients, the mean levels of tissue CEA were lower than the normal level of serum CEA (3 ng/mL). Tissue CEA levels were higher than serum CEA levels in nine patients with colonic carcinoma and in 12 of 16 patients with noncolonic CEA-secreting malignancies. Four patients with noncolonic CEA-secreting malignancies had tissue CEA levels within the normal range (less than 3 ng/mL). Tissue CEA levels were also normal in 13 patients with various non-CEA-secreting tumors. Tissue CEA levels may prove useful in biopsy of necrotic or cystic lesions and assessment of response to ablative therapy for colon metastases.

Adult↗
PubMed1992

Sclerotherapy of malignant pleural effusion through sonographically placed small-bore catheters.

Pleural sclerosis after drainage with a small-bore catheter was performed in 21 patients with malignant pleural effusions. Intrapleural catheters 7- to 24-French in size were placed by using sonographic guidance. Tetracycline (18 patients) and bleomycin (four patients) were used as sclerosing agents (one patient had both). Clinical and radiologic follow-up was available on all patients until they died (range, 2 weeks to 25 months; mean, 3.6 months). Pleural sclerosis was successful in 15 (71%) of 21 patients. Two patients in whom pleurodesis failed had pleural sclerosis repeated, with one success and one failure. All of the failures were in patients in whom the amount of chest-tube drainage was more than 100 ml/day. Pleurodesis with tetracycline was painful in six patients; no pain was associated with use of bleomycin. Small pneumothoraces developed in four patients at the time of chest-tube placement, without consequence. A superimposed infection that developed in a patient having continuous drainage of pleural fluid was successfully treated with antibiotics. Pleural sclerotherapy can be performed through sonographically placed small-bore catheters with results comparable to those seen with large-bore, surgically placed catheters.

Adult↗
PubMed1992

Treatment of bile duct stones by laser lithotripsy: results in 12 patients.

We used a pulsed tunable dye laser (operating at 60 mJ per pulse, 504-nm wavelength) to fragment large (0.8-4.5 cm) stones retained in the hepatic ducts or common bile duct in 12 patients after cholecystectomy. Attempts to extract stones via a T-tube or endoscope had been unsuccessful in all patients. In nine of 12 patients, all stone fragments were successfully eliminated during the initial treatment. In one patient, fragmentation occurred but debris remained, requiring endoscopic stenting. Pseudomonas sepsis developed in this patient 30 days after the procedure and was treated by extraction of the stone fragments. Fragments remaining after lithotripsy were cleared at the same sitting by using saline flushing or endoscopic or percutaneous basket extraction. In two of 12 patients, the treatment was unsuccessful because of laser malfunction. The treatment was performed without complications, except for clinically insignificant hyperamylasemia, which occurred in two patients. Our experience suggests that laser lithotripsy offers a safe alternative for nonsurgical treatment of large retained biliary stones for patients in whom traditional treatments have failed.

Aged↗
PubMed1992

Percutaneous chemical gallbladder sclerosis after laser-induced cystic duct obliteration: results in an experimental model.

OBJECTIVE: Chemical gallbladder sclerosis has been attempted as a way to defunctionalize the gallbladder in patients who have undergone nonsurgical removal of gallstones and who are unable to undergo surgical/laparoscopic cholecystectomy. The purpose of this investigation was threefold: to study an animal model for chemical sclerosis of the gallbladder with 95% ethanol and 3% sodium tetradecyl sulfate, to attempt chemical sclerosis immediately after percutaneous cystic duct obliteration by laser thermocoagulation, and to assess histopathologic changes in the gallbladder after sclerosis. MATERIALS AND METHODS: Percutaneous cholecystostomy and laser thermocoagulation of the cystic duct was performed in 13 pigs. Eight pigs underwent immediate gallbladder sclerosis with 95% ethanol and 3% sodium tetradecyl sulfate while two pigs received 95% ethanol only. The remaining three pigs served as controls. The cholecystostomy catheter was removed immediately after the procedure. All animals were sacrificed 6 weeks after laser thermocoagulation. Multiple sections through the gallbladder, which included the adjacent liver, the cystic duct, and the common bile duct, were obtained for histologic examination. RESULTS: At autopsy, the gallbladder in all 10 animals who underwent gallbladder sclerosis was reduced in size compared with controls. In all treated animals, the gallbladder mucosa was denuded; however, in nine of 10 cases reepithelialization had occurred. Complete sclerosis without reepithelialization was achieved in one pig who received both ethanol and sodium tetradecyl sulfate. In the two animals who received ethanol only, the depth of wall necrosis around the gallbladder lumen was less than in those pigs who received both ethanol and sodium tetradecyl sulfate. No pigs showed signs of hepatic necrosis or injury to the common bile duct. CONCLUSION: Cystic duct laser thermocoagulation allows immediate gallbladder sclerotherapy without injury to the common bile duct. Sclerosis with ethanol and sodium tetradecyl sulfate results in denudation of the gallbladder mucosa. However, a single therapeutic session with immediate removal of the cholecystostomy catheter was inadequate for gallbladder ablation in this model because of reepithelialization.

Animals↗