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Biomedical subjects

M L Howard

Publications and source records attributed to M L Howard.

At least 19 recordsLinked to original sources
PubMed2001

The expression of the urokinase plasminogen activator system in metastatic murine osteosarcoma: an in vivo mouse model.

The role of urokinase plasminogen activator (uPA) in osteosarcoma is poorly understood. We examined the importance of uPA, its receptor, uPAR, and its inhibitor, PAI-1, in our in vivo model of metastatic osteosarcoma. Rodent osteosarcoma cells (UMR 106-01) were inoculated into the tibia of athymic mice. Animals were sacrificed and autopsied at 4 days to 5 weeks after inoculation. Tibiae and lungs were excised, fixed, and examined histologically and by in situ hybridization. Osteosarcoma development was associated with tibial swelling and lameness, and radiographic changes included osteolysis and new bone formation. Lung metastases developed spontaneously. In the tibial tumors, uPAR mRNA was expressed early (4 days), whereas uPA and PAI-1 mRNA increased as the tumor invaded the surrounding tissue (3 weeks). There was also an increase in the mRNA expression of the osteoblast-related genes, alpha1(I) procollagen and osteopontin, but not matrix Gla protein. Lung metastases also expressed mRNA for the uPA system and the bone-related proteins. We have produced a model of metastatic osteosarcoma, which typifies the characteristics of the human tumor. Our results suggest that the uPA system plays a role in the local aggressiveness and metastasis of osteosarcoma and, in particular, indicates a possible therapeutic role for uPAR antagonists in the treatment of osteosarcoma.

Animals↗
PubMed2000

Alcohol up-regulates UDP-glucuronosyltransferase mRNA expression in rat liver and in primary rat hepatocyte culture.

The interactions between alcohol and cytochrome P-450 enzymes have been well investigated. However, the data regarding the effect of alcohol on the regulation of UDP-glucuronosyltranferase (UGT) activity are less clear. The aim of the present study was to determine the role of alcohol in the regulation of UGT mRNA expression by using whole animal and primary cultured hepatocytes. Chronic ethanol feeding of rats significantly increased the expression of liver UGT1A1 mRNA to 177% of control. The mRNA levels for UGT1A5, UGT2B1 and UGT2B3 were also enhanced, but did not reach statistical significance. In cultured hepatocytes, treatment with either ethanol or isopentanol significantly increased the expression of UGT1A1, UGT1A5, UGT2B1, and UGT2B3 mRNAs, but to different degrees. The induction of UGT1A1 and UGT2B1 mRNAs by ethanol or isopentanol was time-dependent and maximal changes occurred at 48 h. The expression of UGT1A6 mRNA was not significantly modified by either ethanol or isopentanol. In conclusion, ethanol and isopentanol have direct roles in the regulation of UGT.

Animals↗
PubMed2000

Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate-glucuronosyltransferase expression in the rat.

BACKGROUND AND AIMS: Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) is a critical enzyme in the elimination of bilirubin and it also plays a role in the metabolism of bile acids. The aim of this study was to determine whether bilirubin and bile acids could modulate their own metabolism by regulating UGT levels in cultured rat hepatocytes. METHODS AND RESULTS: Incubation of hepatocytes with bilirubin (48 micromol/L) for 24 h significantly increased the mRNA expression of UGT1A1 and UGT1A5, two UGT isoforms responsible for the conjugation of bilirubin. The induction of UGT1A1 and UGT1A5 by bilirubin was concentration and time dependent. Treatment with chenodeoxycholic acid, cholic acid, deoxycholic acid, hyodeoxycholic acid and lithocholic acid at a concentration of 100 micromol/L for 48 h significantly enhanced the mRNA expression of UGT2B1, a UGT isoform responsible for the glucuronidation of bile acids. The UGT2B3 mRNA level was also increased by hyodeoxycholic acid. The regulation of UGT2B1 mRNA by chenodeoxycholic acid and hyodeoxycholic acid was dose and time dependent. CONCLUSION: Our results suggest that bilirubin and bile acids can induce UGT expression and as a result, these compounds may modulate their own metabolism. Such regulation could play a compensatory role in the pathological increased concentrations of these compounds in some hepatobiliary diseases.

Animals↗
PubMed1999

The effect of hormones on the expression of five isoforms of UDP-glucuronosyltransferase in primary cultures of rat hepatocytes.

PURPOSE: To investigate the direct effects of sex hormones, growth hormone, thyroid hormones and dexamethasone on the regulation of UDP-glucuronosyltransferase (UGT). METHODS: Rat hepatocytes were cultured on matrigel and treated with various hormones. Northern blot analysis was carried out using cDNA probes to family 1 and family 2 isoforms. RESULTS: Treatment with 10(-5) M testosterone increased the mRNA levels of UGT 2B1 by 29% and UGT2B3 by 32%. Incubation of growth hormone (10 mU) with hepatocytes suppressed the expression of UGT2B1 and UGT2B3 by 17% and 38%, respectively. T3 administration resulted in a time and dose-dependent effect on the expression of UGT 1 isoforms, with increased UGT1A6 by 70%, and decreased UGT1A1 by 38% and UGT1A5 by 35%. All UGT isoforms except UGT 1A6 studied in this assay were up-regulated by dexamethasone, but to different degrees. The regulation of UGT1A1 and UGT2B1 by dexamethasone was dose and time dependent, and the induction of dexamethasone in the expression of UGT1A1 and UGT2B1 was blocked by cycloheximide but not dichloro-1-D-ribofuranosylbenzimidazole. CONCLUSIONS: This study demonstrates that multiple hormones take part in the regulation of UGT mRNA expression in the rat and individual genes can be differentially modulated.

Animals↗
PubMed1998

Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase.

Human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase (PDE5A) cDNAs were isolated. A 3.1-kb composite DNA sequence assembled from overlapping cDNAs encodes an 875-amino-acid protein with a predicted molecular mass of 100012 Da (PDE5A1). Extracts prepared from yeast expressing human PDE5A1 hydrolyzed cGMP. This activity was inhibited by the selective PDE5 inhibitors zaprinast and DMPPO. PDE5A mRNA is expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung. A 5'-splice variant, PDE5A2, encodes an 833-amino-acid protein with eight unique amino acids at the amino terminus. PDE5A maps to chromosome 4q 25-27.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1990

The effect of preoperative endoscopy on recurrence and survival following surgery for colorectal carcinoma.

Numerous studies have elucidated the benefits of endoscopy before surgery for carcinoma of the colon and rectum. In patients with known colon cancer, the incidence of synchronous colon cancers is 1.5 to 7.6 per cent and synchronous colon polyps is 25 to 40 per cent. Standard barium contrast studies are inferior to endoscopic examination in detecting these synchronous lesions. Endoscopy has been shown to alter the planned surgical procedure in 11 to 13 per cent of patients with colorectal cancer. Nevertheless, some authors avoid preoperative endoscopy because of concern that neoplastic cells may be seeded throughout the colon during the examination. They fear that manipulation of the tumor may promote hematogenous or lymphatic spread. Our study seeks to demonstrate whether this concern is valid by comparing rates of local recurrence, distant metastases, and survival between patients who have undergone preoperative endoscopy with those who have not.

Adult↗
PubMed1989

Failure of preoperative staging to assess unresectability in M0 bronchogenic carcinoma.

Despite extensive preoperative staging, unresectability of a bronchogenic carcinoma may not be known until an exploratory thoracotomy is done. Failures in anatomic staging occur because of inability to detect local extent of hilar lesions and inability to detect small deposits of metastatic disease. At the University of South Carolina, nine of 75 patients who underwent thoracotomies were found to be unresectable. Using an extensive staging protocol, the "back out" thoracotomy rate can be reduced to a minimum whereas no patient is denied a chance for surgical cure.

Carcinoma, Bronchogenic↗
PubMed1989

The status of gastrointestinal endoscopy by surgeons in the Veterans Administration Healthcare System. A survey.

Between January and December 1987, a survey was sent to all Chiefs of Surgery in the Veterans Administration Healthcare System to assess current practices of surgical endoscopy. Results of this survey have shown a significant involvement in flexible gastrointestinal endoscopic procedures by most surgical services, especially those affiliated with major resident teaching programs. Total number of procedures performed, based on the projections of numbers of cases as reported, indicate that approximately 60,000 gastrointestinal endoscopic procedures are currently performed by surgeons each year in the Veterans Administration system in order to assess the greater than 90,000 gastrointestinal operations performed. Results of the survey also indicate that Chiefs of Surgery in the VA system enjoy a wide range of support by Gastrointestinal (GI) Medical Services in the VA, but generally this support is adequate. Part-time and full-time surgeons in the VA need to increase overall Continuing Education activities in endoscopy as well as increase the number of surgeons affiliated with organizations interested in endoscopic care.

Digestive System Surgical Procedures↗
PubMed1988

Resistance to atracurium in thermally injured rats. The roles of time, activity, and pharmacodynamics.

Thermal injury induces resistance to nondepolarizing muscle relaxants in patients. Because the mechanism of the resistance is unknown, the authors have sought to establish thermally injured rats as a suitable model for subsequent detailed studies of mechanisms. Two hundred twenty-five- to 250-g rats sustained a 30% total body surface area thermal injury while anesthetized with pentobarbital. Another group had sham injury. Animal activity was monitored both by periods of direct observation and by use of activity cages. At 10, 20, 30, 40, 60, and 90 days after injury, rats were anesthetized and ventilated and the strength of contraction of their gastrocnemius produced by supramaximal stimulation of the sciatic nerve was measured before and after a bolus of atracurium (2.0 mg/kg) was administered. The plasma concentration required to diminish contraction to 50% of the preceding value (Cp50) was determined by atracurium infusion. Animals displayed the greatest resistance to atracurium at 40 days. The Cp50 value was also greatest at this time. The protein binding of atracurium was identical for both sham and injured groups. Activity for thermally injured resistant rats and for sham animals was not different. It appears that pharmacodynamic mechanisms are involved, and inactivity and disuse atrophy are not necessary in rats for development of resistance to nondepolarizing muscle relaxants after thermal injury.

Animals↗
PubMed1988

Echocardiography in determining nonresectability of carcinoma of the lung. A brief report.

Numerous techniques are currently employed to determine resectability of lung cancer to spare patients an unnecessary thoracotomy. Echocardiography may be used to demonstrate invasion of hilar lesions into the heart. We report a case in which echocardiography demonstrated nonresectability of a lung cancer which was confirmed via a Chamberlain procedure.

Carcinoma, Small Cell↗