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Biomedical subjects

M J Miller

Publications and source records attributed to M J Miller.

At least 145 records · Page 8Linked to original sources
PubMed1997

Bone formation by three-dimensional stromal osteoblast culture in biodegradable polymer scaffolds.

Bone formation was investigated in vitro by culturing stromal osteoblasts in three-dimensional (3-D), biodegradable poly(DL-lactic-co-glycolic acid) foams. Three polymer foam pore sizes, ranging from 150-300, 300-500, and 500-710 microns, and two different cell seeding densities, 6.83 x 10(5) cells/cm2 and 22.1 x 10(5) cells/cm2, were examined over a 56-day culture period. The polymer foams supported the proliferation of seeded osteoblasts as well as their differentiated function, as demonstrated by high alkaline phosphatase activity and deposition of a mineralized matrix by the cells. Cell number, alkaline phosphatase activity, and mineral deposition increased significantly over time for all the polymer foams. Osteoblast foam constructs created by seeding 6.83 x 10(5) cells/cm2 on foams with 300-500 microns pores resulted in a cell density of 4.63 x 10(5) cells/cm2 after 1 day in culture; they had alkaline phosphatase activities of 4.28 x 10(-7) and 2.91 x 10(-6) mumol/cell/min on Days 7 and 28, respectively; and they had a cell density that increased to 18.7 x 10(5) cells/cm2 by Day 56. For the same constructs, the mineralized matrix reached a maximum penetration depth of 240 microns from the top surface of the foam and a value of 0.083 mm for mineralized tissue volume per unit of cross sectional area. Seeding density was an important parameter for the constructs, but pore size over the range tested did not affect cell proliferation or function. This study suggests the feasibility of using poly(alpha-hydroxy ester) foams as scaffolding materials for the transplantation of autogenous osteoblasts to regenerate bone tissue.

Alkaline Phosphatase↗
PubMed1997

Ectopic bone formation by marrow stromal osteoblast transplantation using poly(DL-lactic-co-glycolic acid) foams implanted into the rat mesentery.

Porous biodegradable poly(DL-lactic-co-glycolic acid) foams were seeded with rat marrow stromal cells and implanted into the rat mesentery to investigate in vivo bone formation at an ectopic site. Cells were seeded at a density of 6.83 x 10(5) cells/cm2 onto polymer foams having pore sizes ranging from either 150 to 300 to 710 microns and cultured for 7 days in vitro prior to implantation. The polymer/cell constructs were harvested after 1, 7, 28, or 49 days in vivo and processed for histology and gel permeation chromatography. Visual observation of hematoxylin and eosin-stained sections and von Kossa-stained sections revealed the formation of mineralized bonelike tissue in the constructs within 7 days postimplantation. Ingrowth of vascular tissue was also found adjacent to the islands of bone, supplying the necessary metabolic requirements to the newly formed tissue. Mineralization and bone tissue formation were investigated by histomorphometry. The average penetration depth of mineralized tissue in the construct ranged from 190 +/- 50 microns for foams with 500-710-microns pores to 370 +/- 160 microns for foams with 150-300-microns pores after 49 days in vivo. The mineralized bone volume per surface area and total bone volume per surface area had maximal values of 0.28 +/- 0.21 mm (500-710-microns pore size, day 28) and 0.038 +/- 0.024 mm (150-300-microns, day 28), respectively. As much as 11% of the foam volume penetrated by bone tissue was filled with mineralized tissue. No significant trends over time were observed for any of the measured values (penetration depth, bone volume/surface area, or percent mineralized bone volume). These results suggest the feasibility of bone formation by osteoblast transplantation in an orthotopic site where not only bone formation from transplanted cells but also ingrowth from adjacent bone may occur.

Animals↗
PubMed1997

Pharmacokinetics and disposition of methyl t-butyl ether in Fischer-344 rats.

Methyl t-butyl ether (MTBE) is a commonly used octane booster in gasoline. This study examines the pharmacokinetics and disposition of MTBE in Fischer-344 rats after i.v., oral, dermal and inhalation routes of administration. Groups of male and female rats were given single i.v. (40 mg kg-1), oral (40 and 400 mg kg-1) and dermal (40 and 400 mg kg-1 in occluded chambers) doses of [14C]MTBE. For inhalation studies, rats were exposed nose-only for 6 h to low (400 ppm), high (8000 ppm) and repeated daily 6-h low (400 ppm x 15 days) chamber concentrations of [14C]MTBE. Blood, expired air, and excreta (urine and feces) were collected at selected times up to 7 days post-dose and quantified for 14C content. Plasma concentrations of MTBE and t-butyl alcohol (TBA) were quantified and mean values used for pharmacokinetic analysis. The mean total recoveries of 14C ranged from 91 to 105%. Methyl t-butyl ether was rapidly and completely absorbed after oral and inhalation exposures; dermal absorption was low. After all routes, MTBE was rapidly eliminated from blood (ti = 0.5 h) by exhalation and metabolism to TBA. At the high doses, metabolism was saturated and the proportion of renal 14C excretion decreased relative to the pulmonary route. At 48 h post-exposure, virtually all of the 14C was eliminated. The major metabolites recovered in urine were 2-methyl-1,2-propanediol and alpha-hydroxyisobutyric acid. There were no significant gender or route-dependent differences in the pharmacokinetics and disposition of MTBE.

Absorption↗
PubMed1997

Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the adult rat.

The sialomucin CD34 is expressed on human and mouse hematopoietic stem cells and is used as an important marker for isolating the hematopoietic stem/progenitor cells. The involvement of hepatic stem cells in liver regeneration under certain conditions in adult rats is now well supported. The objective of the present research was to explore the idea that CD34 might also be expressed on hepatic stem cell progeny. Polymerase chain reaction (PCR)-based cloning of rat CD34 was partially accomplished. During the hepatic stem cell activation (2-acetylaminofluorene/partial hepatectomy [AAF/PH] model), the CD34 transcripts were increased and reached the peak level between 9 and 12 days after partial hepatectomy when the progenitor cells (e.g., oval cells, early hepatocytes in basophilic foci, and intestinal type of cells) are most abundant. Both in situ hybridization and immunohistochemistry, using anti-mouse CD34 antibody, which recognizes the cytoplasmic domain, clearly showed the expression of CD34 on oval cells as well as on endothelial cells of large hepatic vessels. In addition, bile ductular epithelial (BDE) cells both in the AAF/PH model and in normal liver expressed CD34, suggesting a close relationship between BDE cells and the hepatic stem-cell compartment. Taken together, the data indicate that CD34 would, similar to its role in the hematopoietic system, be an important probe for characterizing the cellular biology of the hepatic stem-cell compartment.

2-Acetylaminofluorene↗
PubMed1997

Peroxynitrite-induced apoptosis in epithelial (T84) and macrophage (RAW 264.7) cell lines: effect of legume-derived polyphenols (phytolens).

Peroxynitrite (ONOO-) has been proposed as a mediator of gut inflammation and as an inducer of cell death by apoptosis. Phytolens (PHY), a water-soluble extract of polyphenolic antioxidants from nonsoy legumes (Biotics Research Corp, patent pending), was evaluated as a cytoprotective agent in human colonic (T84) and murine macrophage (RAW 264.7) cell lines. In the antioxidant testing, PHY showed a significant free radical scavenging ability against 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and superoxide (O2.) radicals with an IC50 of 4.44 and 5.87 microg/ml against DPPH and O2., respectively. Apoptosis (DNA fragmentation) was measured by an ELISA technique. Cells were exposed to oxidative stress by treating them with peroxynitrite (100-300 microM) for 4 h in the presence and absence of PHY. Peroxynitrite elicited a dose-dependent increase in DNA fragmentation in both cell lines compared to the control group receiving decomposed ONOO-. PHY (10, 30, or 50 microg/ml) significantly attenuated the degree of apoptosis in T84 cells induced by ONOO- (P < 0.05). PHY (10-100 microg/ml) did not directly affect T84 cell viability or induce apoptosis after 4 h or overnight exposure. RAW 264.7 cells exposed to PHY alone (>30 microg/ml) for 4 h displayed decreased cell viability (P < 0.05) and increased apoptosis (P < 0.05). Phytolens may have beneficial effects on inflammation by attenuating peroxynitrite-induced apoptosis. The sparing of epithelial cells while compromising the viability of macrophages suggests that PHY may be beneficial in autoimmune disorders.

Animals↗
PubMed1997

Treatment of medically and surgically refractory angina pectoris with high thoracic epidural analgesia: initial clinical experience.

Surgical sympathectomy can relieve symptoms of angina in patients with refractory angina. However, in these high-risk patients this thoracic surgery may result in significant morbidity and mortality rates. Similar sympathetic blockade can now be produced with high thoracic epidural analgesia (HTEA). From September 1995 to August 1996, we treated 10 consecutive patients with HTEA. These eight men and two women, aged 58 +/- 5 years, with extensive three-vessel coronary disease and ejection fractions of 40% +/- 5%, had New York Heart Association (NYHA) class IV angina despite medical therapy, including nitrates, beta-blockade, calcium channel blockade, and narcotics. HTEA was performed at the T1 through T4 levels with a catheter placed either percutaneously or surgically, with radiographic confirmation of catheter placement with an epidurogram or computed tomography scan. Bupivacaine (0.25% to 0.5%), an amide local anesthetic, was given as a bolus through the epidural catheter and then maintained either as a continuous infusion or an intermittent rebolus. The epidural catheter remained in place for 7 days in four patients, 14 days in three patients, and > or =90 days in three patients. Before consideration for HTEA, each patient was deemed unsuitable for or refused coronary bypass surgery and percutaneous coronary angioplasty and had NYHA class IV symptoms of angina. Seven of 10 patients required intravenous nitroglycerin and heparin and were unable to be discharged from the intensive care unit because of anginal symptoms. Two of these seven patients also required an intraaortic balloon pump for symptom control. After HTEA, all 10 patients had improved symptoms, with five patients improving to NYHA class II symptoms and five improving to NYHA class III. All seven patients receiving intravenous nitroglycerin, heparin, or intraaortic balloon pump support had these modalities discontinued. Six of these seven patients were subsequently discharged from the hospital. One patient died from a non-HTEA related cause. There were no HTEA-related deaths. There were three catheter-related complications necessitating catheter removal during 12 months of HTEA use. Local infection developed in one patient, one had catheter occlusion caused by fibrosis, and one patient had chronic back pain exacerbation from a paraspinous muscle spasm. No patient had a myocardial infarction or a significant arrhythmia. In patients with otherwise intractable angina pectoris, HTEA is an effective modality that produces symptomatic relief of angina pectoris and allows increased activity level.

Adrenergic beta-Antagonists↗
PubMed1997

Characteristics of hypoxemic episodes in very low birth weight infants on ventilatory support.

OBJECTIVE: To characterize hypoxemic episodes in very low birth weight infants with mechanically ventilated lungs and to describe their natural history and the effect of body position. STUDY DESIGN: Tidal volume, respiratory rate, oxygen saturation, heart rate, and body movement were continuously recorded in 10 very low birth weight infants who exhibited episodes of hypoxemia during mechanical ventilation (birth weight, 810 +/- 133 gm; postconceptional age at study, 30 +/- 1.6 weeks). Frequency of hypoxemic episodes was compared in both prone and supine positions. RESULTS: Seventy-eight percent of hypoxemic episodes began in association with body movement as well as heart rate acceleration. Thereafter the spontaneous and delivered minute ventilation both decreased during the first 15 seconds of hypoxemia. The former decrease was due to a significant decrease in frequency of spontaneous respiration, whereas the latter was associated with a significant decrease in delivered tidal volume. Minute ventilation returned to normal before recovery of oxygenation. A change in body position from supine to prone significantly decreased the frequency of hypoxemic episodes. CONCLUSION: Hypoxemic episodes in infants who are on ventilatory support are characterized by (1) movement and cardioacceleration at initiation; (2) a decrease in both spontaneous and delivered minute ventilation, and (3) a lower incidence in the prone position. We speculate that spontaneous movement during sleep can trigger cardiopulmonary reflex responses that initiate and propagate these episodes.

Heart Rate↗
PubMed1997

Adrenomedullin binds with high affinity, elevates cyclic AMP, and stimulates c-fos mRNA in C6 glioma cells.

The effects of adrenomedullin (ADM) on C6 glioma cells were investigated. [125I]ADM bound with high affinity (Kd = 24 nM) to a single class of sites (Bmax = 36,000/cell) in C6 cells. Specific [125I]ADM binding was inhibited with high affinity by ADM (IC50 value of 10 nM) but not ADM(22-52) or pro-adrenomedullin N-terminal 20 peptide (PAMP). By RT-PCR, ADM receptors were detected in C6 cells. ADM elevated cAMP (ED50 value of 10 nM) whereas PAMP and ADM(22-52) did not. ADM stimulated transiently c-fos mRNA in a concentration-dependent manner. Monoclonal antibody G6, which neutralizes ADM, significantly inhibited C6 proliferation and decreased the ability of ADM to elevate c-fos mRNA. These data suggest that ADM is a regulatory peptide of C6 cells.

Adrenomedullin↗
PubMed1997

Peroxynitrite-induced apoptosis in T84 and RAW 264.7 cells: attenuation by L-ascorbic acid.

The free radicals nitric oxide and superoxide react to form peroxynitrite (ONOO-), a potent cytotoxic oxidant. This study was designed to evaluate whether addition of L-Ascorbic acid (AsC) into the culture medium decreases peroxynitrite-induced apoptosis in human intestinal epithelial (T84) and murine macrophage (RAW 264.7) cell lines. In Experiment 1, T84 and RAW 264.7 cells were divided in two protocols: (1) treated with 100-300 microM ONOO- and incubated for 4 h, and (2) treated with 10-100 microM ONOO- and incubated overnight (14 h). In Experiment 2, T84 and RAW 264.7 cells were treated with 300 microM ONOO- and 500 microM AsC and incubated for 4 h. In Experiment 3, T84 and RAW 264.7 cells were preincubated for 2 h with 500 microM AsC then exposed to 300 microM ONOO- for 4 h. Cell viability (necrosis) was assessed by trypan blue dye exclusion. Apoptosis was quantified with a cell death detection ELISA assay. In the 4 h protocol, ONOO- induced apoptosis in T84 and RAW 264.7 cells, at levels of 100-300 microM. Concentrations of ONOO- greater than 300 microM caused necrosis. In contrast, extension of the protocol to 14 h indicated that ONOO- induced apoptosis at lower concentrations (50;-75 microM), with concentrations > 75 microM resulting in necrosis. AsC administered to the media or with preincubation plus washout, decreased peroxynitrite-induced apoptosis in T84 and RAW 264.7 cells. These results indicate that ONOO- may contribute to the pathophysiology of gut inflammation by promoting cell death and ascorbic acid may protect against peroxynitrie-induced damage.

Animals↗
PubMed1997

New aromatic inhibitors of EPSP synthase incorporating hydroxymalonates as novel 3-phosphate replacements.

A new, aromatic analogue of the EPSP synthase enzyme reaction intermediate 1 has been identified, which contains a 3-hydroxymalonate moiety in place of the usual 3-phosphate group. This simplified inhibitor was readily prepared in five steps from ethyl 3,4-dihydroxybenzoate. The resulting tetrahedral intermediate mimic 9 is an effective, competitive inhibitor versus S3P with an apparent Ki of 0.57 +/- 0.06 microM. This result demonstrates that 3-hydroxymalonates exhibit potencies comparable to aromatic inhibitors containing the previously identified 3-malonate ether replacements and can thus function as suitable 3-phosphate mimics in this system. These new compounds provide another example in which a simple benzene ring can be used effectively in place of the more complex shikimate ring in the design of EPSP synthase inhibitors. Furthermore, the greater potency of 9 versus the glycolate derivative 10 and the 5-deoxy-analog 11, again confirms the requirement for multiple anionic charges at the dihydroxybenzoate 5-position in order to attain effective inhibition of this enzyme.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed1997

Peroxynitrite-induced apoptosis in human intestinal epithelial cells is attenuated by mesalamine.

BACKGROUND & AIMS: Peroxynitrite (PN), a potent oxidant, has been implicated in the pathogenesis of gut inflammation and epithelial cell apoptosis. The aim of this study was to investigate mesalamine, a standard therapy for inflammatory bowel disease, to see if it attenuates PN-induced cytotoxicity in human intestinal epithelial cells and if mesalamine directly interacts with PN or its precursor, nitric oxide. METHODS: T84 and HT29 cells were divided in several protocols: mesalamine was administered 2 hours before, simultaneously, or 30 minutes after PN. T84 cells, grown in filter chamber inserts, were used to determine if basolateral or apical administration of PN initiated apoptosis and epithelial barrier function. The effects of mesalamine on PN decomposition and NO half-life were determined. RESULTS: Mesalamine resulted in a dose-dependent decrease in PN-induced apoptosis, whether mesalamine was administered before (>10 micromol/L; IC50, 16 micromol/L), simultaneously (25-200 micromol/L; IC50, 24 micromol/L), or 30 minutes (200 micromol/L) after PN exposure. Mesalamine protected the epithelial barrier function of T84 cells against PN. Mesalamine rapidly degraded PN, whereas the half-life of NO was not affected. CONCLUSIONS: The beneficial effects of mesalamine in the treatment of inflammatory bowel disease may involve an attenuation of PN-induced cell injury and apoptosis through direct and indirect mechanisms without affecting NO levels.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Viral taxonomy.

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Humans↗
PubMed1997

Adjuvant therapy: the effects on microvascular lower extremity reconstruction.

Adjuvant therapy and microsurgery have allowed advances in surgical extirpation of lower extremity neoplasms. This retrospective study was designed to evaluate the microvascular transfer for lower extremity reconstruction in patients receiving pre- or post-operative irradiation and chemotherapy alone and in combination. Over a 5-year period, 24 free tissue transfers were performed in 22 patients undergoing surgical resection with adjuvant therapy for lower extremity neoplasms. There were 13 male and 9 female patients with an average age of 51 years. The latissimus dorsi muscle was most commonly transferred (N = 15). Eighteen tumors received pre- and three received postoperative radiotherapy. Two tumors received a combination of radiotherapy and brachytherapy. Pre- and/or postoperative chemotherapy was used in 14 patients. Twelve of these patients had both chemo- and radiation therapy. A total of six complications occurred, with no flap loss. Complications were evenly distributed among adjuvant regimens. All patients who underwent attempted limb salvage were able to ambulate postoperatively, except for 1 patients who had local recurrence. In conclusion, adjuvant therapy did not increase the complication rate for free tissue transfer in the lower extremity. Adjuvant therapy did not require alterations in the free tissue transfer and, similarly, free tissue transfer did not alter adjuvant therapy. We believe that free tissue transfer in complicated wounds allows for better wound healing with adjuvant therapy rather than local or primary wound closure alone.

Adult↗
PubMed1997

Impacting cost and appropriateness of stress ulcer prophylaxis at a university medical center.

OBJECTIVE: To determine the appropriateness and medication cost of stress ulcer prophylaxis before and after a targeted educational intervention. DESIGN: In the preintervention cohort (phase 1), 264 patients were evaluated over 2 months, using stress ulcer prophylaxis guidelines developed by a comprehensive literature search. Targeted educational programs were subsequently used to inform trauma housestaff on appropriate usage of stress ulcer prophylaxis medications with emphasis on using sucralfate. The postintervention cohort (phase 2) involved concurrent evaluation of 279 patients. Length of inappropriate stress ulcer prophylaxis (i.e., did not meet approved guidelines) between phases was compared using a Student's t-test for independent samples (alpha = .05). SETTING: A 365-bed university medical center. PATIENTS: Patients admitted to any of the intensive care units and all patients who were placed on histamine-2-antagonists or sucralfate for stress ulcer prophylaxis. INTERVENTIONS: Educational intervention regarding appropriate stress ulcer prophylaxis directed at the trauma service. MEASUREMENTS AND MAIN RESULTS: Patient demographics in the two phases were similar and there was no difference in the number of patient risk factors for stress-induced bleeding. The mean length of inappropriate stress ulcer prophylaxis was 5.78 +/- 4.36 days in phase 1 and 4.66 +/- 3.10 days in phase 2 (p < .05). Eighty-nine patients in phase 1 received inappropriate stress ulcer prophylaxis for a drug cost of $2,272.00 (mean $25.53 +/- 25.52) compared with 90 patients in phase 2 with a drug cost of $1,417.00 (mean $15.75 +/- 13.06). Three patients in each phase had clinically important bleeding (hemodynamic compromise or transfusion); all were receiving ranitidine. The mean total cost (fixed and variable) of hospitalization was $69,288.00 and $74,709.00 for the three patients who bled in each phase compared with $19,850.00 and $15,812.00 for all patients admitted to the intensive care unit in phases 1 and 2, respectively. The mean length of hospital stay was 30.00 days and 29.33 days for the three patients who bled in each phase compared with 11.54 days and 10.27 days for all patients admitted to the intensive care unit in phases 1 and 2, respectively. CONCLUSIONS: Cost savings are associated with more appropriate stress ulcer prophylaxis. Clinically important bleeding is uncommon but results in prolonged hospital stays and increased costs.

Academic Medical Centers↗
PubMed1997

A comparison of resource costs for head and neck reconstruction with free and pectoralis major flaps.

A series of 178 immediate reconstructions with regional or distant tissue for repair of oropharyngeal defects caused by treatment of head and neck cancer was reviewed to determine whether reconstruction with free flaps was more or less expensive than reconstruction with regional myocutaneous flaps. In this series, three types of flaps were used: the radial forearm free flap (n = 89), the rectus abdominis free flap (n = 56), and the pectoralis major myocutaneous flap (n = 33). Resource costs were determined by adding all costs to the institution of providing each service studied using salaried employees (including physicians). The two free-flap groups were combined to compare free flaps with the pectoralis major myocutaneous flap, a regional myocutaneous flap. Failure rates in the two groups were similar (3.0 percent for pectoralis major myocutaneous flap, 3.4 percent for free flaps). The mean costs of surgery were slightly higher for the free flaps, but the subsequent hospital stay costs were lower. Therefore, the total mean resource cost for the free-flap group ($28,460) was lower than the cost for the myocutaneous flap group ($40,992). The pectoralis major myocutaneous flap may have been selected for more patients with advanced disease and systemic medical problems, contributing to longer hospitalization and added cost. Nevertheless, this study suggests that free flaps are not more expensive than other methods and may provide cost savings for selected patients.

Age Factors↗
PubMed1997

Adrenomedullin receptor expression in human lung and in pulmonary tumors.

Adrenomedullin (AM) is a multifunctional regulatory peptide that stimulates cyclic AMP production in many target tissues and is highly expressed in the lung. Analysis of the distribution of the recently cloned AM receptor (AM-R) by non-radioactive in situ hybridization revealed abundant expression in the basal cells of the airway epithelium and Type II pneumocytes. The expression of AM-R in the two cell types involved in epithelial regeneration of the lung suggests that AM may be relevant in such functions as organ development, wound repair, and epithelial turnover. AM-Rs are also synthesized in vivo and in vitro by a variety of tumor cells that also express the ligand, suggesting the existence of an autocrine loop that may be involved in tumor growth stimulation. The present findings suggest that the AM/AM-R regulatory system plays a major role in respiratory physiology and lung carcinogenesis and that new functions for AM remain to be identified.

Adenocarcinoma↗