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Biomedical subjects

M Shea

Publications and source records attributed to M Shea.

At least 19 recordsLinked to original sources
PubMed2001

Phenotypic characterization of mice bred for high and low peak bone mass.

In humans, peak bone mineral density (BMD) is a highly heritable trait and a strong determinant of subsequent osteoporotic fracture risk. To identify the genetic factors responsible for variation in peak BMD, investigators have turned to animal models. In this study we examined the heritability of BMD acquisition and characterized differences in skeletal geometry, histomorphometry, and biomechanical competence between two lines of mice artificially selected for extremes of peak whole body BMD. F2 progeny from a cross between C57BL/6 and DBA/2 inbred strains was used as the foundation population to develop lines selected for either high or low BMD. Whole body BMD was measured by dual-energy X-ray absorptiometry (DXA). By the third generation of selection, highest-scoring BMD (HiBMD) mice exhibited 14% greater peak BMD than lowest-scoring BMD (LoBMD) mice. The mean realized heritability of peak BMD was 36%. Femoral shaft cortical area and thickness and vertebral cancellous bone volume (BV) were significantly greater (16-30%) in the HiBMD line compared with the LoBMD line. Mean cancellous bone formation rates (BFRs) were 35% lower in HiBMD mice compared with LoBMD mice. Failure load and stiffness in the femoral shaft, femoral neck, and L6 vertebrae were all substantially greater (by 25-190%) in HiBMD mice. Thus, these divergently selected murine lines serve to illustrate some of the means by which genetic mechanisms can affect skeletal structure and remodeling. Identification of the individual genes influencing peak BMD in this experimental system will likely reveal some of the genetic determinants of overall bone strength.

Analysis of Variance↗
PubMed1998

Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells.

Bone marrow contains a population of rare progenitor cells capable of differentiating into bone, cartilage, tendon, and other connective tissues. These cells, referred to as mesenchymal stem cells, can be purified and culture-expanded from animals and humans and have been shown to regenerate functional tissue when delivered to the site of musculoskeletal defects in experimental animals. To test the ability of purified human mesenchymal stem cells to heal a clinically significant bone defect, mesenchymal stem cells isolated from normal human bone marrow were culture-expanded, loaded onto a ceramic carrier, and implanted into critical-sized segmental defects in the femurs of adult athymic rats. For comparison, cell-free ceramics were implanted in the contralateral limb. The animals were euthanized at 4, 8, or 12 weeks, and healing bone defects were compared by high-resolution radiography, immunohistochemistry, quantitative histomorphometry, and biomechanical testing. In mesenchymal stem cell-loaded samples, radiographic and histologic evidence of new bone was apparent by 8 weeks and histomorphometry demonstrated increasing bone formation through 12 weeks. Biomechanical evaluation confirmed that femurs implanted with mesenchymal stem cell-loaded ceramics were significantly stronger than those that received cell-free ceramics. These studies demonstrate that human mesenchymal stem cells can regenerate bone in a clinically significant osseous defect and may therefore provide an alternative to autogenous bone grafts.

Animals↗
PubMed1997

Surgical delay for acute type A dissection with malperfusion.

BACKGROUND: An acute type A aortic dissection is considered a surgical emergency. Review of the risk factors for a type A dissection showed that preoperative malperfusion was associated with a 22% (2/9) intraoperative mortality and an 89% (8/9) hospital mortality. Intraoperative deaths were secondary to pulmonary failure resulting from capillary leak; the remaining patients died of multiorgan failure resulting from reperfusion injury. METHODS: The surgical delay approach was adopted for malperfused patients, and treatment in these patients included percutaneous reperfusion, with aortic fenestration and branch stenting where appropriate. Twenty patients had a type A dissection and malperfusion shown by pulsed-wave Doppler echocardiography, transesophageal echocardiography, or spiral computed tomographic scanning. Malperfusion was documented by angiography. After reperfusion, all patients' conditions were stabilized in the intensive care unit; intravenous beta-blockers were administered to decrease the maximum rate of increase of left ventricular pressure. Once patients completely recovered from the consequences of malperfusion, surgical repair was performed. Statistical comparison of the non-delay and delay groups was performed using Fisher's exact test and Student's t test. Multiple logistic regression analysis was used to establish independent predictors for mortality. RESULTS: The mean delay to repair was 20 days (2 to 67 days). Four (31%) patients were discharged home and readmitted for operation. Three patients (15%) died preoperatively, 1 of retrograde dissection and rupture and 2 of reperfusion injury. Seventeen underwent surgical repair, with two deaths (12%); 15 (75%) were discharged, with an average follow-up of 16.8 months (p < 0.003). Delay was the only independent predictor of outcome. CONCLUSIONS: Patients with an acute type A dissection and malperfusion should undergo percutaneous reperfusion, and surgical repair should be delayed until the reperfusion injury resolves.

Adult↗
PubMed1997

Biomechanical effects of operative nerve mobilization and transposition in a canine ulnar nerve model.

The purpose of this study was to evaluate the effects that operative mobilization and transposition of the ulnar nerve have on both neural excursion and mechanical properties. Twelve dogs underwent ulnar nerve transposition and postoperative casting. Four animals were killed at 3 weeks and four animals were killed at 6 weeks. Four animals had their casts removed at 3 weeks, were allowed to ambulate, and were killed at 6 weeks. Operated and contralateral control nerves were compared. Neural excursion was measured near the elbow and 12 cm proximally. The nerves were harvested and their mechanical properties determined. Repeated measures analysis of variance revealed significant differences in longitudinal excursion between control and experimental groups at both sites. Ultimate strain, ultimate strength, and modulus were significantly reduced in the experimental groups. No differences were seen in cross-sectional area or stiffness between control and experimental groups. Analysis revealed no independent effect of the rehabilitation method. Results of this study indicate that significant changes in neural excursion, ultimate strain, ultimate strength, and modulus occur following ulnar nerve mobilization and transposition and that these changes persist throughout the early postoperative period.

Analysis of Variance↗
PubMed1996

New features of the locust optic lobe: evidence of a role for nitric oxide in insect vision

The enzyme nitric oxide synthase can be localised by NADPH-diaphorase histochemistry. Here we have applied this technique to the optic lobe of the locust Schistocerca gregaria and revealed new features of the insect visual system. Extensive but locally intense staining is associated with identified tracts, distinct neuropiles and cell body groups, and a detailed analysis of stained elements is provided here. The most striking staining occurs in the anterior lobe of the lobula complex and its connection with the medulla by means of the dorsal uncrossed bundle. Eleven groups of cell bodies are identified and their contribution to fibre tracts and neuropile areas is described. Diaphorase-positive fibre tracts pass between all major subdivisions of the optic lobe, but there are no conspicuous fibre connections from the optic lobe to the brain. The widespread distribution of NADPH-diaphorase staining in the optic lobe suggests that nitric oxide is likely to play an important role in information processing in insect vision.

Journal Article↗
PubMed1996

Long-term safety of the aminobisphosphonate alendronate in adult dogs. I. General safety and biomechanical properties of bone.

Alendronate (4-amino-1-hydroxybutylidene bisphosphonate, ALN) is an aminobisphosphonate that is being developed for the treatment of diseases characterized by increased bone resorption. The purpose of this study was to assess the long-term safety of ALN with special emphasis on bone strength and bone morphology. Thirty-two (16 males and 16 females) 83- to 86-week-old beagle dogs were treated p.o. for up to 3 years with ALN at 0.00, 0.25, 0.5 or 1.0 mg/kg/day. The following parameters of toxicity were assessed: physical signs, body weight, ophthalmology, radiographic evaluation of bone, electrocardiography, hematology, clinical chemistry, urinalysis, necropsy including organ weight assessment, histopathology and biomechanical testing of bone. There were no apparent compound-related alterations in any of the above mentioned parameters except the expected changes (related to the pharmacological activity of ALN) in serum phosphorus and Ca concentrations and in the histology of bones with active endochondral bone formation (rib). There were mild transient reductions in the serum phosphorus and Ca concentrations at the 1.0 mg/kg/day dose level during the early part of the study. There was a dose-dependent delay in bone remodeling in the ribs of all dogs treated with ALN. There was no similar change in the tibia. Most importantly, there were no spontaneous fractures and there were no changes in the structural properties of femoral or vertebral bone. The total ALN content of bone in an average dog (10 kg) after 3 years of treatment with approximately five items of the intended dose for the treatment of osteoporosis was approximately 8 mg, which is only 0.001% of total bone mass (700 g). Introduction.

Administration, Oral↗
PubMed1995

Flexibility and distraction after monosegmental and bisegmental lumbosacral fixation with angular stable fixators.

STUDY DESIGN: In human lumbosacral spines, the flexibility and intersegmental distraction allowed by four monosegmental and bisegmental intrapedicular devices during compression and flexion/compression loading were investigated. OBJECTIVES: To compare the flexibility and intersegmental distraction allowed by four monosegmental and bisegmental intrapedicular, lumbosacral fixation devices applied to destabilized cadaveric spines, and to determine the effect of each device on the flexibility and intersegmental distraction of the motion segment above each fused segment. SUMMARY OF BACKGROUND DATA: The lumbosacral segment is the most mobile region in the lumbar spine, exhibiting the highest range of motion in both flexion and extension. Therefore, the fixation of this and the adjacent segment is of special clinical interest. METHODS: L5-S1 facetectomy or L5 laminectomy procedures were performed on cadaveric human lumbosacral spines. Fixation devices then were applied across one or two levels, and intersegmental motion under flexion/compression or under pure compression loads was monitored. RESULTS: The flexibility and posterior strain allowed by the four implants did not differ significantly between implants. The strain across the stabilized site (monosegmental and bisegmental) was below 10% for all devices tested. The flexibility and distraction were reduced to levels below intact after the fixators were applied. The distraction across the segment above the fusion was not increased because of fixation with these four fixators. CONCLUSIONS: Angular stable fixation devices, such as those described here, provide adequate stabilization of the posteriorly destabilized spine.

Adult↗
PubMed1995

Optimization technique for the calculation of in vitro three-dimensional vertebral motion.

A method for the calculation of translations and Eulerian rotations of an orthogonal axis system with respect to a fixed reference is described with application to the measurement of position in a vertebral motion segment. Kinematic equations were derived to compute the three-dimensional motion of a moving vertebra relative to an adjacent fixed body, without the requirement of a direct physical link between the two bodies. For this calculation, the quadratic error of the lengths of six position vectors was minimized to obtain a mathematically optimal estimate of the translations and rotations. Tests with a rigid model resulted in mean maximum overall system errors of 2.8 percent for the measurement of translation (translations less than 3.5 mm) and 6.1 percent for the measurement of rotations (rotations less than 10 deg) limited by transducer accuracy. The mathematical techniques presented for the quantitative description of rigid body motion, based on the measurement of three reference vectors, may be extended to a broad range of kinematic problems.

Biomechanical Phenomena↗
PubMed1995

Cortical cerebral blood flow cycling: anesthesia and arterial blood pressure.

Cycling of various cerebral metabolic substances, arterial vascular diameter, and flow has been noted by many workers at a frequency near 0.1 Hz. Suspicion that this phenomenon is dependent on the type of anesthesia led us to investigate the occurrence of cerebral blood flow (CBF) cycling with different anesthetics. Fifteen Sprague-Dawley rats were anesthetized with either pentobarbital (n = 5, 40-50 mg/kg), alpha-chloralose (n = 5, 60 mg/kg), or halothane (n = 5, 1-0.5%). Body temperature was maintained at 37 degrees C. Femoral arterial and venous catheters were placed, and a tracheotomy was performed, permitting artificial ventilation with 30% O2-70% N2. A closed cranial window was formed over a 3-mm diameter craniotomy. Mean arterial pressure (MABP), arterial partial pressures of CO2 and O2 (PaCO2 and PaO2), and pH were controlled and stabilized at normal values. CBF was determined using laser Doppler flowmetry. To induce cycling, MABP was transiently and repeatedly lowered by exsanguination. Fast Fourier analysis of selected 64-s flow recordings (n = 38) was performed. CBF cycling was observed, independent of the type of anesthesia, in all animals. In 36 epochs, cycling was induced when MABP was reduced to a mean pressure of 65 +/- 1.5 mmHg. The mean frequency and amplitude were 0.094 +/- 0.003 Hz and 6.6 +/- 0.5%, respectively. Cycling occurred without blood withdrawal in two epochs. With the use of the blood-withdrawal epochs (n = 36), all three anesthetics shared a common linear slope between amplitude and blood pressure (P < 0.02) and blood pressure change (P < 0.01). Pentobarbital differed from alpha-chloralose and halothane in the relation between cycling frequency and blood pressure. Only pentobarbital exhibited correlation between frequency and blood pressure (P < 0.02) and blood pressure change (P < 0.001). The occurrence of these oscillations is not related to the type of anesthesia, and they usually occur at MABP values that are near or just above the lower limit of autoregulation. At this pressure level, CBF oscillations would suggest that vasoconstrictive and dilatory forces are no longer in balance, but alternatively vying for control.

Analysis of Variance↗
PubMed1995

Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study.

Fluoride stimulates trabecular bone formation, whereas bisphosphonates reduce bone resorption and turnover. Fracture prevention has not been convincingly demonstrated for either treatment so far. We compared the effects of 1-yr treatment of 9-mo-old minipigs with sodium fluoride (NaF, 2 mg/kg/d p.o.) or alendronate (ALN, 4 amino-1-hydroxybutylidene bisphosphonate monosodium, 1 mg/kg/d p.o.) on the biomechanical and histomorphometric properties of pig bones. As expected, NaF increased and ALN decreased bone turnover, but in these normal animals neither changed mean bone volume. NaF reduced the strength of cancellous bone from the L4 vertebra, relative to control animals, and the stiffness (resistance to deformation) of the femora, relative to the ALN group. In the ALN-treated animals, there was a strong positive correlation between bone strength and L5 cancellous bone volume, but no such correlation was observed in the NaF group. Furthermore, the modulus (resistance to deformation of the tissue) was inversely related to NaF content and there was a relative decrease in bone strength above 0.25 mg NaF/g bone. Moreover, within the range of changes measured in this study, there was an inverse correlation between bone turnover, estimated as the percentage of osteoid surface, and modulus. These findings have relevant implications regarding the use of these agents for osteoporosis therapy.

Alendronate↗
PubMed1995

Nitric oxide synthesis in locust olfactory interneurones

The brain of the locust Schistocerca gregaria contains a nitric oxide synthase (NOS) that has similar properties to mammalian neuronal NOS. It catalyses the production of equimolar quantities of nitric oxide (NO) and citrulline from l-arginine in a Ca2+/calmodulin- and NADPH-dependent manner and is inhibited by the Nomega-nitro and Nomega-monomethyl analogues of l-arginine. In Western blots, an antiserum to the 160 kDa rat cerebellar NOS subunit recognises a locust brain protein with a molecular mass of approximately 135 kDa. NOS is located in several parts of the locust brain, including the mushroom bodies, but it is particularly abundant in the olfactory processing centres, the antennal lobes. Here it is present in two groups of local interneurones (a pair and a cluster of about 50) that project into the neuropile of the antennal lobes. The processes of these neurones terminate in numerous glomerulus-like structures where the synapses between primary olfactory receptor neurones and central interneurones are formed. NOS-containing local interneurones have also been identified in the mammalian olfactory bulb, suggesting that NO performs analogous functions in locust and mammalian olfactory systems. As yet, nothing is known about the role of NO in olfaction, but it seems likely that it is involved in the processing of chemosensory input to the brain. The locust antennal lobe may be an ideal 'simple' system in which this aspect of NO function can be examined.

Journal Article↗
PubMed1994

Healing of large segmental defects in rat femurs is aided by RhBMP-2 in PLGA matrix.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) can be used to enhance the repair of congenital or acquired bone pathologies when formulated in the appropriate carrier. Poly [D,L-(lactide-co-glycolide)] (PLGA) has been shown to be an effective carrier of rhBMP-2. We investigated several particle sizes PLGA and several doses of rhBMP-2 in a rat orthotopic model. We also investigated the effects of a fibrinolytic inhibitory agent, epsilon aminocaproic acid (EACA), on the healing response. Our data indicate that higher doses of rhBMP-2 resulted in increased failure torque (408 +/- 70 N-mm or 60% of the intact value) and higher incidence of union (100%). The induced bone in femurs treated with the smaller particle size PLGA achieved the greatest torsional stiffness and strength. The presence of rhBMP-2 was necessary for new bone to form, but the presence of EACA did not change these results; the use of the PLGA carrier appeared to increase bone strength and stiffness. In fact, with higher doses of rhBMP-2 in PLGA, the stiffness of the new bone was equal to that of intact controls (64 +/- 20 N-mm/deg [intact femurs] versus 45 +/- 10 N-mm/degree [medium dose in small PLGA], 61 +/- 17 N-mm/degree [high dose in small PLGA], and 36 +/- 11 N-mm/degree [medium dose in large PLGA]; P > .05). In conclusion, PLGA implanted with rhBMP-2 effectively aided in healing large segmental defects in rat femurs.

Animals↗
PubMed1994

Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer.

PURPOSE: To determine the maximum dose-intensity of cisplatin (DDP) that could be administered by selective intraarterial (IA) infusion in combination with systemic sodium thiosulfate neutralization to patients with head and neck carcinoma. PATIENTS AND METHODS: Forty-two patients (23 untreated stage III/IV, 19 recurrent) received highly selective IA DDP, rapidly delivered through microcatheters placed angiographically, to a maximum dose-intensity of 200 mg/m2/wk. Concurrently, the systemic effects of DDP were neutralized by intravenous (IV) bolus sodium thiosulfate. RESULTS: Problems related to the infusion technique occurred in eight of 140 courses, all of which were inconsequential. The rates of reversible grade I/II and grade III/IV toxicity were 14.8% and 1.1%, respectively. Dose-limiting toxicity, which consisted of severe electrolyte loss, occurred at a dose of 200 mg/m2/wk. The maximum-tolerated dose of DDP was 150 mg/m2 administered weekly for four doses. The overall and complete response rates in 38 assessable patients were 19 of 22 (86%) and nine of 22 (41%) for stage III/IV untreated tumors and 10 of 16 (62%) and four of 16 (25%) for patients with recurrent disease, respectively. CONCLUSION: This pharmacologic strategy permits the selective and rapid delivery of extremely high doses of DDP to head and neck carcinomas with minimal procedural complications, low systemic toxicity, and high tumor response rates.

Adult↗
PubMed1994

A comparison of the effects of automated percutaneous diskectomy and conventional diskectomy on intradiscal pressure, disk geometry, and stiffness.

Diskectomy, chemonucleolysis, percutaneous diskectomy, and laser ablation are used to treat patients with sciatica. The effects of percutaneous diskectomy on the intradiscal pressure of the human disk are not known. Our aims were to determine (a) whether removal of nucleus through automated percutaneous diskectomy significantly reduces intradiscal pressure without altering the disk geometry and stiffness, and if so, how much nucleus removal is required to achieve these goals; and (b) whether the effects of conventional diskectomy on these same parameters are equivalent to removal of nucleus through automated percutaneous diskectomy. Cyclic compressive loads of 20-900 N were applied to lumbar disks. Conventional diskectomy or automated percutaneous diskectomy (performed for 40 min with biomechanical measurements made four times at 10-min intervals) was then performed under zero load and the specimens retested under the same cyclic compressive loading. There were significant (p < 0.01) decreases in intradiscal pressure (by 7% under 900 N) after 10 min of automated percutaneous lumbar diskectomy. There were no further significant decreases in pressure during the next 30 min of percutaneous diskectomy. There were also significant decreases in pressure due to a puncture hole made with the Nucleotome trephine alone, without removal of disk material, and there was no difference in pressure after trephining alone and after percutaneous diskectomy. Decreases in disk height were significant, ranging from 5% at 10 min to 7% at 40 min of treatment. There were equivalent decreases in intradiscal pressure and disk height due to removal of similar amounts of nucleus during conventional diskectomy and during 40 min of percutaneous diskectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Effects of combined prostaglandin and alendronate treatment on the histomorphometry and biomechanical properties of bone in ovariectomized rats.

Prostaglandin E2 (PGE2) has been shown to stimulate both bone resorption and formation in experimental animals, leading to augmentation of trabecular and cortical bone. The amino bisphosphonate alendronate (ALN) is a potent inhibitor of bone resorption. The objectives of this study were to examine if PGE2 stimulation of bone formation was dependent on bone resorption and if the bone accrued as a result of PGE2 treatment contributed to bone strength. The 48 female Sprague-Dawley rats were assigned to six groups as follows: five groups (8/group) were ovariectomized at the age of 6 months. One group was sacrificed 2 months later to establish baseline conditions, and four groups were treated for 25 days with (1) vehicle, (2) PGE2 at 3 mg/kg/day, (3) ALN sc at 0.8 micrograms/kg/day, and (4) PGE2 + ALN at the respective doses. The sixth group served as nonovariectomized untreated controls. Histomorphometric analysis of 6-10 microns thick tibial sections after in vivo fluorochrome double labeling showed that treatment with PGE2 alone increased endocortical mineral apposition rate and bone formation rate, stimulated production of bone trabeculae in the marrow cavity, and increased cortical porosity. Combined ALN + PGE2 treatment prevented the resorption induced by PGE2 but not the stimulation of bone formation on endocortical and periosteal surfaces and resulted in a significant increase in cortical thickness. Consistent with these observations, the femoral midshaft tested to failure in three-point bending showed a significant increase in strength in the PGE2 + ALN group (181 +/- 15 N) compared to time 0 controls (145 +/- 23 N) or to the ovariectomized vehicle-treated group (141 +/- 28 N).(ABSTRACT TRUNCATED AT 250 WORDS)

Alendronate↗