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The effect of clodronate (dichloromethylene diphosphonate) on the mineral concentration of dental enamel and bone of the miniature swine.

Diphosphonates are compounds which prevent the crystallisation of calcium phosphates from solution. Our aim was to study the effects of clodronate (dichloromethylene diphosphonate), one of the diphosphonates, on the mineral concentrations of dental enamel and bone. In a subchronic experiment the effects of this compound were investigated. The drug was administered orally in three doses (100, 300, 1000 mg/kg) per day to 32 Göttingen miniature swines for six months. From the acid etch biopsy of enamel the amount of dissolved hydroxyapatite and the concentrations of fluoride and magnesium were measured. The calcium, phosphorus, fluoride, magnesium, carbonate and citrate concentrations were determined from the cancellous bone sample. All values were calculated for dry bone. Calcium/phosphorus and calcium/magnesium ratios were calculated for both enamel and bone. In tooth enamel the magnesium concentration showed a significant dose dependent decrease and calcium/magnesium ratio a significant dose dependent rise. Calcium phosphorus/ratio exhibited a dose dependent increase in surface enamel. Bone fluoride concentration showed a highly significant and calcium/magnesium ratio a significant dose dependent rise. Clodronate seems to interfere with the remineralization process of tooth enamel, through its effect on magnesium. Incorporation of the drug also appears to exhibit a marked action on the fluoride metabolism of bone. This may require attention in certain long term treatment situations with clodronate in high fluoride areas.

Animals↗

Miniature pig as an animal model to study photoaging.

Seven miniature pigs were irradiated thrice weekly over a 14 months period with suberythematogenic doses of UVB and UVA. Another seven were not exposed, to record innate aging changes. Chronic irradiation induced the following changes: 1. Increased scaling, with thickening of the stratum corneum and decreased reactivity to acetic acid. 2. Increased minimum erythema dose, corresponding to decreased transmission of UV-radiation through isolated epidermis. 3. Increased elastic fibers, accompanied by strong deposition of glycosaminoglycans in the upper dermis. 4. Increased laxity with greater extensibility to a deforming torque. 5. Increased density of vessels. 6. More disorderly arrangement of collagen bundles with minor alterations in collagen biochemistry. These changes mimic those in photoaged human skin but are milder in degree, attributable to the low total dosage of ultraviolet radiation.

Aging↗

Miniature C-shaped transducers for chordae tendineae force measurements.

C-shaped strain gauge force transducers were designed to enable dynamic measurements of the tension of the individual mitral valve chordae tendineae during the cardiac cycle. The force transducers were constructed from a C-shaped brass ring with a diameter of 6 mm, width of 2 mm, thickness of 0.5 mm, and a mass of <80 mg. Miniature strain gauges elements were cemented onto the inner and outer side of the ring. The strain gauges were connected to thin Teflon wires and coupled in a Wheat-stone half-bridge circuit to a signal conditioner and amplifier. The transducer was coated with a resistive sealing ensuring electrical insulation as well as mechanical protection. Technical testings of sensitivity, linearity, noise level, and frequency response characteristics demonstrated that the transducers were suitable for dynamic chordal force measurements performed under in vitro and in vivo experimental conditions.

Animals↗

Miniature tissue-equivalent proportional counters for BNCT and BNCEFNT dosimetry.

A dual miniature tissue-equivalent proportional counter (TEPC) system has been developed to facilitate microdosimetry for Boron Neutron Capture Therapy (BNCT). This system has been designed specifically to allow the analysis of the single event charged particle spectrum in phantom in high intensity BNCT beams and to provide this microdosimetric information with excellent spatial resolution. Paired A-150 and 10B-loaded A-150 TEPCs with 12.3 mm3 collecting volumes have been constructed. These TEPCs allow more accurate neutron dosimetry than current techniques, offer a direct measure of the boron neutron capture dose, and provide a framework for predicting the biological effectiveness of the absorbed dose. Design aspects and characterization of these detectors are reviewed, along with an exposition of the advantages of microdosimetry using these detectors over conventional dosimetry methods. In addition, the utility of this technique for boron neutron capture enhancement of fast neutron therapy (BNCEFNT) is discussed.

Biophysical Phenomena↗

A new miniature x-ray device for interstitial radiosurgery: dosimetry.

A miniature, battery operated 40 kV x-ray device has been developed for the interstitial treatment of small tumors ( < 3 cm diam) in humans. X rays are emitted from the tip of a 10 cm long, 3 mm diameter probe that is stereotactically inserted into the tumor. The beam, characterized by half-value layer (HVL), spectrum analysis, and isodose contours, behaves essentially as a point isotropic source with an effective energy of 20 keV at a depth of 10 mm in water. The absolute output from the device was measured using a parallel plate ionization chamber, modified with a platinum aperture. The dose rate in water determined from these chamber measurements was found to be nominally 150 cGy/min at a distance of 10 mm for a beam current of 40 microA and voltage of 40 kV. The dose in water falls off approximately as the third power of the distance. To date, 14 patients have been treated with this device in a phase I clinical trial.

Biophysical Phenomena↗

Two-dimensional dose distribution of a miniature x-ray device for stereotactic radiosurgery.

The Photon Radiosurgery System is a miniature x-ray device developed for the treatment of small intracranial neoplasms. The x-rays are generated at the tip of a 10-cm-long, 3-mm-diam probe with a nearly isotropic distribution. Results from measurements of the two-dimensional dose distribution around the x-ray source are presented using two methods: (1) dose measurement with an ionization chamber and a water phantom system and (2) dose measurement with radiochromic film and a solid water phantom. The shape of the two angular dose distributions in the axial plane agree with each other to with approximately 10% and the dose at 10 mm from the source, orthogonal to the probe axis, was about 20% lower than at the same distance along the axis. The relative dose difference of 20% corresponds to a change in distance from the source of +/- 0.3 mm at 10 mm. It is shown that the anisotropy of radiation distribution in the axial plane can be improved to approximately 10% by adjusting the electron beam with a 12% reduction in the overall radiation output.

Calibration↗

Coronary artery spasm induced in atherosclerotic miniature swine.

Angiographically demonstrable coronary artery spasm could be provoked repeatedly by giving intracoronary or intravenous injections of histamine to miniature swine with experimentally induced atherosclerotic lesions of the coronary artery. The spasm induced in this way subsided either spontaneously or after the administration of nitroglycerin and was prevented by a calcium antagonist or an agent that blocks histamine H1 receptors. This model, which suggests that atherosclerotic changes may be one of the primary factors in the occurrence of coronary artery spasm, should facilitate studies on the pathogenesis of this condition.

Animals↗

Pharmacokinetic interaction between itraconazole and ceftriaxone in Yucatan miniature pigs.

Since ceftriaxone and itraconazole are highly protein bound, are excreted via a biliary pathway, and are in vitro modulators of the efflux pump P glycoprotein, a pharmacokinetic interaction between these antimicrobial agents can be hypothesized. Therefore, we evaluated the pharmacokinetics of itraconazole and ceftriaxone alone and in combination in a chronic model of catheterized miniature pigs. Itraconazole does not influence ceftriaxone kinetic behavior. The mean areas under the concentration-time curve (AUC) were 152.2 microg x h/ml (standard deviation [SD], 22.5) and 129.2 microg x h/ml (SD, 41.2) and the terminal half-lives were 1.1 h (SD, 0.3) and 0.9 h (SD, 0.2) when ceftriaxone was given alone and combined with itraconazole, respectively. Regarding itraconazole kinetics, ceftriaxone was shown to alter the disposition of the triazole. Contrary to what was expected, the AUC (from 0 to 8 h) decreased from 139.3 ng h/ml with itraconazole alone to 122.7 ng h/ml with itraconazole and ceftriaxone combined in pig 1, from 398.5 to 315.7 ng x h/ml in pig 2, and from 979.6 to 716.6 ng x h/ml in pig 3 (P of <0.01 by analysis of variance).

Administration, Oral↗

Identification of a full-length cDNA for an endogenous retrovirus of miniature swine.

Endogenous retroviruses of swine are a concern in the use of pig-derived tissues for xenotransplantation into humans. The nucleotide sequence of porcine endogenous retrovirus taken from lymphocytes of miniature swine (PERV-MSL) has been characterized. PERV-MSL is a type C retrovirus of 8,132 bp with the greatest nucleic acid sequence identity to gibbon ape leukemia virus and murine leukemia virus. Constitutive production of PERV-MSL RNA has been detected in normal leukocytes and in multiple organs of swine. The copy numbers of full-length PERV sequences per genome (approximately 8 to 15) vary among swine strains. The open reading frames for gag, pol, and env in PERV-MSL have over 99% amino acid sequence identity to those of Tsukuba-1 retrovirus and are highly homologous to those of endogenous retrovirus of cell line PK15 (PK15-ERV). Most of the differences in the predicted amino acid sequences of PK15-ERV and PERV-MSL are in the SU (cell attachment) region of env. The existence of these PERV clones will enable studies of infection by endogenous retroviruses in xenotransplantation.

Amino Acid Sequence↗

Effects of phenoxybenzamine, metoprolol, captopril, and meclofenamate on cardiovascular function in deoxycorticosterone acetate hypertensive Yucatan miniature swine.

Eight adult Yucatan miniature swine were implanted with deoxycorticosterone acetate (DOCA) impregnated silicone strips (100 mg X kg-1). After 16 weeks of DOCA treatment mean arterial pressure (MAP) increased to 183 +/- 4 mmHg (1 mmHg = 133.322 Pa). In four normal animals arterial pressure was 126 +/- 8 mmHg. The increase in MAP in the DOCA animals was due to an elevated total peripheral resistance (TPR) with cardiac output remaining normal. In tests with conscious animals, phenoxybenzamine (1 mg X kg-1) significantly decreased arterial pressure via a selective decrease in TPR. Neither meclofenamate, metoprolol, nor captopril affected MAP in these DOCA hypertensive animals. Dose--response curves to exogenous norepinephrine and angiotensin II revealed that the DOCA animals had an increased pressor sensitivity to both of these agents. These data suggest that in the DOCA hypertensive Yucatan swine an increase in alpha adrenergic activity and (or) an increase in smooth muscle responsiveness to circulating catecholamines is responsible for the increase in blood pressure as a result of an increase in total peripheral resistance.

Animals↗

A miniature cadmium telluride detector module for continuous monitoring of left-ventricular function.

The authors describe a miniature cadmium telluride (CdTe) detector module for continuous monitoring of ventricular function using an equilibrium radionuclide blood-pool label. The detector and collimator are small, light, and suitable for direct attachment to the chest wall. Clinical studies in 18 patients using a prototype system demonstrated reasonably good correlation with left-ventricular ejection fractions (LVEF) determined by first-pass studies performed with a multicrystal scintillation camera (r = 0.74) and gated equilibrium studies performed with a computerized sodium iodide (Nal) probe (r = 0.76). The CdTe device may prove to be useful in patients in intensive and coronary care units as well as in ambulatory patients.

Adult↗

US-assisted bronchoscopy with use of miniature transducer-containing catheters.

PURPOSE: To demonstrate the value of ultrasound (US) guidance during flexible bronchoscopic procedures in a series of patients with known or suspected pulmonary neoplasms. MATERIALS AND METHODS: US-guided bronchoscopy was carried out as an adjunct to conventional bronchoscopy for the diagnosis of mediastinal, hilar, or parenchymal neoplasms in 25 patients with masses previously detected with chest radiography or computed tomography. Miniature transducer-containing catheters were inserted through the biopsy port of the flexible bronchoscope, and cross-sectional real-time US scans of tumors, lymph nodes, and blood vessels were obtained. RESULTS: Among six cases of peripheral masses and 19 cases of central masses, additional information was provided in 18 cases (72%). This information was used to choose the optimal site for transmural biopsy. CONCLUSION: These preliminary results suggest that this US procedure may become an important diagnostic tool during bronchoscopy, due to the ability to identify structures beyond the lumen of the tracheobronchial tree.

Adult↗

Intracervical US with a high-frequency miniature probe: a method for diagnosing early invasive cervical cancer.

PURPOSE: To determine whether intracervical ultrasound (US) with a high-frequency miniature probe can depict cervical neoplasms, especially in early invasive stages. MATERIALS AND METHODS: Forty-eight women with cervical cancer underwent preoperative transvaginal and intracervical US. US scans were compared with findings from histologic examination or surgery. RESULTS: Intracervical US was completed in 45 of the 48 patients. Both intracervical and transvaginal US were unable to depict preinvasive cancer. Intracervical US depicted the lesion in eight of 16 patients (50%) in whom the depth of cancer invasion was less than or equal to 5 mm, whereas transvaginal US failed to depict the lesion in all 16 patients. Intracervical US depicted the lesions in all 19 patients in whom the depth of cancer invasion was more than 5 mm, whereas transvaginal US was successful only in 14 (74%). CONCLUSION: Intracervical US is useful for evaluating invasive cervical cancer and is especially suitable for detecting early invasion in the endocervix.

Adult↗

Glucose production measured by tracer and balance data in conscious miniature pig.

The rate of glucose production was estimated in the conscious, unrestrained miniature pig during metabolic adaptation to starvation (up to 120 h) by the simultaneous use of three different techniques: 1) the isotopedilution technique, 2) the arteriohepatovenous catheter technique, and 3) the urinary nitrogen balance. During the experimental period 1) whole-body glucose turnover decreased, whereas the amount of glucose recycling increased; 2) splanchnic glucose output decreased, whereas the rate of splanchnic precursor extraction increased up to 48 h, followed by a decrease; 3) gut glucose consumption amounted to about 30% of splanchnic glucose output; and 4) urinary nitrogen excretion declined continuously. The comparison of the different methods revealed that during starvation 1) tracer-determined glucose production rate was within the range (+/- 10%) of the splanchnic glucose output; 2) mean hepatic glucose output overestimated the tracer data by about 30-40%; 3) splanchnic glucose output underestimated hepatic glucose production by the amount of gut glucose consumption; 4) tracer-determined glucose recycling corrected for isotope dilution and amino acid contribution was within the range of splanchnic gluconeogenic precursor extractions. Considering the limitations (e.g., gut glucose consumption, gut lactate and alanine release, blood flow measurement) and methodological problems of the different approaches applied, it is evident that each method reflects different events. It is suggested that the versatile tracer technique combined with nitrogen balance should be preferred for measurement of endogenous glucose production.

Alanine Transaminase↗

Effects of dipyridamole on muscle blood flow in exercising miniature swine.

The purpose of this study was to determine whether a vasodilator reserve exists in respiratory muscles and forelimb skeletal muscles in miniature swine during treadmill exercise. Blood flow (BF) was measured with radiolabeled microspheres during preexercise and before and after dipyridamole (DYP; 1 mg/kg iv) at 2 min of treadmill exercise at 11.2 (70% Vo2 max) and 17.6 km/h (Vo2 max). Muscle BFs were increased during exercise, and the relationship between exercise intensity and BF varied among the muscles. The high-oxidative extensor muscles and the flexor muscles attained peak BFs at 11.2 km/h, whereas the more superficial, lower oxidative extensor muscles showed increases in BF up to maximal exercise. During running at 11.2 km/h, DYP produced increases in BF only in cardiac muscle, respiratory muscle and the medial head of the triceps muscle (MHT), which is composed of 91% slow-twitch oxidative (SO) fibers. During maximal exercise (17.6 km/h), DYP produced a 31-mmHg decrease in mean arterial pressure (MAP) and increases in vascular conductance in all muscles studied. BF was only increased in MHT and cardiac muscle. We conclude that vasodilator reserve remains in skeletal muscle and respiratory muscle even during maximal exercise in swine. If it is assumed that DYP-induced vasodilation in a muscle sample is indicative of adenosine production, these results suggest that SO skeletal muscle (MHT) and respiratory muscle are similar to cardiac muscle in that they produce adenosine even when adequately perfused. Furthermore, during maximal exercise, all skeletal muscle appears to produce adenosine, suggesting that muscle BF is restricted under these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

In vivo murine left ventricular pressure-volume relations by miniaturized conductance micromanometry.

The mouse is the species of choice for creating genetically engineered models of human disease. To study detailed systolic and diastolic left ventricular (LV) chamber mechanics in mice in vivo, we developed a miniaturized conductance-manometer system. alpha-Chloralose-urethan-anesthetized animals were instrumented with a two-electrode pressure-volume catheter advanced via the LV apex to the aortic root. Custom electronics provided time-varying conductances related to cavity volume. Baseline hemodynamics were similar to values in conscious animals: 634 +/- 14 beats/min, 112 +/- 4 mmHg, 5.3 +/- 0.8 mmHg, and 11,777 +/- 732 mmHg/s for heart rate, end-systolic and end-diastolic pressures, and maximum first derivative of ventricular pressure with respect to time (dP/dtmax), respectively. Catheter stroke volume during preload reduction by inferior vena caval occlusion correlated with that by ultrasound aortic flow probe (r2 = 0.98). This maneuver yielded end-systolic elastances of 79 +/- 21 mmHg/microliter, preload-recruitable stroke work of 82 +/- 5.6 mmHg, and slope of dP/dtmax-end-diastolic volume relation of 699 +/- 100 mmHg.s-1.microliter-1, and these relations varied predictably with acute inotropic interventions. The control normalized time-varying elastance curve was similar to human data, further supporting comparable chamber mechanics between species. This novel approach should greatly help assess cardiovascular function in the blood-perfused murine heart.

Animals↗

Indomethacin attenuates exercise-induced proteinuria in hypertensive miniature swine.

Exercise-induced proteinuria may be increased in hypertensives. The mechanisms underlying the increased proteinuria are not known, and it has not been determined whether animal models of hypertension exhibit a similar response. We investigated whether indomethacin (Indo) altered exercise-induced proteinuria in normal and hypertensive deoxycorticosterone acetate (DOCA) Yucatan miniature swine (YMS). Five normal and four DOCA YMS underwent 30 min of treadmill exercise at 80% of maximal heart rate. Cumulative (exercise + recovery) albumin excretion in the DOCA YMS was 25-fold (P < 0.01) greater than observed in the normal YMS. Indo had no effect on resting or exercise-induced proteinuria in the normal YMS. However, Indo decreased the slightly elevated proteinuria at rest, and normalized the exaggerated exercise-induced proteinuria in the DOCA YMS. The antiproteinuric effect of Indo in the DOCA YMS was not associated with altered exercise, recovery blood pressure, or glomerular filtration rate. Thus hypertensive DOCA YMS exhibit an exaggerated exercise-induced proteinuria. It is suggested that eicosanoids are involved in this abnormal renal proteinuric response to exercise.

Animals↗