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PubMed2002

Ex vivo pharmacodynamics of amoxicillin-clavulanate against beta-lactamase-producing Escherichia coli in a yucatan miniature pig model that mimics human pharmacokinetics.

The objective of the present study was to investigate the potential bactericidal activity of amoxicillin-clavulanate against beta-lactamase-producing Escherichia coli strains and to elucidate the extent to which enzyme production affects the activity. Six adult Yucatan miniature pigs received a single intravenous dose of 1.1 g of amoxicillin-clavulanate as an intravenous infusion over 30 min. The pharmacokinetic parameters were determined for the serum samples and compared to the published data for humans (2.2-g intravenous dose). The parameters were comparable for the two species, and therefore, the miniature pig constitutes a good model for pharmacodynamic study of amoxicillin-clavulanate. Therefore, the model was used in an ex vivo pharmacodynamic study of amoxicillin-clavulanate against four strains of Escherichia coli producing beta-lactamases at different levels. The E. coli strains were cultured with serial dilutions (1:2 to 1:256) of the serum samples from the pharmacokinetic study, and the number of surviving bacteria was determined after 1, 3, and 6 h of exposure. Amoxicillin-clavulanate at concentrations less than the MIC and the minimal bactericidal concentration had marked bactericidal potency against the strain that produced low levels of penicillinase. For high-level or intermediate-level beta-lactamase-producing strains, the existence of a clavulanate concentration threshold of 1.5 to 2 micro g/ml, below which there was no bactericidal activity, was demonstrated. The index of surviving bacteria showed the existence of mixed concentration- and time-dependent actions of amoxicillin (in the presence of clavulanate) which varied as a function of the magnitude of beta-lactamase production by the test strains. This study shows the effectiveness of amoxicillin-clavulanate against low- and intermediate-level penicillinase-producing strains of E. coli. These findings are to be confirmed in a miniature pig experimental infection model.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2001

Identification of novel porcine endogenous betaretrovirus sequences in miniature swine.

PCR amplification of genomic DNA from miniature swine peripheral blood lymphocytes, using primers corresponding to highly conserved regions of the polymerase (pol) gene, allowed the identification of two novel porcine endogenous retrovirus (PERV) sequences, PMSN-1 and PMSN-4. Phylogenetic analyses of the nucleotide sequences of PMSN-1 and PMSN-4 revealed them to be most closely related to betaretroviruses. The identification of PERVs belonging to the Betaretrovirus genus shows that endogenous retroviruses of this family are more broadly represented in mammalian species than previously appreciated. Both sequences contained inactivating mutations, implying that these particular loci are defective. However, Southern blot analysis showed additional copies of closely related proviruses in the miniature swine genome. Analyses of fetal and adult miniature swine tissues revealed a broad mRNA expression pattern of both PMSN-1 and PMSN-4. The most abundant expression was detected in whole bone marrow c-kit(+) (CD117(+)) progenitor bone marrow cells, fetal liver, salivary gland, and thymus. It appears unlikely that functional loci encoding these novel PERV sequences exist, but this remains to be established. The betaretrovirus sequences described in this report will allow such investigations to be actively pursued.

Animals↗
PubMed2004

Genotyping of porcine endogenous retroviruses from a family of miniature swine.

The identification of animals in an inbred miniature swine herd that consistently fail to produce replication- competent humantropic porcine endogenous retrovirus (PERV) has prompted studies on the biology of PERV in transmitter and nontransmitter animals. We analyzed PERV RNA transcript profiles in a family of inbred miniature swine (SLA(d/d) haplotype) in which individual members differed in their capacity to generate humantropic and ecotropic (i.e., pigtropic) virus. We identified unique HaeIII and HpaII gag restriction fragment length polymorphism (RFLP) profiles resulting from single nucleotide polymorphisms in blood cells; these were found only in animals that produced humantropic PERV. These HaeIII and HpaII gag RFLP profiles proved to be components of humantropic PERV as they were transmitted to 293 human target cells in vitro. The humantropic HaeIII and HpaII gag RFLP genotypes in the family of study were not present in other miniature swine in the herd that produced humantropic PERV, indicating that these RFLP profiles relate specifically to this family's lineage.

Animals↗
PubMed2000

Growth pattern of the maxillary sinus in the miniature pig (Sus scrofa).

The biological role of the paranasal sinuses is obscure, can be elucidated through a cross-sectional growth study of the maxillary sinus in miniature pigs. The maxillary sinus area was obtained from lateral cephalograms of left skull halves of 103 female miniature pigs of known ages, from newborn to 24 months. Out of several nonlinear models, the growth of the maxillary sinus was best described with the Gompertz model. The first derivative of the Gompertz curve revealed an increase in the growth rates of the maxillary sinus until 4 months, after which sinus growth slowed down. The eruption of the permanent molars did not seem to have a significant influence on this growth pattern. Furthermore, growth in maxillary sinus size in the miniature pig does not follow growth in skull size closely, which showed the highest growth rates in newborn animals. In addition, a correlation analysis revealed that the relationship between maxillary sinus area and different characteristics of the masticatory apparatus (including linear cranial dimensions, and the dry weight of the masseter and zygomatico-mandibularis muscles) were influenced greatly by skull size. These results suggest that the existence of pneumatic cavities within the mammalian skull is not satisfactorily explained solely by an architectural theory. Epigenetic factors are likely to influence the final shape of the maxillary sinus.

Animals↗
PubMed1998

LDL hypercholesterolemia is associated with accumulation of oxidized LDL, atherosclerotic plaque growth, and compensatory vessel enlargement in coronary arteries of miniature pigs.

The association between accumulation of oxidized low density lipoprotein (LDL) and (1) progression of atherosclerotic plaques and (2) compensatory enlargement was assessed in the coronary arteries of LDL-hypercholesterolemic miniature pigs. In miniature pigs fed a 4% cholesterol diet, LDL cholesterol levels increased from 27+/-3.5 mg/dL (mean+/-SEM, n=36) to 250+/-28 mg/dL (n=10), 260+/-15 mg/dL (n=6), and 260+/-17 mg/dL (n=10) at 6, 14, and 24 weeks, respectively. Mean intimal areas of lesions in the left anterior descending coronary artery of hypercholesterolemic pigs were 0.16+/-0.046 mm2 at 6 weeks (n=10) and increased 5.4-fold (n=6, P<.05) and 10.6-fold (n=10, P<.001) at 14 and 24 weeks, respectively. Plaque growth was associated with an increase in mean internal elastic lamina area, from 1.44+/-0.17 to 4.38+/-0.52 mm2 (P=.007) and in mean luminal area from 1.42+/-0.15 mm2 in control pigs to 4.38+/-0.52 mm2 in pigs fed a cholesterol diet for 24 weeks (P=.007 vs control). Levels of total LDL in the intima, measured immunocytochemically, were 0.031+/-0.0098, 0.11+/-0.057 (P< or =.05), and 0.43+/-0.082 U (P<.001) at 6, 14, and 24 weeks, respectively. Corresponding levels of oxidized LDL were 0.034+/-0.023, 0.11+/-0.050 (P<.05), and 0.44+/-0.065 U (P<.001), respectively, suggesting that virtually all LDL in the intima is oxidized. Levels of oxidized LDL in the lesions were correlated with the intimal areas (r=.85, P<.0001) but were independent of plasma levels of LDL cholesterol and of oxidized LDL. Plaque levels of oxidized LDL were also correlated with internal elastic lamina areas (r=.72, P<.0001) and with luminal areas (r=.50, P=.0098). Plaque growth in the coronary arteries of LDL-hypercholesterolemic miniature pigs is associated with (1) an increase in plaque levels of oxidized LDL at constant plasma levels of LDL cholesterol and of oxidized LDL and (2) compensatory vessel enlargement proportional to plaque levels of oxidized LDL.

Adaptation, Physiological↗
PubMed2000

Coronary artery bypass grafting using a miniature right ventricular support system.

Cardiopulmonary bypass (CPB) with cardioplegic myocardial preservation has long been the gold standard for surgical care of coronary artery disease. More recently, alternatives to the conventional approach of CPB-myocardial revascularization have been developed. Epicardial stabilizing devices have been used to immobilize areas of the beating heart to provide a stable surface for some coronary anastomoses. These approaches are often limited to anterior aspects of the heart because revascularization of posterior and lateral vessels often requires the heart to be manipulated or contorted. Excessive manipulation can lead to hemodynamic compromise as a result of partially obstructing pulmonary blood flow. A miniature extracorporeal system has been developed that uses right ventricular support and allows for epicardial surgical procedures to be conducted on a beating heart without standard CPB. The extracorporeal system consists of a coaxial atrial cannula that is connected to a miniature centrifugal pump. Blood is drained from the right atrium, passes through the miniature centrifugal pump and is delivered through the cannula's inner reinfusion lumen into the pulmonary artery. The entire circuit volume is approximately 30 ml. The system is positioned on the sterile operative field. The pump is controlled by a console positioned adjacent to the patient. The centrifugal pump is capable of delivering blood flow at rates of 1-6 l/min. This extracorporeal system may be of benefit in maintaining adequate cardiac output during epicardial beating heart surgery.

Coronary Artery Bypass↗
PubMed2000

Miniaturization of a functional transcription assay in yeast (human progesterone receptor) in the 384- and 1536-well plate format.

Miniaturization of high throughput screening assays to high-density microplate formats (384 or 1536 wells) is currently the focus of research activity in modern drug discovery facilities. In this article, we describe the adaptation of a fluorescence-based functional transcription assay in yeast for assessing modulators of human progesterone receptor to the 384- and 1536-well microplate format, comparing the experimental results to those obtained in the well-established 96-well format. The experiences gained from the optimization of the liquid-handling procedures and the miniaturization of an enzyme assay (beta-galactosidase) were implemented. Thus optimized pipetting protocols were developed to perform a reporter gene assay in yeast in microplate formats of higher density. In the functional transcription assay in yeast, the reporter gene expression showed the expected dependence on the ligand's dose and affinity in principle in all three microplate formats. For the first time, this assay system has been established in the 1536-well microplate format using CyBi-Well 96/384/1536 as the liquid-handling unit. The comparison of the signal:background ratios showed a lower sensitivity of the assay in the microplate formats of higher density. This study is an example of a successful miniaturization of a yeast cell-based assay to high-density plate formats on the basis of a careful adaptation procedure and optimized liquid-handling conditions.

Cloning, Molecular↗
PubMed2001

Posttransplantation lymphoproliferative disease in miniature swine after allogeneic hematopoietic cell transplantation: similarity to human PTLD and association with a porcine gammaherpesvirus.

Posttransplantation lymphoproliferative disease (PTLD) is a major complication of current clinical transplantation regimens. The lack of a reproducible large-animal model of PTLD has limited progress in understanding the pathogenesis of and in developing therapy for this clinically important disease. This study found a high incidence of PTLD in miniature swine undergoing allogeneic hematopoietic stem cell transplantation and characterized this disease in swine. Two days before allogeneic peripheral blood stem cell transplantation, miniature swine were conditioned with thymic irradiation and in vivo T-cell depletion. Animals received cyclosporine daily beginning 1 day before transplantation and continuing for 30 to 60 days. Flow cytometry and histologic examination were performed to determine the cell type involved in lymphoproliferation. Polymerase chain reaction was developed to detect and determine the level of porcine gammaherpesvirus in involved lymph node tissue. PTLD in swine is morphologically and histologically similar to that observed in human allograft recipients. Nine of 21 animals developed a B-cell lymphoproliferation involving peripheral blood (9 of 9), tonsils, and lymph nodes (7 of 9) from 21 to 48 days after transplantation. Six of 9 animals died of PTLD and 3 of 9 recovered after reduction of immunosuppression. A novel porcine gammaherpesvirus was identified in involved tissues. Miniature swine provide a genetically defined large-animal model of PTLD with many characteristics similar to human PTLD. The availability of this reproducible large-animal model of PTLD may facilitate the development and testing of diagnostic and therapeutic approaches for prevention or treatment of PTLD in the clinical setting.

Amino Acid Sequence↗
PubMed2005

QT PRODACT: usability of miniature pigs in safety pharmacology studies: assessment for drug-induced QT interval prolongation.

To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg/kg, p.o. prolonged the QTcF interval (Fridericia's formula) by 8%-16%. The plasma concentration of haloperidol at which QT interval was prolonged (Cmax=42.9 ng/mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg/kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg/kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7%-12%. dl-Sotalol at 10 mg/kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.

Animals↗
PubMed2005

Optimization of Ca2+ concentrations in fusion and activation media for production of cloned embryos from miniature pig somatic cells.

The effects of Ca(2+) concentration in activation medium and cytochalasin B treatment after activation on the parthenogenetic development of pig oocytes were examined. In addition, cloned embryos derived from miniature pig somatic cells were activated under optimal conditions and the effects of Ca(2+) in fusion medium on the development of embryos after activation was examined. When oocytes were activated in 0.1 mM Ca(2+) and then treated with cytochalasin B, the blastocyst formation rate (28.6%) was significantly higher than those activated in 0-0.05 or 1.0 mM (11.0-18.3%). Treatment with cytochalasin B decreased the second polar body extrusion rate of activated oocytes. The presence or absence of Ca(2+) in fusion medium did not affect the fusion rate of miniature pig somatic cells with recipient oocytes. A few cloned embryos developed to the blastocyst stage (2.7-9.0%) without an additional activation treatment. On the other hand, significantly more embryos developed to the blastocyst stage after activation treatment when they were fused in the absence (28.9%) of Ca(2+) rather than the presence (16.5%) of it. These results show that the highest blastocyst formation rate for miniature pig cloned embryos is obtained when donor cells and recipient oocytes are fused in the absence of Ca(2+) and then activated in 0.1 mM Ca(2+) and treated with cytochalasin B.

Animals↗
PubMed2002

[First experiences with a miniaturized heart-lung-machine].

Conventional heart-lung-machines (HLM) used for many cardiosurgical procedures lead to an impaired function of nearly all organs. This deleterious effect may be reduced by miniaturized HLMs. Therefore we report on our first experiences in 9 patients (4 women, 5 men) undergoing beating heart coronary artery bypass grafting from 10/01 to 04/02 in our department employing a miniaturized HLM with the Deltastream extracorporeal rotary blood pump. Eight patients had an uneventful postoperative course, one patient died on the first postoperative day. Using this miniaturized HLM beating heart coronary artery bypass grafting was successful in all patients. Further studies are necessary to support these results.

Aged↗
PubMed1996

Branching patterns in coronary artery and ischemic areas induced by coronary arterial occlusion in the CLAWN miniature pig.

This study of 28 CLAWN miniature pigs (male 17, female 11, mean weight 29 kg) was undertaken to investigate the coronary arterial branching patterns and the ischemic area induced by surgical occlusion of the left anterior descending artery (LAD) and change in the ischemic area over time. These results were compared with those in dogs, which have frequently been used in myocardial ischemic research. Regarding the coronary arterial branching pattern, there were fewer ventricular branches from the right and left coronary arteries than in dogs. The septal branches arose from only the LAD and the posterior descending artery (PD). The largest septal artery branched from the LAD. There were two types of septal artery branching patterns. In approximately 80% of the CLAWN miniature pigs, the PD arose from the right coronary artery (Right dominance). The peculiarity of the coronary arterial branching pattern in the CLAWN miniature pigs was more similar to human beings than to dogs. The ischemic area induced by occlusion at three-fifths distal section of the LAD was 12.1% to 22.6% (mean 17.1%) of the left ventricle. The ischemic area in all animals that died of global left ventricular malfunction and hemodynamic instability after LAD occlusion was more than 25% of the left ventricle.

Animals↗
PubMed1992

Effect of free gingival grafts on naturally-occurring recession in miniature swine.

Miniature swine exhibit naturally-occurring, progressive recession on facial surfaces of the permanent mandibular incisors. The purpose of this study was to determine whether placing a free gingival graft to augment the width of keratinized gingiva of mandibular incisors in miniature swine would prevent or retard recession at the grafted site compared to an untreated contralateral control site. In 8 litter-mate miniature swine, free gingival grafts were placed on the facial surface of the permanent central and lateral incisors on one side of the mandible. The contralateral mandibular incisors did not receive any treatment and served as controls. Clinical measurements, including eruption, recession, pocket depth, attachment level, and keratinized gingival width were obtained preoperatively, 2 to 3 weeks after surgery to assess the success of gingival augmentation, and 3, 6, and 9 months postoperatively. Eight grafted sites were successful and showed significant augmentation of the keratinized gingival width, with a mean increase of 5.8 +/- 0.7 mm, while 6 grafts failed and showed a slight decrease in the mean width of -0.4 +/- 0.5 from the preoperative to postoperative examination. All sites showed significant recession during the experimental period. Successful sites showed no statistically significant or clinically major difference in the rate or amount of recession than contralateral control sites. By 9 months, the average increase in recession from the baseline examination was 2.8 +/- 1.5 mm for successfully grafted sites and 2.6 +/- 1.3 mm for contralateral controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

The course of the mandibular canal in the growing miniature pig.

Miniature pigs are extensively used as laboratory animals in studies concerning craniofacial growth and adaptation. However, in contrast to the vast amount of literature regarding the overall growth pattern of the pig's mandible, little is known about the internal structures of the mandible such as the mandibular canal. In order to investigate the position of the mandibular canal (MC) and the thickness of its buccal and lingual walls, a cross-sectional study was performed on female miniature pigs MINI-LEWE covering the period from newborn to adult. The position of the MC was analyzed at bony segments that were obtained by cutting the drys mandibles interdentally. At each segment a central point of the MC was defined and its relation to the buccal and lingual margin of the mandible was measured. Located at the lower part of the mandibular corpus, the MC runs in the form of an arch within the sagittal plane in anterior direction, getting enlarged into the form of an ampulla in the molar and premolar region. Whereas during the primary dentition the biggest size of the MC was found behind the third deciduous molar, during the secondary dentition the biggest size of the MC was seen in the region of the first and second permanent molar. With regard the buccolingual aspect, the central point of the MC was found mainly in the center of the mandibular corpus. Between the 2nd and 5th month as well as at the beginning of the 18th month the thickest canal wall existed on the buccal side. In the period of the eruption of the succedaneous teeth, however, the lingual wall was thicker than the buccal wall. Results suggest that the definite course of the MC achieves relatively early in the miniature pig with the completion of the primary dentition. There were no major changes of the position of the MC in the postnatal period suggesting that the age factor has only a minor effect on the location of the MC.

Age Factors↗
PubMedDate not supplied

Can the infusion of elastase in the abdominal aorta of the Yucatán miniature swine consistently produce experimental aneurysms?

The intraluminal elastase perfusion model has been proved to be potentially effective in producing abdominal aortic aneurysm in rodents, but it produced unpredictable results in larger animals. The purpose of this study was to explore the potential ability of such a model to produce experimental aneurysm consistently in the Yucatán miniature swine. Six Yucatán miniature swine received infusion with porcine elastase into an isolated segment of the infrarenal aorta. The excised arterial segments were examined macroscopically to assess the luminal surface characteristics and histologically to describe the different pathologic injuries induced by the elastase treatment on the intima, media, and adventitia of the arterial wall. Histologic examination revealed that the elastic network of the media was destroyed. In the first week after perfusion, altered smooth muscle cells were located in the intima and innermost layer of the media in juxtaposition with the occlusive thrombus. Infiltration of inflammatory cells was observed in these regions of elastic network and smooth muscle cell alterations. In the arterial segments of swine sustained for 3 weeks, a reduction of smooth muscle cells was noted in some areas. An important number of necrotic lesions was observed, and they were associated with the development of calcium deposits. Significant intimal hyperplasic reaction was identified at day 19 and again at day 21. However, no aneurysmal development was observed. This study constituted the first experiment with infusion of porcine elastase in the Yucatán miniature swine infrarenal aorta. The present experimental protocol induced important elastic network and smooth muscle cell alterations leading to severe necrotic lesions associated with calcium deposition, but it produced no aneurysmal dilatation. This model requires further testing to obtain a more complete degradation of the elastic network in both the media and adventitia and more significant collagenolysis without early thrombotic events.

Animals↗
PubMed1985

Use of the Goettingen miniature pig for studying pyrimethamine teratogenesis.

Although pigs are suitable animals for experimental teratology, use of miniature pigs developed as a medicobiological experimental animal is essential for this purpose. Miniature pigs are established genetically so that the background data on the naturally occurring birth defects are reliable, whereas the commercial breeds are always improved genetically to seek higher productivity. In this review the authors summarized pyrimethamine teratogenesis in Goettingen miniature pigs. Pyrimethamine administration to a pregnant sow during the early stage of the organogenetic period caused cleft palate and other birth defects, and also hind leg paralysis, a functional defect in newborns.

Abnormalities, Drug-Induced↗
PubMed2003

Temporal increase in the gastric colonization of Helicobacter pylori after healing of acetic acid-induced gastric ulcer in a miniature pig.

While the eradication of Helicobacter pylori has been reported to reduce the frequency of ulcer relapse, the preventative mechanism remains unknown. We investigated the changes in the level of gastric colonization 140 days after inducing gastric ulcer by acetic acid in the antral mucosa of a miniature pig infected with H. pylori. The gastric ulcer was induced endoscopically with 1 mL of 40% acetic acid 12 days after inoculation of H. pylori in a 3-month-old miniature pig. Gastric ulcer was healed by 30 days after ulcer induction and the levels of H. pylori in cardiac and antral mucosa increased gradually from 30 to 71 days. The peak bacterial counts in the cardia and antrum were 6.1 and 6.6 log10 cfu/g, respectively, or about 100-fold higher than the initial levels. The levels of H. pylori in cardiac and antral mucosa steadily decreased until reaching the initial levels at 127 days, while that in the fundic mucosa remained constant throughout the observation period. No ulcer recurrence was detected by endoscopy. These results suggested that the levels of H. pylori colonization increased temporally after healing of the acetic acid-induced gastric ulcer in the miniature pig.

Acetic Acid↗
PubMed1990

Fasting energy metabolism of the Yucatan miniature pig.

The fasting metabolic rates (FMR) of Yucatan miniature swine were determined using an open-circuit indirect respiration calorimeter. Mature nulliparous females had a mean FMR of 93 kcal/kg BW.75 and did not change significantly during the estrous cycle. This value is comparable to that observed in mature domestic swine. The calculated metabolizable energy requirement for maintenance for the Yucatan sow is 116 kcal/kg BW.75. Growing Yucatan boars had FMR of 127, 119 and 101 kcal/kg BW.75 at 15, 21 and 38 weeks of age, respectively, and were similar to values for comparably aged domestic swine. The calculated estimate for the metabolizable energy requirement for maintenance for Yucatan boars ranged from 158 kcal at 15 weeks of age to 126 kcal/kg BW.75 for 38 week old animals. Based on the similarity between the FMR of the Yucatan miniature swine in the present study and values published for standard size commercial hogs, it is concluded that the metabolic rates of these breeds of pig are similar. It is suggested that the daily energy needs of the Yucatan miniature pig may be met using values published for production livestock having similar physiological condition when adjusted for the smaller body size of the Yucatan breed.

Animals↗