BACKGROUND & AIMS: :The toxicity of Prednisolone farnesylate (PNF) gel, a synthetic glucocorticoid, was investigated in the Beagle dog. PNF gel was administered percutaneously at doses of 0.2, 0.8 and 3.2 mg/kg/day for 13 weeks, then the drug was withdrawn for 5 weeks to evaluate the reversibility. In addition, 2 mg/kg/day prednisolone gel (PN gel), which is approximate to 3.2 mg/kg/day PNF gel in prednisolone molarity, was also administered for comparison. The results are summarized as follows: 1. No deaths were observed in any of the PNF gel test groups or the PN gel group, nor were there any abnormal findings in the clinical signs of the animals. 2. In the hematology, a tendency toward a decrease in the lymphocyte ratio was observed in males from the PNF gel 0.8 mg/kg/day and above groups. In the PN gel group, a significant decrease or a tendency toward a decrease in the lymphocyte ratio was observed, as well as an increase in the white blood cell count in some animals. 3. In the blood biochemistry, a significant decrease or a tendency toward a decrease in total cholesterol and phospholipid was observed in males from the PNF gel 3.2 mg/kg/day group and a tendency toward an increase in triglyceride in females from the PNF gel 3.2 mg/kg/day group was observed. In the PN gel group, a tendency toward an increase in AIP activity, a tendency toward an increase in triglyceride were observed. 4. In the histological examinations, a decrease in the weight of the thymus and adrenal glands, vacuolation of hepatocytes in the middle zone of the liver, atrophy of zona fasciculata of the adrenal glands, hypertrophy of zona glomeruli, swelling of cortical cells of zona faciculate and atrophy of the thymus were observed in the PNF gel 0.8 mg/kg/day and above groups. In the PN gel group, atrophy of submandibular lymph nodes and mesenteric lymph nodes was observed in addition to the same changes as observed in the PNF gel groups. Furthermore, thinning, atrophy or a decrease in the weight of the adrenal glands was also observed both in the PNF gel 3.2 mg/kg/day group and the PN gel group at the end of the 5-week recovery period. 5. As described above, a decrease in the lymphocyte ratio, in the weight of the thymus and adrenal glands and vacuolation of hepatocytes were observed in the PNF gel 0.8 mg/kg/day and above groups.(ABSTRACT TRUNCATED AT 400 WORDS)

背景与目标： : 在Beagle犬中研究了合成糖皮质激素法呢酸泼尼松龙 (PNF) 凝胶的毒性。PNF凝胶以0.2、0.8和3.2 mg/kg/天的剂量经皮给药13周，然后撤回药物5周以评估可逆性。此外，还施用2 mg/kg/天的泼尼松龙凝胶 (PN凝胶)，其在泼尼松龙摩尔浓度中约为3.2 mg/kg/天的PNF凝胶，以进行比较。研究结果总结如下: 1.在任何PNF凝胶测试组或PN凝胶组中均未观察到死亡，动物的临床体征也没有任何异常发现。2.在血液学中，从PNF凝胶0.8 mg/kg/天及以上组的男性中观察到淋巴细胞比率下降的趋势。在PN凝胶组中，观察到淋巴细胞比率显着降低或趋于降低，并且某些动物的白细胞计数增加。3.在血液生物化学中，在PNF凝胶3.2 mg/kg/天组的男性中观察到总胆固醇和磷脂的显着降低或趋于降低，而在PNF凝胶3.2 mg/kg/天组的女性中观察到甘油三酯的增加趋势。在PN凝胶组中，观察到AIP活性增加的趋势，甘油三酸酯增加的趋势。4.在组织学检查中，胸腺和肾上腺的重量减少，肝脏中间区域的肝细胞空泡化，肾上腺束状带萎缩，肾小球带肥大，在0.8 mg/kg/天及以上的PNF凝胶中观察到透明带皮质细胞肿胀和胸腺萎缩。在PN凝胶组中，除了与PNF凝胶组相同的变化外，还观察到下颌下淋巴结和肠系膜淋巴结的萎缩。此外，在5周恢复期结束时，在PNF凝胶3.2 mg/kg/天组和PN凝胶组中也观察到肾上腺变薄、萎缩或重量减少。5.如上所述，在0.8毫克/千克/天及以上的PNF凝胶中观察到淋巴细胞比率、胸腺和肾上腺重量的降低以及肝细胞的空泡化。(摘要截短于400字)

BACKGROUND & AIMS: :Guided bone regeneration (GBR) is a principle adopted from guided tissue regeneration (GTR). Wherein, GBR is used for the healing of peri-implant bony dehiscences, for the immediate placement of implants into extraction sockets and for the augmentation of atrophic alveolar ridges. This procedure is done by the placement of a resorbable or non-resorbable membrane that will exclude undesirable types of tissue growth between the extraction socket and the soft tissue to allow only bone cells to regenerate in the surgically treated lesion. Here, we investigated the biodegradable effect of polylactic-co-glycolic acid (PLGA) membrane in the alveolar bone on Beagle dogs. Results show that both collagen and PLGA membrane had been fully resorbed, biodegraded, at four weeks post-operative reentry into the alveolar bone. Histological results under light microscopy revealed formation of new bone trabeculae in the extraction sites on both collagen and PLGA membrane. In conclusion, PLGA membrane could be a potential biomaterials for use on GBR and GTR. Nevertheless, further studies will be necessary to elucidate the efficiency and cost effectiveness of PLGA as GBR membrane in clinical.

背景与目标： 引导骨再生 (GBR) 是引导组织再生 (GTR) 的原则。其中，GBR用于修复种植体周围的骨开裂，将植入物立即放置到拔牙窝中以及增加萎缩性牙槽脊。此过程是通过放置可吸收或不可吸收的膜来完成的，该膜将排除拔牙窝和软组织之间不希望的组织生长类型，从而仅允许骨细胞在手术治疗的病变中再生。在这里，我们研究了聚乳酸-乙醇酸 (PLGA) 膜在比格犬牙槽骨中的可生物降解作用。结果表明，胶原蛋白和PLGA膜在术后四周均被完全吸收，生物降解，再次进入牙槽骨。光学显微镜下的组织学结果显示，在胶原蛋白和PLGA膜的提取部位均形成了新的骨小梁。总之，PLGA膜可能是用于GBR和GTR的潜在生物材料。然而，需要进一步的研究来阐明PLGA作为GBR膜在临床中的效率和成本效益。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Male and female dogs, aged 17--21 months, were administered orall M 73101 (0, 60, 120 and 240 mg/kg/day), a new analgesic and antiinflammatory drug, for 27 weeks, and following recovery test was carried out for 5 weeks. Dead animals were not found throughout the experimental period. Body weight gain, and food and water consumption were not affected due to M 73101 administration. Except for a slight increase of vomitting in the highest dose, there were no abnormal symptoms. Biochemical examination showed the slight increase in serum alkaline phosphatase activity and free cholesterol level. Pathological examination revealed a dose-dependent increase of liver weight and hypertrophy of hepatocytes due to proliferation of smooth endoplasmic reticulum. In addition, mitochondria became irregularly large in the highest dose. There were no abnormal findings in the gastro-intestinal tracts except for an erosion of gastric mucosa, which was noted in a female dog treated 240 mg/kg/day of M 73101. From these results, it was suggested that the maximum non-toxic dose was 60 mg/kg/day or less, and the greatest safety dose was 120 mg/kg/day in beagle dogs.

背景与目标： : 雄性和雌性犬，年龄17-21个月，给予或所有M 73101 (0、60、120和240 mg/kg/天) (一种新的止痛和抗炎药物) 27周，然后进行5周的恢复试验。在整个实验期间都没有发现死动物。由于M 73101给药，体重增加以及食物和水的消耗没有受到影响。除了最高剂量的呕吐物略有增加外，没有异常症状。生化检查显示血清碱性磷酸酶活性和游离胆固醇水平略有增加。病理检查显示，由于光滑内质网的增殖，肝脏重量和肝细胞肥大呈剂量依赖性增加。此外，线粒体在最高剂量下不规则地变大。除了胃黏膜的侵蚀外，在胃肠道中没有异常发现，这在240 mg/kg/天的M 73101中被发现。从这些结果表明，在beagle犬中，最大无毒剂量为60 mg/kg/天或更少，最大安全剂量为120 mg/kg/天。

BACKGROUND & AIMS: :The aim of the present study was to find a method to increase oral bioavailability of silymarin, that is to say, by the preparation of silymarin proliposome and to compare the pharmacokinetic characteristics and bioavailability after oral administration of silymarin proliposome and silymarin in beagle dogs. Silymarin proliposome was prepared by the film-deposition on carriers. After the proliposome was contacted with water, the silymarin liposome suspensions formed automatically. The tests of physicochemical properties including SEM, TEM, encapsulation efficiency, dissolution studies, particle size of the reconstituted liposome and stability of the silymarin proliposome were determined by laser-particle-sizer, HPLC, etc. The concentrations of silymarin in plasma of beagle dogs and its pharmacokinetic behaviors after oral administration of silymarin liposome suspensions and silymarin were studied by RP-HPLC. The pharmacokinetic parameters were computed by software program 3p97. The encapsulation efficiency of silymarin liposome could be more than 90%, with an average particle size of about 196.4 nm and the proliposome appeared a very stability at 40 degrees C during 3 months. It was found that mean plasma concentration-time curves of silymarin after oral administration of liposome suspensions and silymarin in beagle dogs were both in accordance with open two-compartments model and first-order absorption. Pharmacokinetic parameters of silymarin proliposome and silymarin in beagle dogs were Tmax both 30 min; Cmax 472.62 and 89.78 ng mL(-1); and AUC0-infinity 2606.21 and 697 ng mL(-1)h, respectively. The high bioavailability of silymarin proliposome could be obtained by oral administration. Silymarin proliposome was stable and did enchance the gastrointestinal absorption of silymarin.

背景与目标： 本研究的目的是找到一种提高水飞蓟素口服生物利用度的方法，即通过制备水飞蓟素前脂质体，并比较口服水飞蓟素前脂质体和水飞蓟素后的药代动力学特征和生物利用度。比格犬。水飞蓟素前体脂质体是通过在载体上沉积膜来制备的。前脂质体与水接触后，水飞蓟素脂质体悬浮液自动形成。通过激光-颗粒-sizer，HPLC等方法测定了水飞蓟素前体脂质体的理化性质，包括SEM，TEM，包封率，溶出度研究，重组脂质体的粒径和稳定性。通过rp-hplc研究了口服水飞蓟素脂质体悬浮液和水飞蓟素后，比格犬血浆中水飞蓟素的浓度及其药代动力学行为。药代动力学参数由软件程序3p97计算。水飞蓟素脂质体的包封效率可以超过90%，平均粒径约为196.4 nm，并且前脂质体在40 ℃ 下在3个月内表现出非常稳定。发现在beagle犬中口服脂质体悬浮液和水飞蓟素后，水飞蓟素的平均血浆浓度-时间曲线均符合开放的两室模型和一阶吸收。水飞蓟素前脂质体和水飞蓟素在比格犬中的药代动力学参数为Tmax均为30分钟; Cmax 472.62和89.78 ng mL(-1); 和AUC0-infinity 2606.21和697 ng mL(-1)h。水飞蓟素前脂质体的高生物利用度可通过口服获得。水飞蓟素前脂质体稳定，并能促进水飞蓟素的胃肠道吸收。

BACKGROUND & AIMS: BACKGROUND:MicroRNAs (miRNA) are varied in length, under 25 nucleotides, single-stranded noncoding RNA that regulate post-transcriptional gene expression via translational repression or mRNA degradation. Elevated levels of miRNAs can be detected in systemic circulation after tissue injury, suggesting that miRNAs are released following cellular damage. Because of their remarkable stability, ease of detection in biofluids, and tissue specific expression patterns, miRNAs have the potential to be specific biomarkers of organ injury. The identification of miRNA biomarkers requires a systematic approach: 1) determine the miRNA tissue expression profiles within a mammalian species via next generation sequencing; 2) identify enriched and/or specific miRNA expression within organs of toxicologic interest, and 3) in vivo validation with tissue-specific toxicants. While miRNA tissue expression has been reported in rodents and humans, little data exists on miRNA tissue expression in the dog, a relevant toxicology species. The generation and evaluation of the first dog miRNA tissue atlas is described here. RESULTS:Analysis of 16 tissues from five male beagle dogs identified 106 tissue enriched miRNAs, 60 of which were highly enriched in a single organ, and thus may serve as biomarkers of organ injury. A proof of concept study in dogs dosed with hepatotoxicants evaluated a qPCR panel of 15 tissue enriched miRNAs specific to liver, heart, skeletal muscle, pancreas, testes, and brain. Dogs with elevated serum levels of miR-122 and miR-885 had a correlative increase of alanine aminotransferase, and microscopic analysis confirmed liver damage. Other non-liver enriched miRNAs included in the screening panel were unaffected. Eli Lilly authors created a complimentary Sprague Dawely rat miRNA tissue atlas and demonstrated increased pancreas enriched miRNA levels in circulation, following caerulein administration in rat and dog. CONCLUSION:The dog miRNA tissue atlas provides a resource for biomarker discovery and can be further mined with refinement of dog genome annotation. The 60 highly enriched tissue miRNAs identified within the dog miRNA tissue atlas could serve as diagnostic biomarkers and will require further validation by in vivo correlation to histopathology. Once validated, these tissue enriched miRNAs could be combined into a powerful qPCR screening panel to identify organ toxicity during early drug development.

背景与目标：

BACKGROUND & AIMS: :The absorption characteristics of vitamin E acetate (VEA) formulated into a dry emulsion system after its oral administration to beagle dogs were determined and compared to those of two different dosage forms (an oily mixture of the drug with cottonseed oil and an oil (drug)-in-water emulsion). The three dosage forms were administered in a crossover fashion to six nonfasting subjects, and the drug absorption was assessed from the plasma concentration of the major metabolite (free vitamin E). VEA formulated in the dry emulsion was rapidly absorbed, which suggested that a considerable amount was released as reformed emulsion droplets in the gastrointestinal tract as well as in water in vitro. Based on the analysis of variance, no significant differences in bioavailability parameters (AUC, Cmax or Tmax) were observed among the three dosage forms.

背景与目标： : 测定了口服给比格犬后配制成干乳液系统的维生素e乙酸酯 (VEA) 的吸收特性，并将其与两种不同剂型 (药物与棉籽油和油 (药物) 的油性混合物) 的吸收特性进行了比较。-水包乳液)。以交叉方式向六名非禁食受试者施用三种剂型，并根据主要代谢物 (游离维生素e) 的血浆浓度评估药物吸收。配制在干燥乳剂中的VEA被迅速吸收，这表明在胃肠道以及体外水中以重整乳剂液滴的形式释放了大量。根据方差分析，在三种剂型之间未观察到生物利用度参数 (AUC，Cmax或Tmax) 的显着差异。

BACKGROUND & AIMS: :The placement of oral implants into jaw bone has a high predictability provided an adequate bone volume surrounding the implant is present to ensure primary stability and resistance to functional loading forces after completion of osseointegration. In the distal area of the maxilla, an adequate bone volume is often lacking because of the proximity of the sinus cavities. The aim of this study was to evaluate histologically the simultaneous placement of endosseous implants into the sinus cavity and the surgical elevation of the sinus floor including filling the cavity with different grafting materials. In 9 sinus areas of 5 beagle dogs, 9 titanium implants (ITI Dental Implant System) were placed, and the void space of the sinus cavity was filled simultaneously with either demineralized freeze-dried human cortical bone (Musculoskeletal Transplant Foundation), resorbable hydroxyapatite (Osteogen) or natural cancelleous bovine bone mineral (Bio-Oss). To study bone formation, fluorochrome markers (tetracycline HCl and calcein green) were used at 2 and 8 weeks. Clinically, all implants healed uneventfully, and 5 months after implant placement the dogs were killed for histologic evaluation. All implants exhibited osseointegration within the pre-existing cortical bone of the sinus floor. The implants surrounded by freeze-dried bone xenografts yielded no formation of new bone, whereas the sites with hydroxyapatite or natural bovine bone mineral demonstrated newly formed bone with direct contact at the implant surface. The average extent of bone to implant contact was 25% (SD = 10.6%) and 27% (SD = 8.8%), respectively in relation to the length of the originally denuded implant surface.(ABSTRACT TRUNCATED AT 250 WORDS)

背景与目标： : 口腔植入物在颌骨中的放置具有很高的可预测性，前提是植入物周围存在足够的骨体积，以确保在完成骨整合后的主要稳定性和对功能加载力的抵抗力。在上颌骨的远端区域，由于窦腔的接近，通常缺乏足够的骨骼体积。这项研究的目的是从组织学上评估将骨内植入物同时放置到窦腔中以及窦底的手术抬高，包括用不同的移植材料填充腔。在5只beagle犬的9个窦区，放置9个钛植入物 (ITI牙科植入物系统)，同时用脱矿质冻干的人皮质骨 (肌肉骨骼移植基础) 填充窦腔的空隙，可吸收的羟基磷灰石 (骨原) 或天然的非天然牛骨矿物质 (Bio-Oss)。为了研究骨形成，在第2周和第8周使用了荧光染料标记物 (四环素HCl和钙绿素)。临床上，所有植入物均顺利愈合，植入后5个月，将狗杀死以进行组织学评估。所有植入物均在窦底预先存在的皮质骨内表现出骨整合。被冻干的异种骨所包围的植入物没有形成新的骨，而羟基磷灰石或天然牛骨矿物质的部位显示出新形成的骨，并在植入物表面直接接触。骨与植入物接触的平均程度分别为25% (SD = 10.6%) 和27% (SD = 8.8%)，与最初剥去的植入物表面的长度有关。(摘要截断为250字)

BACKGROUND & AIMS: :We isolated and purified 35 kDa protein from the myocardium of the beagle dog and identified it to be annexin V from partial amino acid sequence determination. It was confirmed that anticanine cardiac annexin V rabbit polyclonal antibody, which was produced using the 35 kDa protein, cross-reacts with annexin V of the myocardium, lung, liver, kidney, and brain of the rat. The localization of cardiac annexin V and the effect of ischemia for 30-180 min in the rat were immunohistochemically studied with the use of the Langendorff perfusion heart. In the normal myocardium, annexin V, accompanied by cross-striation, was observed throughout the cell. In ischemia of 30 min, extracellular leakage of annexin V was observed with uneven staining in the cytoplasm. When the ischemic time exceeded 60 min, annexin V was observed in the cell membrane with a decrease of annexin V in the cytoplasm. Also, extracellular leakage of annexin V was observed prominently. In ischemia for 180 min, almost all the annexin V in the cytoplasm disappeared. These results suggest that the level of ischemia can be estimated from the changes in localization of annexin V.

背景与目标： : 我们从beagle犬的心肌中分离并纯化了35 kDa蛋白，并通过部分氨基酸序列测定将其鉴定为膜联蛋白V。已证实，使用35 kDa蛋白产生的抗ancine心脏膜联蛋白V兔多克隆抗体与大鼠心肌，肺，肝，肾和脑的膜联蛋白V发生交叉反应。使用Langendorff灌注心脏免疫组织化学研究了大鼠心脏膜联蛋白V的定位和缺血30-180分钟的作用。在正常心肌中，在整个细胞中观察到膜联蛋白V伴有横纹。在缺血30分钟时，观察到膜联蛋白V的细胞外渗漏，细胞质染色不均匀。当缺血时间超过60分钟时，在细胞膜中观察到膜联蛋白V，胞浆中膜联蛋白V减少。此外，显着观察到膜联蛋白V的细胞外渗漏。在缺血180分钟时，细胞质中的膜联蛋白V几乎全部消失。这些结果表明，可以从膜联蛋白V的定位变化来估计缺血水平。

BACKGROUND & AIMS: Bergamottin, a furanocoumarin isolated from grapefruit juice, was investigated for the ability to increase diazepam bioavailability and for its effect on cytochrome P450 (P450) enzymes in the beagle dog liver and intestine. To study the effect of bergamottin on diazepam pharmacokinetics, male beagle dogs were dosed with bergamottin (1 mg/kg) p.o. 0 or 2 h before p.o. diazepam (10 mg). In a second experiment, bergamottin (0.1 mg/kg) was dosed i.v. or p.o. 1 h before p.o. diazepam (10 mg). Plasma samples were collected over 24 h postdose, analyzed by liquid chromatography/mass tandem spectrometry, and diazepam pharmacokinetic parameters were determined. To study the effect of bergamottin on P450 enzymes, beagle dog liver and jejunum was harvested after a 10-day dosing regimen of bergamottin (1 mg/kg) p.o. per day; microsomes were prepared and analyzed for CYP3A12, CYP2B11, CYP1A1/2, and tolbutamide hydroxylase activity. Bergamottin predosing increased the plasma levels of diazepam as observed by C(max) (278.75 ng/ml versus 5.49 ng/ml) and the area under the curve [AUC((0-TLDC))] (247.69 versus 2.79 ng x hr/ml) in bergamottin versus placebo groups, respectively, indicating P450 enzyme inhibition. Diazepam plasma concentrations were increased to a similar level in the presence of i.v. and p.o. administered bergamottin. In hepatic microsomes, bergamottin treatment for 10 days reduced the activity of CYP3A12 by 50% and CYP1A1/2 by 75%. Tolbutamide hydroxylase activity did not change, and CYP2B11 activity was moderately induced. In jejunal microsomes, CYP3A12 activity doubled with bergamottin treatment. CYP2B11, CYP1A1/2 activity and tolbutamide hydroxylation was not detected. In conclusion, bergamottin is both an inhibitor and an inducer of P450 enzymes.

背景与目标： 研究了从葡萄柚汁中分离出的呋喃香豆素bergamotin，以提高地西epa的生物利用度及其对beagle狗肝脏和肠中的细胞色素P450 (P450) 酶的影响。为了研究佛手柑汀对地西epa药代动力学的影响，雄性比格犬服用佛手柑汀 (1 mg/kg) p.o.p.o.前0或2小时。地西epa (10 mg)。在第二个实验中，静脉注射佛手柑 (0.1 mg/kg)。或者p.o.邮政前1小时。地西epa (10 mg)。给药后24小时内收集血浆样品，通过液相色谱/质谱分析，并确定地西epa的药代动力学参数。为了研究佛手柑素对P450酶的影响，在佛手柑素 (1 mg/kg) p.o的10天给药方案后，收获了beagle狗的肝脏和空肠。每天; 制备微粒体并分析CYP3A12，CYP2B11，CYP1A1/2和甲苯磺丁酰胺羟化酶活性。Bergamotgin预给药增加了C(max) (278.75 ng/ml对5.49 ng/ml) 和曲线下面积 [AUC((0-TLDC))] (247.69对2.79 ng x hr/ml) 观察到的地西epa的血浆水平/ml) 在bergamotgin与安慰剂组中分别，表明P450酶抑制。在静脉注射的情况下，地西epa的血浆浓度增加到相似的水平。和p.o.注射佛手柑。在肝微粒体中，佛耳加莫汀治疗10天可使CYP3A12的活性降低50% 和CYP1A1/2的活性降低75%。甲苯磺丁酰胺羟化酶活性没有变化，并且适度诱导了CYP2B11活性。在空肠微粒体中，贝加莫丁治疗后CYP3A12的活性增加了一倍。未检测到CYP2B11，CYP1A1/2活性和甲苯磺丁酰胺羟基化。总之，佛手柑既是P450酶的抑制剂又是诱导剂。

BACKGROUND & AIMS: :1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2. The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg-1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg-1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg-1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h-1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3. Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min-1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4. ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of propranolol (approximately by 30 beats min-1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone.5. Cardiac inotropism, as indicated by dPLv/dt max, was not affected by ZD7288 or zatebradine at rest,although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3mg kg-1).6. Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, propranolol did not affect resting stroke volume and decreased the responses to exercise.7. Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction.8. In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.

背景与目标： : 1。ZENECA ZD7288 (4-(N-乙基-N-苯基氨基)-1,2-二甲基-6-(甲基氨基) 嘧啶鎓氯化物，以前称为ICI D7288) 是一种新型的心房结功能调节剂，可选择性地减慢心率。2.评估了ZD7288 (0.1、0.3和1.0 mg kg-1，静脉注射) 的血流动力学作用，并将其与安慰剂 (生理盐水)，扎雷丁 (ULFS 49、0.1、0.3和1.0 mg kg-1，i.v.) 和普洛尔 (0.03，0.1和0.3 mg kg-1，i.v.) 在比格犬中长期用于测量心率，主动脉压，主动脉流量和dPLV/dtmax。训练狗在水平跑步机上以6.5 k h-1在4小时的时间内以半小时间隔跑步5分钟。在第二，第四和第六个运动期之后累计给药。3.对照实验证明了在4小时内对重复运动的适应程度。静息心率min-1降低了21次，但对运动的心率响应得以维持，而静息时dPLV/dtmax保持稳定，而对运动的响应显着降低 (2小时后25%，P <0.05)。4. ZD7288和zatebradine均以剂量依赖性方式降低了运动期间的心率，而静息时的心率与盐水剂量的对照动物的静息心率没有差异。相比之下，最低剂量的普萘洛尔 (min-1约30次搏动) 可使休息和运动期间的心率平均降低，而额外剂量仅引起轻微的额外降低。运动诱发的心动过速维持在给药前水平的12% 内，可能是通过停用迷走神经音来实现的。5.如dPLv/dt max所示，心脏正性肌力在静止时不受ZD7288或zatedradine的影响，尽管对运动的正性肌力反应与运动引起的心动过速的减少成正比。普萘洛尔引起运动诱导的正性肌力反应的显著剂量依赖性降低 (以0.3mg kg-1 85%) 6.尽管窦房结调节剂增加了静息时的中风量，并增加了对运动的反应，但普萘洛尔不影响静息的中风量，并降低了对运动的反应7.在ZD7288和zatebradine的存在下，可以很好地维持静息时的心输出量和心输出量的增加，而普萘洛尔在静息和运动期间均引起明显的心输出量下降。普萘洛尔也引起明显的全身性血管收缩。总之，尽管ZD7288的化学性质不同，但其血液动力学作用可与zatebradine相当。ZD7288可以通过降低心率而不损害心脏功能来治疗缺血性心脏病。

BACKGROUND & AIMS: BACKGROUND AND PURPOSE:Body core temperature (Tc) changes affect the QT interval, but correction for this has not been systematically investigated. It may be important to correct QT intervals for drug-induced changes in Tc. EXPERIMENTAL APPROACH:Anaesthetized beagle dogs were artificially cooled (34.2 degrees C) or warmed (42.1 degrees C). The relationship between corrected QT intervals (QTcV; QT interval corrected according to the Van de Water formula) and Tc was analysed. This relationship was also examined in conscious dogs where Tc was increased by exercise. KEY RESULTS:When QTcV intervals were plotted against changes in Tc, linear correlations were observed in all individual dogs. The slopes did not significantly differ between cooling (-14.85+/-2.08) or heating (-13.12+/-3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 degrees C: QTcVcT (QTcV corrected for changes in core temperature)=QTcV-14 (37.5 - Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 degrees C) and marked QTcV shortening (-29%) was induced. After Tc correction, using the above formula, this decrease was abolished. In these re-warmed dogs, we observed significant increases in T-wave amplitude and in serum [K(+)] levels. No arrhythmias or increase in pro-arrhythmic biomarkers were observed. In exercising dogs, the above formula completely compensated QTcV for the temperature increase. CONCLUSIONS AND IMPLICATIONS:This study shows the importance of correcting QTcV intervals for changes in Tc, to avoid misleading interpretations of apparent QTcV interval changes. We recommend that all ICH S7A, conscious animal safety studies should routinely measure core body temperature and correct QTcV appropriately, if body temperature and heart rate changes are observed.

背景与目标：

BACKGROUND & AIMS: :Regeneration of the corpus spongiosum helps prevent complications following urethral reconstruction, but currently there is a lack of effective therapeutic methods in clinic. In previous studies, we fabricated a fusion protein collagen-binding domain (CBD)-basic fibroblast growth factor (bFGF) that specifically binds to and releases from collagen biomaterials. We demonstrated that CBD-bFGF could promote angiogenesis and tissue regeneration in vivo. In this study, we established a beagle model with extensive urethral defects, and reconstructed the defects with collagen biomaterials that were unmodified or modified with CBD-bFGF. The results demonstrate that CBD-bFGF promotes corpus spongiosum regeneration resulting in improved outcomes following urethral reconstruction. Modifying collagen biomaterials with CBD-bFGF may represent an effective strategy for urethral substitution in urethral reconstruction.

背景与目标： : 海绵体再生有助于预防尿道重建术后并发症，但目前临床上缺乏有效的治疗方法。在先前的研究中，我们制造了一种融合蛋白胶原结合结构域 (CBD)-碱性成纤维细胞生长因子 (bFGF)，该蛋白特异性结合并从胶原生物材料中释放。我们证明CBD-bFGF可以促进体内血管生成和组织再生。在这项研究中，我们建立了具有广泛尿道缺陷的beagle模型，并用未经CBD-bFGF修饰或修饰的胶原蛋白生物材料重建了缺陷。结果表明，CBD-bFGF促进海绵体再生，从而改善尿道重建后的预后。用cbd-bfgf修饰胶原蛋白生物材料可能是尿道重建中尿道替代的有效策略。

BACKGROUND & AIMS: :The 2003 Beagle 2 Mars lander has been identified in Isidis Planitia at 90.43° E, 11.53° N, close to the predicted target of 90.50° E, 11.53° N. Beagle 2 was an exobiology lander designed to look for isotopic and compositional signs of life on Mars, as part of the European Space Agency Mars Express (MEX) mission. The 2004 recalculation of the original landing ellipse from a 3-sigma major axis from 174 km to 57 km, and the acquisition of Mars Reconnaissance Orbiter High Resolution Imaging Science Experiment (HiRISE) imagery at 30 cm per pixel across the target region, led to the initial identification of the lander in 2014. Following this, more HiRISE images, giving a total of 15, including red and blue-green colours, were obtained over the area of interest and searched, which allowed sub-pixel imaging using super high-resolution techniques. The size (approx. 1.5 m), distinctive multilobed shape, high reflectivity relative to the local terrain, specular reflections, and location close to the centre of the planned landing ellipse led to the identification of the Beagle 2 lander. The shape of the imaged lander, although to some extent masked by the specular reflections in the various images, is consistent with deployment of the lander lid and then some or all solar panels. Failure to fully deploy the panels-which may have been caused by damage during landing-would have prohibited communication between the lander and MEX and commencement of science operations. This implies that the main part of the entry, descent and landing sequence, the ejection from MEX, atmospheric entry and parachute deployment, and landing worked as planned with perhaps only the final full panel deployment failing.

背景与目标： : 2003 Beagle 2火星着陆器已在Isidis Planitia中被识别为90.43 °  E，11.53 °  N，接近90.50 °  E，11.53 °  N的预测目标。Beagle 2是一种外生物学着陆器，旨在寻找火星上的同位素和成分生命迹象，这是欧洲航天局火星快车 (MEX) 任务的一部分。2004从3西格玛长轴从174  km重新计算到57  km的原始着陆椭圆，以及在目标区域以每像素30  cm的速度获取火星侦察轨道器高分辨率成像科学实验 (HiRISE) 图像，导致着陆器2014年的初步识别。此后，在感兴趣的区域上获得了更多HiRISE图像，总共获得了15张，包括红色和蓝绿色，并进行了搜索，从而可以使用超高分辨率技术进行亚像素成像。尺寸 (约1.5  m)，独特的多叶形状，相对于当地地形的高反射率，镜面反射以及靠近计划着陆椭圆中心的位置导致了Beagle 2着陆器的识别。成像的着陆器的形状虽然在某种程度上被各种图像中的镜面反射所掩盖，但与着陆器盖的部署以及部分或全部太阳能电池板的部署一致。如果无法完全部署面板 (可能是由于着陆过程中的损坏造成的)，则将禁止着陆器与MEX之间的通信以及科学操作的开始。这意味着进入，下降和着陆序列的主要部分，从MEX的弹出，大气进入和降落伞的部署以及着陆按计划进行，可能只有最终的完整面板部署失败。

BACKGROUND & AIMS: :Tooth agenesis is a common craniofacial congenital malformation in humans, but little is known about the mechanisms of root resorption in this condition. The purpose of this study was to investigate the mechanisms of root resorption in primary molars without successors. An animal model without permanent tooth germs was established by surgery in beagles. The times of onset of primary molar root resorption, with and without successors, were compared. The distribution of immune cells, odontoclasts, and their activating factors were determined by histochemistry and immunohistochemistry. Root resorption of primary mandibular molars without successors began later than physiological resorption. In primary molars without permanent germs, odontoclasts and immune cells were present mainly in the apical pulp at the start of root resorption, whereas in control teeth receptor activator of nuclear factor-κB ligand (RANKL)-positive cells were found mainly in the region of the periodontal ligament. CD14(+) and CD3(+) cells were found in both the pulp and the periodontal ligament region. These results suggest that the dental pulp of primary molars, as well as immune cells, may play an important role in root resorption in primary molars without permanent tooth germs.

背景与目标： : 牙齿发育不全是人类常见的颅面先天性畸形，但对这种情况下的牙根吸收机制知之甚少。目的探讨无后继磨牙根吸收的机制。通过手术在小猎犬中建立了没有恒牙病菌的动物模型。比较了有和没有后继的初级磨牙根吸收的开始时间。通过组织化学和免疫组织化学确定免疫细胞，牙本质细胞及其激活因子的分布。没有后继的下颌磨牙的根部吸收比生理吸收晚。在没有永久性细菌的初级磨牙中，牙本质细胞和免疫细胞主要存在于牙根吸收开始时的根尖牙髓中，而在对照牙齿中，核因子-κ b配体 (RANKL) 阳性细胞的受体激活剂主要存在于牙周膜区域。在牙髓和牙周膜区域均发现CD14 () 和CD3 () 细胞。这些结果表明，在没有恒牙病菌的初级磨牙中，初级磨牙的牙髓以及免疫细胞可能在牙根吸收中起重要作用。