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J D Cooper

Publications and source records attributed to J D Cooper.

At least 91 records · Page 5Linked to original sources
PubMed1997

Adenovirus mediated gene transfer into rat lung grafts at the time of harvest.

OBJECTIVE: New methods to introduce genetic material into cells in vivo may revolutionize current treatment modalities. Expression of functional genes in lung allografts could be used as a prophylactic strategy for reperfusion injury and rejection. We studied the feasibility of ex vivo adenovirus mediated transfection of rat lung allografts. METHODS: In group I (n = 3) donor rat lungs (Fisher) were flushed with Low Potassium Dextran Glucose (LPDG) solution (20 ml, 20 degrees C). 4 x 10(11) viral particles of adenovirus 5 containing the E. coli lacZ reporter gene coding for beta-galactosidase (AdCMV-beta-Gal) were added to the last milliliter of the flush solution. Lung grafts were stored for 3.5 h at room temperature followed by syngenic orthotopic transplantation (Fisher to Fisher) using a microsurgical cuff technique. On postoperative day 5 the heart lung block was extracted and flushed with x-Gal (beta-Gal substrate) and kept in x-Gal for 3 h at 37 degrees C. Color development was observed macroscopically and plastic embedded sections were used for histologic examination. Group II grafts (n = 3) served as controls and were flushed without adenovirus. RESULTS: X-Gal stained the transfected lung grafts blue, indicating high reporter gene expression. Control lungs did not stain with x-Gal. In group I histological examination demonstrated transfection predominantly in type II pneumocytes. Surprisingly endothelial cells showed no beta-Gal activity. CONCLUSION: This study demonstrates that ex vivo transfection of lung grafts at the time of harvest is a feasible method of gene transfer and results in gene expression after transplantation.

Adenoviridae↗
PubMed1997

Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers.

AIMS: The aim of this study was to compare the pharmacokinetics of the anti-epileptic agent, lamotrigine, in patients with chronic renal failure and healthy volunteers. METHODS: Non-compartmental pharmacokinetics of a single oral dose (200 mg) of the anti-epileptic agent, lamotrigine, and its main metabolite, lamotrigine N2-glucuronide, were determined for 10 patients with chronic renal failure of mean estimated creatinine clearance 18 ml min-1 and a control group of 11 healthy volunteers, matched for age and gender. RESULTS: For lamotrigine, there were no significant differences in Cmax, tmax, AUC, t1/2,z, CL/F and amount excreted in urine although t1/2,z tended to be longer for the renal failure group with a mean (+/-s.d.) of 35.9 +/- 10.7 h vs 27.8 +/- 4.3 h for the control group. For the renal failure group. VZ/F was 18% higher (95% CI 1% to 39%) compared with controls and CLR was reduced to 61% (95% CI 46% to 80%) of the control group value. For lamotrigine glucuronide, Cmax was increased 4-fold (95% CI 3.1 to 5.3) and AUC 7.8-fold (95% CI 6.0 to 10.1) in the renal failure group compared with controls. CLR was approximately 9-fold lower and apparent t1/2 was increased by 53% (95% CI 27% to 84%). Concentrations of an N2-methylated cardio-active metabolite, previously observed in dogs, were below the limit of detection (2 ng ml-1) of the ASTED/h.p.l.c. assay in the renal failure group as well as controls. CONCLUSIONS: These results indicate that impaired renal function will have little effect on the plasma concentrations of lamotrigine achieved for a given dosing regimen.

Administration, Oral↗
PubMed1997

Recent advances in surgery for emphysema.

Volume reduction surgery is based on the removal of volume-occupying but nonfunctioning emphysematous lung, which is thought to improve pulmonary elastic recoil. The reduction in thoracic volume may also improve thoracic cage and inspiratory muscle function. In addition, dyspnea is lessened, exercise tolerance is increased, and measured pulmonary function is improved. Alveolar gas exchange may also be improved. Selection criteria include marked airway obstruction secondary to emphysema, marked hyperinflation of the chest wall, and regional heterogeneity in the distribution of the emphysema. The best results are obtained with a bilateral procedure utilizing stapling resection. The two surgical approaches are median sternotomy and video-assisted thoracic surgery.

Endoscopy↗
PubMed1997

Patients with emphysema: quantitative CT analysis before and after lung volume reduction surgery. Work in progress.

PURPOSE: To quantitatively assess the morphologic changes in the lungs after lung volume reduction surgery and determine whether changes at quantitative computed tomography (CT) reflect changes in lung function. MATERIALS AND METHODS: In 10 patients, chest CT images were obtained at full inspiration and expiration before and after surgery. A semiautomated segmentation method was developed to isolate the lung regions and calculate the lung volumes and frequency distribution of attenuation values. The changes in lung volume and attenuation after surgery were compared with clinical findings, and an exploratory evaluation of outcome predictors was conducted. RESULTS: Semiautomated segmentation and quantitative analysis compared favorably with manual techniques, and there was good correlation between the emphysema indexes and percentage predicted forced expiratory volume in 1 second, forced expiratory volume in 1 second/forced vital capacity, and diffusing capacity. The emphysema index decreased from 60% to 38% at inspiration and from 60% to 27% at expiration after surgery. The average CT lung volume decreased from 7.5 to 5.6 L at inspiration (25%) and from 6.4 to 3.8 L (41%) at expiration after surgery and correlated well with measurements at plethysmography. CONCLUSION: Substantial decreases in the lung volumes and emphysema index, increased airflow, possible reexpansion of some remaining lung, and the relation between preoperative quantitative CT indexes and clinical outcome suggest a multifactorial mechanism for improvement seen after surgery.

Adult↗
PubMed1997

Lung volume reduction surgery: comparison of preoperative radiologic features and clinical outcome.

PURPOSE: To examine the relationship between preoperative radiologic findings and clinical outcome after lung volume reduction surgery. MATERIALS AND METHODS: In 50 consecutive patients, preoperative chest radiographs and computed tomographic (CT) scans were scored by four radiologists for features related to the severity and distribution of emphysema and compared with clinical improvement in forced expiratory volume in 1 second (FEV1), arterial partial pressure of oxygen, and exercise tolerance 6 months after surgery. RESULTS: In the 47 surviving patients, follow-up data showed greater postoperative improvement in function in patients with a global pattern of predominantly upper-lobe emphysema (P < .05) and in patients with a more heterogeneous distribution of emphysema, compressed lung, and a larger percentage of normal and mildly emphysematous lung (P < .05 for improvement in FEV1). Radiographic scores for individual features were more strongly correlated with outcome than CT scores. The combination of upper-lobe severity and percentage of normal and mildly emphysematous lung at CT were the strongest predictors of improvement in FEV1 (r2 = .49). The three patients who died were older (P = .05) and had more severe, diffuse emphysema compared with other patients. CONCLUSION: Imaging studies may help predict the degree of improvement and therefore should be considered an integral part of an objective patient selection process. Radiography alone may be adequate for initial screening.

Adult↗
PubMed1997

Pulmonary emphysema: comparison of preoperative quantitative CT and physiologic index values with clinical outcome after lung-volume reduction surgery.

PURPOSE: To compare quantitative computed tomographic (CT) and preoperative physiologic values in emphysema with outcome after lung-volume reduction surgery. MATERIALS AND METHODS: In 46 patients, emphysema was quantified by measuring lung attenuation on preoperative CT scans. Quantitative CT and preoperative physiologic values and postoperative outcomes (1-second forced expiratory volume, PaO2, and 6-minute walk distance) were compared. RESULTS: Moderately strong correlations were found between several quantitative CT and preoperative physiologic values (magnitude of r = .29-.58, P < .05) and several quantitative CT and outcome measures (magnitude of r = .31-.47, P < .05). With stratification, postoperative outcome was better with mean lung attenuation greater than -900 HU; 75% or greater of upper lung below -900 HU (emphysema index); greater than 25% of lung below -960 HU (severe emphysema index); ratio of upper- and lower-lung emphysema indexes 1.5 or greater; volume of normally attenuated lung (-850 to -701 HU) greater than 1 L; and full width at half maximum of attenuation-frequency distribution 80 HU or less. Differences in outcome measures between groups stratified with quantitative CT values were often two- to threefold; patients with greater numbers of favorable quantitative CT values had better outcome. Correlations between preoperative physiologic measures and outcome were few. CONCLUSION: In emphysema, quantitative CT values correlate with outcome. Quantitative assessment of emphysema in candidates for lung-volume reduction surgery is potentially useful.

Adult↗
PubMed1997

Perfusion scintigraphy in the evaluation for lung volume reduction surgery: correlation with clinical outcome.

PURPOSE: To identify preoperative pulmonary perfusion scintigraphic findings that might be associated with clinical outcomes after lung volume reduction surgery. MATERIALS AND METHODS: Preoperative perfusion scintigrams in 103 patients (56 men, 47 women; age range, 41-76 years; mean age, 61 years +/- 9) were reviewed and graded for emphysematous heterogeneity (from isolated areas to diffuse distribution), extent of maximally perfused lung, and lobar predominance (upper-lobe vs lower-lobe asymmetry). These findings were correlated with clinical outcome on the basis of pulmonary function, arterial blood gas levels, and exercise test results before and 6 months after surgery. RESULTS: Among the 96 patients who survived surgery, there was an average improvement of 47% in the forced expiratory volume in 1 second (FEV1), of 20% in arterial oxygen tension, and of 20% in the 6-minute walking distance. Scintigraphic markers correlated best with FEV1 improvement. The strongest scintigraphic predictor of increase in FEV1 was upper-lobe predominance (r = .38, P < .001), which was followed by heterogeneity (r = .31, P = .002). The seven patients who died had a significantly lower percentage of maximally perfused lung than the survivors (25% vs 34%, P = .004). CONCLUSION: Perfusion scintigraphy can provide modest prognostic information in patients who undergo evaluation for lung volume reduction surgery.

Adult↗
PubMed1997

Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVE: The objective of this study was to assess the performance of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in the staging of cancer in patients with esophageal carcinoma. MATERIALS AND METHODS: The findings of FDG PET and of CT in the chest and upper abdomen of 36 patients with newly diagnosed esophageal carcinoma were compared with pathologic findings obtained either during a curative surgical procedure with tissue sampling (n = 29) or by tissue sampling alone (n = 7). RESULTS: Abnormal FDG uptake was identified on PET in the esophageal tumors of all patients. In 29 patients who underwent curative esophagectomy, PET and CT accurately revealed the extent of nodal disease in 76% (22/29) and 45% (13/29) of patients, respectively. In the seven patients who underwent tissue sampling instead of complete esophagectomy, PET revealed metastatic disease in five patients, all of whom avoided needless surgery. CT failed to reveal metastatic disease in these five patients. In addition, PET incidentally revealed an unsuspected primary long carcinoma in one patient. CONCLUSION: FDG PET is more sensitive than CT for revealing regional and distant metastases in patients with esophageal carcinoma. The use of PET in the staging of esophageal cancer may prove to be cost-effective by decreasing the number of unnecessary surgeries in patients with unresectable tumors.

Adenocarcinoma↗
PubMed1997

Current role of esophageal function studies.

The introduction of laparoscopic techniques for performing anti-reflux surgery has led to a significant increase in the number of such procedures being performed. Furthermore, the threshold of symptoms required for performance of such procedures seems to have been lowered. For these reasons, it is more important than ever to ensure that symptoms attributed to gastroesophageal reflux are appropriately evaluated for a high rate of clinical success after anti-reflux surgery. Clinical assessment requires a careful history, expert radiographic assessment, and endoscopy by an experienced observer. Objective measurements including esophageal manometry, acid perfusion studies, and 24-hour esophageal pH monitoring continue to play an important role in the diagnosis and management of associated functional disorders of the esophagus.

Esophagus↗
PubMed1997

Carbohydrate selectin inhibitor CY-1503 reduces neutrophil migration and reperfusion injury in canine pulmonary allografts.

BACKGROUND: Neutrophil adhesion is initiated by the interaction of rapidly expressed endothelial selectins with oligosaccharide structures (sialyl Lewis(x) on polymorphonuclear neutrophils (PMN). The carbohydrate sialyl Lewis X analogue CY-1503 blocks selectin receptors, thereby inhibiting PMN rolling and subsequent firm adhesion and migration. METHODS: We evaluated the inhibitory effect of CY-1503 on PMN migration and reperfusion injury in canine left lung allografts. Donor lungs were flushed with modified Euro-Collins solution (1500 ml, 4 degrees C) and preserved for 21 hours at 1 degree C. Left lung allotransplantation was subsequently performed in 14 mongrel dogs. Immediately after transplantation and allograft reperfusion, the recipient contralateral right pulmonary artery and bronchus were ligated to permit assessment of isolated allograft function during a 6-hour postreperfusion period (FIO2 = 1.0). Allograft gas exchange (q 15 minutes) and hemodynamics (q 60 minutes) were assessed. After sacrifice, allograft bronchoalveolar lavage fluid (BALF) PMN count and allograft tissue myeloperoxidase (MPO) activity were measured. Two groups were studied: In group I (n = 7) CY-1503 was added to the donor lung flush (20 mg/L) and given to the recipient (35 mg/kg intravenous bolus) before reperfusion, followed by a continuous infusion (5.25 mg/kg/h intravenously) during the 6-hour assessment period. Group II animals (n = 7) received no CY-1503. RESULTS: Gas exchange in group I was superior throughout the assessment period (p < 0.01 at 6 hours after reperfusion). BALF PMN count in group I was reduced to 0.57 +/- 0.3 x 10(6) PMN/ml compared with 3.9 +/- 1.3 x 10(6) PMN/ml in group II (p < 0.05). Group I allograft MPO activity was 0.21 +/- 0.06 compared with 0.40 +/- 0.02 delta OD/mg/ min in controls (p < 0.02). Two animals in each group died early after reperfusion as a result of graft failure and were excluded from analysis. CONCLUSIONS: Our observations indicate that selectin inhibition effectively reduces PMN adhesion, migration, and subsequent reperfusion injury in preserved canine lung allografts.

Animals↗
PubMed1997

Preharvest nitroprusside flush improves posttransplantation lung function.

BACKGROUND: Morbidity as a result of early allograft dysfunction remains a significant problem in clinical lung transplantation. We previously demonstrated that nitroprusside (NP), a potent nitric oxide donor, administered before storage and again during reperfusion, reduced lung reperfusion injury. The purpose of the present study was to determine whether these observations were storage effects, reperfusion effects, or both. MATERIALS AND METHODS: Fifteen dogs underwent left lung allotransplant. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1 degree C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (FIO2 1.0) were assessed for 6 hours before sacrifice. Allograft myeloperoxidase (MPO) activity and wet to dry weight (W/D) ratio were assessed. Animals were divided into three groups for timing of NP administration. Group I (n = 5) animals received no NP. In group II (n = 5), donor lungs received NP (10 mg/L) in the flush solution only. In group III (n = 5), recipient animals received NP (0.2 mg/kg) just before reperfusion, as well as a continuous infusion (0.1 mg/kg/hr) during the assessment period. RESULTS: Significant improvement in gas exchange was apparent in groups II and III compared with group I, but there was no significant difference between groups II and III. After 6-hour reperfusion, mean PaO2 values were 85.46 +/- 13.32 mm Hg in group I, 298.74 +/- 61.25 mm Hg in group II (p < 0.05), and 311.12 +/- 43.39 mm Hg in group III (p < 0.05). Systemic vascular resistance was significantly lower in group III than in group I (p < 0.05). MPO activities decreased in groups II (p < 0.05) and III (p < 0.05), indicating reduced neutrophil sequestration. W/D ratio was significantly lower in groups II and III. CONCLUSION: Both methods of NP administration are effective, but NP administration in the recipient is accompanied by a decrease in systemic vascular resistance. From a clinical point of view, NP administration in the flush solution is a sufficiently effective and practical method to reduce lung allograft reperfusion injury.

Analysis of Variance↗
PubMed1996

Results of a trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall cell lung cancer.

PURPOSE: To conduct a dose escalation clinical study with topotecan and concurrent standard dose thoracic irradiation to assess its feasibility and toxicity in the treatment of patients with locally advanced, inoperable nonsmall cell lung cancer (NSCLCA). METHODS AND MATERIALS: Between April 1993 and August 1994, 12 patients with inoperable, loco-regionally advanced NSCLCA were entered in a prospective dose escalation trial and assigned to receive concurrent thoracic radiotherapy and topotecan. Patients received thoracic irradiation to a total tumor dose of 60 Gy in 30 fractions. Initial fields were to encompass the gross disease plus the mediastinum. Topotecan was delivered by bolus injection days 1 through 5, and days 22 through 26, beginning on the same day as the radiation therapy. The initial dose level was 0.5 mg/m2. Two additional dose levels of 0.75 mg/m2 and 1.0 mg/m2 were tested. RESULTS: Six patients were accessioned to the 0.5 mg/m2 dose level, three patients to the 0.75 mg/m2 dose level, and three patients to the 1.0 mg/m2 dose level. At the 0.5 mg/m2 dose level, zero of six patients had > or = Grade 4 hematologic toxicity. One of the six had Grade 3 esophagitis. At the 0.75 mg/m2 dose level, two of three patients had > or = Grade 3 nonhematologic toxicity including anorexia, fatigue, nausea, vomiting, and weakness; zero patients experienced > or = Grade 4 hematologic toxicity. At the 1.0 mg/m2 dose level one of three patients had > or = Grade 3 esophagitis, and two of three patients experienced Grade 4 neutropenia. With a follow-up of 12 to 24 months, two patients are alive and free of disease, three patients are alive with disease (two with distant metastasis, one with local disease and distant metastasis), and the remaining seven patients are dead of disease. CONCLUSIONS: The combination of topotecan and thoracic radiotherapy for nonsmall lung cancer, in the manner given by this protocol, could be safely given at a dose level of only 0.5 mg/m2 days 1 to 5 and 22 to 26 with 60 Gy of external beam radiotherapy. Higher doses of topotecan were associated with high hematologic and gastrointestinal toxicity. Distant metastasis was the primary pattern of failure.

Aged↗
PubMed1996

Attenuation of rat lung isograft reperfusion injury with a combination of anti-ICAM-1 and anti-beta2 integrin monoclonal antibodies.

Four different combinations of monoclonal antibodies against rat ICAM-1, CD-11a, and CD-18 were utilized to determine the relative importance of LFA-1, Mac-1, and ICAM-1 in a rat model of severe lung allograft reperfusion injury. Negative control animals were given phosphate buffered saline (the carrier solution for the antibodies), while positive control animals were rendered neutropenic by the administration of a polyclonal mouse IgG. Antibodies were given with the donor lung flush, prior to left lung graft reperfusion, or both. Isolated graft function was determined 24 hr after implantation by arterial blood gas (ABG), and after sacrifice the native and transplanted lungs underwent bronchoalveolar lavage for alveolar protein quantitation, cell count and differential, and myeloperoxidase assay. Additionally, whole lung homogenates were assayed for myeloperoxidase activity. We found that the combination of anti-ICAM-1 (1 mg/kg) added to the donor lung flush, and anti-CD11a, anti-CD18, and anti-ICAM-1 (2 mg/kg i.v. of each) given to the recipient prior to reperfusion, resulted in significantly improved lung graft pAO2 by ABG, and decreased alveolar protein, cell count, and myeloperoxidase activity compared with control animals. Improvement was less than that seen in the neutropenic recipients, however. We conclude that LFA-1, Mac-1, and ICAM-1 are all important adhesion molecules in lung allograft reperfusion injury--yet even with antibody blockade of all three there are additional mechanisms allowing for neutrophil influx into the lungs.

Animals↗
PubMed1996

Allelotype analysis of esophageal adenocarcinomas: evidence for the involvement of sequences on the long arm of chromosome 4.

The incidence of esophageal adenocarcinoma has increased dramatically over the past 20 years. The causes for this change in incidence and the genetic defects that underlie tumorigenesis are unknown. We performed loss of heterozygosity (LOH) studies in esophageal adenocarcinomas in an effort to map the location of tumor suppressor genes involved in the initiation or progression of this cancer. A genome-wide search for LOH was undertaken using microsatellite repeat polymorphisms and a panel of 27 tumor and matched normal DNAs. This is the first report of an allelotype analysis of esophageal adenocarcinomas. We observed frequent loss of sequences on the short arm of chromosome 17 in the region of the TP53 gene. We also identified a region on 4q lost in more than half of the tumors investigated. The high rate of LOH for 4q sequences speaks to the involvement of an as yet unidentified tumor suppressor gene in esophageal adenocarcinoma tumorigenesis.

Adenocarcinoma↗
PubMed1996

Delayed death of septal cholinergic neurons after excitotoxic ablation of hippocampal neurons during early postnatal development in the rat.

To investigate the role of neuron-target interactions in regulating the survival of developing septo-hippocampal cholinergic neurons, hippocampal neurons were excitotoxically ablated in early postnatal rats. Four weeks after hippocampal ablation, hippocampal levels of brain-derived neurotrophic factor and nerve growth factor (NGF) mRNA had fallen to 15% of control values, and ipsilateral septal levels of NGF protein had fallen to 45% of control values. Four weeks after hippocampal ablation, the number of immunoreactive septal cholinergic neurons had fallen to 30% of control values. The number of cholinergic neurons in the septum correlated significantly with the amount of hippocampal tissue present. Ultrastructural analysis of the septal region at 3 days after hippocampal ablation showed no evidence of excitotoxic damage, but at 7 or 10 days showed degenerative profiles compatible with the delayed cell death of large septal neurons. Two weeks of NGF administration, initiated at 4 weeks after hippocampal lesions, failed to increase the number of detectable cholinergic neurons in the septal region, suggesting that the loss of immunoreactive neurons seen at 4 weeks represented cell death rather than downregulation of cholinergic markers. These findings suggest that septal cholinergic neurons depend for survival during early postnatal development on interactions with hippocampal neurons and are compatible with the possibility that neurotrophins play a role these interactions.

Animals↗
PubMed1996

Lidocaine reduces reperfusion injury and neutrophil migration in canine lung allografts.

BACKGROUND: Depletion of neutrophils (PMNs) and inhibition of PMN endothelial adhesion ameliorate post-ischemic lung reperfusion injury. Lidocaine reduces PMN adhesion to endothelial surfaces in vivo, and inhibits upregulation of PMN-CD11b/CD18 (Mac-1) in vitro. We evaluated the effect of lidocaine on reperfusion injury, PMN adhesion, and PMN migration in preserved lung allografts. METHODS: Donor lungs were flushed with modified Euro-Collins solution (4 degrees C) after prostaglandin E1 administration (250 micrograms), inflated with 550 mL (inspired oxygen fraction = 1.0), and stored for 24 hours at 1 degree C. Left lung allotransplantation was performed in 13 mongrel dogs. Immediately after reperfusion the recipient right pulmonary artery and bronchus were ligated to permit assessment of allograft function during a 6-hour postreperfusion period. Allograft gas exchange (every 15 minutes) and hemodynamics (every 60 minutes) were assessed. Peripheral blood PMN CD11b expression was determined by flow cytometry. After sacrifice allograft bronchoalveolar lavage fluid PMN count and allograft tissue myeloperoxidase activity were measured. Two groups were studied: In group I (n = 8) lidocaine hydrochloride was added to the donor flush (20 mg/L) solution. In addition lidocaine was given to the recipient at the time of thoracotomy (intravenous bolus of 4 mg/kg) followed by a continuous infusion of 4 mg/kg/h during implantation and the assessment period. Three dogs that did not reach effective lidocaine blood levels at the time of reperfusion (3 to 4 micrograms/mL) were excluded from analysis. Group II animals (n = 5) received no lidocaine. RESULTS: Gas exchange in group I was superior throughout the assessment period (p < 0.05). Bronchoalveolar lavage fluid PMN count in group I was reduced (0.36 x 10(6)PMN/mL versus 6.2 x 10(6) PML/mL; p < 0.03). Group I allograft myeloperoxidase activity was 0.17 U/mg/min compared with 0.28 U/mg/min in group II (p < 0.01). In lidocaine-treated animals PMN CD11b expression was maintained at basal levels 2 hours after reperfusion, compared with group II, in which upregulation of CD11b was observed. Lower lobe wet/dry ratio was not different in the two groups. CONCLUSIONS: Our observations indicate that lidocaine reduces reperfusion injury and inhibits PMN adhesion and subsequent migration to the lung allograft.

Animals↗