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Circulating myosin light chain I levels after coronary reperfusion: a comparison with myocardial necrosis evaluated from single photon emission computed tomography with pyrophosphate.

This study was performed to assess the influence of coronary reperfusion on the serial serum myosin light chain (LC)I levels and to evaluate the relationship between the peak LCI level and the infarct size calculated from single photon emission computed tomography (SPECT) with technetium-99m pyrophosphate (Tc-99m PYP) in 11 patients who underwent coronary reperfusion. Blood was drawn before reperfusion, immediately after reperfusion, and once a day for 14 days, to estimate the time course of serum LCI release. The infarct size estimated by Tc-99m PYP ranged from 7.3 to 62.4 ml. The LCI levels obtained before reperfusion were less than 2.5 ng/ml but those obtained immediately after reperfusion were much higher. The value ranged from 2.7 to 9.7 ng/ml and that expressed as a percentage of peak LCI (% peak LCI) ranged from 19 to 83%. Collateral circulation, reperfusion arrhythmia and the degree of residual stenosis had no influence upon the % peak LCI. The correlation between peak LCI levels and SPECT-determined infarct size was good, with a correlation of 0.76 (p less than 0.01, regression line by least squares method y = 3.31 + 1.53x). Early serum LCI might be influenced by coronary reperfusion but the peak LCI value reflected acute myocardial necrosis in patients who underwent coronary reperfusion.

Adult↗

Technetium-99m pyrophosphate tomogram of nontransmural myocardial infarction: a case report.

Single-photon emission computed tomography (SPECT) with 99mTc-pyrophosphate (99mTc-PYP) has been reported to be useful in the detection and localization of acute nontransmural infarctions. Localized uptake of 99mTc-PYP has been shown in patients with nontransmural infarction in these studies. It is likely, however, that anatomically transmural infarctions could be mislabelled as nontransmural infarctions, since the absence of new abnormal Q waves has been used in differentiating between nontransmural and transmural infarctions. We report a case of relatively diffuse nontransmural infarction demonstrated by a semicircle of 99mTc-PYP activity which significantly overlapped 201Tl uptake on the SPECT study.

Aged↗

Local deposition of calcium pyrophosphate crystals in evolution of knee osteoarthritis.

The aim of the study was to investigate the frequency of development of local calcium pyrophosphate (CPPD) crystal deposition in patients with knee OA initially found negative for these crystals, as well as to discover whether prognostic indicators for this subset of patients can be found. A clinical follow-up of records of outpatients with idiopathic knee OA was established. An anteroposterior plain radiography of the knee joints was made initially and at the end of the observation period. The follow-up period needed to be more than 1 year. Patients were divided into two groups. The first included patients with knee OA who did not develop intra-articular CPPD crystal deposition during the observation period (OA group). The second included those patients whose X-rays or synovial fluid (SF) analysis in the follow-up showed these crystal deposits to be present (OA + CPPD group). There were 59 patients (42 women, 17 men) who met the selection criteria. During the observation period (8.1 + 7.4 years in the OA group, 10.4 +/- 6 years in the OA + CPPD group), intra-articular CPPD deposits were observed in 15 patients (25%): 10 on the X-rays, eight in the SF and three in both examinations. Age at diagnosis of OA and incidence of obesity were similar in both groups. There was a trend (P = 0.21) towards men developing intra-articular CPPD crystal deposits more frequently than women. OA in only one knee joint was significantly more frequent in the group with CPPD (P<0.01). Of those with CPPD deposits 40% required surgery at the end of the observation period, compared to 27.2% of those without deposits (P = 0.27). The waiting period before knee surgery was shorter in the OA + CPPD group but the difference was not statistically significant. In conclusion, local CPPD crystal deposition was observed in 25% of cases during the evolution of knee OA. No predictive factors were found. OA of the knee could, per se, favour the development of CPPD deposits. The occurrence of intra-articular CPPD deposits seemed to be related to a more rapid and severe evolution of OA of the knee.

Aged↗

The effect of inhibiting topoisomerase I and II on the anti-apoptotic response associated with pro-inflammatory crystals of calcium pyrophosphate dihydrate in human neutrophils.

OBJECTIVE AND DESIGN: To investigate the ability of various topoisomerase I and II inhibitors to reverse the pro-survival effects of calcium pyrophosphate dihydrate (CPPD) crystals on human neutrophils, thereby identifying potential agents that may promote the resolution of neutrophil accumulation typical of crystal associated inflammatory diseases. MATERIALS AND METHODS: Freshly isolated human neutrophils incubated in the presence of CPPD crystals, with or without the pro-apoptotic cytokine TNF-alpha, were pre-incubated in the presence or absence of the topoisomerase I inhibitors camptothecin, nogalamycin or beta-lapachone, or topoisomerase II inhibitors etoposide, doxorubicin or mitoxantrone. Neutrophil respiratory burst was assessed via chemiluminescence, and two quantitative methods were used for the determination of neutrophil apoptosis; cytoplasmic histone-associated-DNA fragmentation assessment, and endogenous caspase 3 substrate (Ac-DEVD-AMC) cleavage. RESULTS: Beta-lapachone and mitoxantrone effectively repressed CPPD crystal associated respiratory burst, whereas the other topoisomerase inhibitors had no inhibitory or stimulatory effect. Camptothecin and all of the topoisomerase II inhibitors induced neutrophil apoptosis, even in the presence of the CPPD crystals that normally repress TNF-alpha-induced and spontaneous apoptosis. CONCLUSIONS: These results suggest that although topoisomerase II antagonists are distinctively effective agents at reversing the pro-survival effects of crystals on neutrophils, camptothecin was unique as a topoisomerase I inhibitor in that it was significantly more effective as a pro-apoptosis inducer than the topoisomerase II poisons without affecting normal neutrophil activation responses.

Apoptosis↗

Thiamine pyrophosphate: an essential cofactor for the alpha-oxidation in mammals--implications for thiamine deficiencies?

The identification of 2-hydroxyphytanoyl-CoA lyase (2-HPCL), a thiamine pyrophosphate (TPP)-dependent peroxisomal enzyme involved in the alpha-oxidation of phytanic acid and of 2-hydroxy straight chain fatty acids, pointed towards a role of TPP in these processes. Until then, TPP had not been implicated in mammalian peroxisomal metabolism. The effect of thiamine deficiency on 2-HPCL and alpha-oxidation has not been studied, nor have possible adverse effects of deficient alpha-oxidation been considered in the pathogenesis of diseases associated with thiamine shortage, such as thiamine-responsive megaloblastic anemia (TRMA). Experiments with cultured cells and animal models showed that alpha-oxidation is controlled by the thiamine status of the cell/tissue/organism, and suggested that some pathological consequences of thiamine starvation could be related to impaired alpha-oxidation. Whereas accumulation of phytanic acid and/or 2-hydroxyfatty acids or their alpha-oxidation intermediates in TRMA patients given a normal supply of thiamine is unlikely, this may not be true when malnourished.

Anemia, Megaloblastic↗

Human osteoarthritic cartilage matrix vesicles generate both calcium pyrophosphate dihydrate and apatite in vitro.

Calcium crystals in osteoarthritic (OA) joints promote enzymatic degradation of articular tissues. Matrix vesicles provide a nidus for calcium crystal formation in chick epiphyseal and mature porcine articular cartilage. In order to examine a potential role for matrix vesicles from OA cartilage in generating pathologic crystals, we sought to determine whether vesicles derived from human OA cartilage (OAMV) could mineralize; and we characterized the resultant mineral species. OAMV were isolated and examined for alkaline phosphatase (AP) and nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity. OAMV ATP-dependent and independent mineralization were measured in a radiometric biomineralization assay, and newly formed OAMV crystals were examined using Fourier transform infrared spectroscopy (FTIR) and compensated polarized light microscopy. The mean specific activity of OAMV AP was approximately 6 times higher and NTPPPH activity 11 times lower than that of previously characterized, mature, porcine, articular cartilage vesicles. OAMV progressively precipitated 45Ca over time both in the presence and absence of ATP. The FTIR spectra of mineral formed in ATP-dependent assays most closely resembled the standard spectrum for calcium pyrophosphate dihydrate (CPPD). The FTIR spectra of OAMV mineral formed in the absence of ATP closely resembled apatite. These data support the hypothesis that OAMV may form mineral phases of two key crystals found in degenerating cartilage and provide further evidence for the role of matrix vesicles in pathologic articular cartilage biomineralization.

Aged↗

Calcification in calcium pyrophosphate dihydrate (CPPD) crystalline deposits in the knee: anatomic, radiographic, MR imaging, and histologic study in cadavers.

OBJECTIVE: To demonstrate and determine the frequency and location of calcification within cadaveric knees with or without calcification typical of calcium pyrophosphate dihydrate (CPPD), utilizing histologic, radiographic and MR imaging techniques. DESIGN AND PATIENTS: Ten cadaveric knees of elderly individuals that demonstrated no radiographic evidence of prior surgery or trauma were studied with MR imaging and subsequently sectioned in planes corresponding to those obtained with MR imaging. The slices were imaged with high-resolution radiography. Two musculoskeletal radiologists correlated the anatomic, MR and radiographic findings. Three of the knees, which did not demonstrate calcifications, were utilized as controls. Histologic sections were obtained from four knees that contained calcifications and from the three controls, and analyzed with special histologic stains that demonstrate phosphorus and calcium. RESULTS: Radiographic imaging and histologic analysis demonstrated widespread CPPD crystal deposition in four of the 10 knee specimens (40%). MR imaging demonstrated some calcifications only within the articular cartilage of the femoral condyles in three of the four (75%) specimens that had CPPD deposits. In all four specimens radiographs and histologic analysis were more sensitive than MR imaging. Histologic analysis demonstrated no evidence of CPPD crystals in the control specimens. CONCLUSION: MR imaging is insensitive to the presence of CPPD deposits in the knee, even when such deposits are widespread. Our study suggests that the sensitivity of MR imaging was significantly better in detecting CPPD deposits in the hyaline cartilage of the femoral condyles when compared with other internal structures, even when such structures contained a higher amount of calcification.

Aged↗

Biosynthesis of hydroxymethylpyrimidine pyrophosphate in Saccharomyces cerevisiae.

Two redundant genes, THI20 and THI21, of Saccharomyces cerevisiae encode a 2-methyl-4-amino-5-hydroxymethylpyrimidine monophosphate (HMP-P) kinase required for thiamin biosynthesis. Using functional complementation analysis with an Escherichia coli mutant strain and a defined biochemical system containing partially purified proteins for the reconstitution of thiamin monophosphate synthesis, we demonstrate that both Thi20p and Thi21p proteins also have HMP kinase activity. Although each isoform independently can synthesize HMP pyrophosphate (HMP-PP) from HMP, there is a marked difference in efficiency between the two proteins. The thi20 deletion strain grows at the same rate as the parental strain in minimal medium without thiamin, but its ability to synthesize HMP-PP from HMP is significantly decreased. We discuss the possibility that HMP is not involved in the pathway of de novo thiamin synthesis in S. cerevisiae.

Phosphotransferases (Phosphate Group Acceptor)↗

Diagnosis of idiopathic myositis: value of 99mtechnetium pyrophosphate muscle scintigraphy and magnetic resonance imaging in targeted muscle biopsy.

Our objective was to study the value of 99mtechnetium-pyrophosphate (99mTc-PYP) muscle scintigraphy and magnetic resonance imaging (MRI) in detecting areas of likely muscle inflammation and in increasing the rate of positive muscle biopsies in patients with suspected myositis. The results showed that in 13 out of 13 patients with clinical and/or signs of inflammatory muscle disease, increased 99mTc-PYP uptake was demonstrated at different muscle sites 3 h after isotope injection. Subsequent MRI of symmetric muscle areas with enhanced 99mTc-PYP uptake revealed signal patterns suggesting inflammation in all cases. Biopsy of these targeted muscles demonstrated characteristic histopathologic signs of muscle inflammation in 9 out of 13 patients. Four of these 9 patients had clinically atypical disease or did not show elevated creatine phosphokinase levels. Seven of these 9 patients had not been pretreated with corticosteroids. In 4 patients only muscle fiber atrophy and/or necrosis without cellular infiltrations was seen. These 4 patients had received either high doses of corticosteroids or low doses over longer periods of time before muscle biopsy. In conclusion, the combination of 99mTc-PYP muscle scintigraphy and MRI demonstrated muscle areas with maximum inflammatory signal patterns. Targeting of muscles by MRI only will probably yield reliable results of muscle biopsy in cases of clinically and serologically characteristic myositis. 99mTc-PYP muscle scintigraphy may provide useful initial information about localization of inflamed muscle tissue, especially in atypical disease. Treatment with corticosteroids prior to histologic diagnosis may abolish inflammatory infiltrations in affected muscle tissue.

Adolescent↗

[Mixed tophi. Calcium pyrophosphate dihydrate crystals in gout tophi].

Calcification of tophi is a well-known secondary phenomenon in gout. Because there are no data available on the nature of the calcium component, light and scanning electron microscopic as well as X-ray microanalysis studies were performed on calcified tophi. In unstained histological slides, urate crystals were detected as negative birefringent needles; after incubation of the slides in distilled water, the urate crystals had disappeared, only positive birefringent calcium pyrophosphate dihydrate (CPPD) crystals of different size remained. An identical result was obtained by scanning electron microscopy. By X-ray microanalysis, peaks for calcium and phosphorus were measured, indicating the presence of CPPD. The occurrence of CPPD crystals in urate tophi as well as in foreign body granulomata indicates that the occurrence of CPPD is not restricted to articular tissues. The biochemical mechanism leading to the appearance of these crystals remains unknown, but it may be assumed that an increase of connective tissue destruction may be responsible for this calcification process.

Adult↗

Calcium pyrophosphate dihydrate deposition in degenerate lumbar discs.

Calcium pyrophosphate dihydrate (CPPD) crystal deposition in lumbar intervertebral discs has been described, but its clinical significance remains unclear. The present study analyzed histological sections of lumbar discs that were obtained from patients undergoing anterior lumbar interbody fusion. Immunohistological staining was undertaken to identify neural elements and blood vessels. Patients with CPPD deposition were compared with a group without CPPD deposition undergoing the same operation. CPPD was found in 15.7% of investigated patients (12.6% of analyzed discs). Deposits were found in areas of the annulus and nucleus showing advanced degeneration. Two patterns were identified: one comprised sharply demarcated rounded deposits, while the other showed diffuse deposition of crystals. There was no association with ingrowth of vascular or neural tissue. Clinical data did not differ significantly in the two groups of patients. However, in all patients with CPPD deposition there was a history of trauma, previous surgery, or both. Isolated CPPD deposition in lumbar intervertebral discs appears to be an incidental finding that is not related to systemic diseases or general arthropathies.

Adult↗

99mTechnetium pyrophosphate scintigraphy in the detection of skeletal muscle disease.

We aimed to assess the specificity and sensitivity of (99m)technetium pyrophosphate muscle scintigraphy in the diagnostic workup of patients with suspected myopathy. We reviewed the charts of 166 patients; 52% of the subjects had myalgias, 36% had muscle weakness, 45% had an elevated serum creatine kinase (CK), and 49% had an increased C reactive protein (CRP). Scintigraphy was positive in 34 patients (20%). The test was more sensitive in the presence of muscle weakness, elevated CK, or increased CRP. The presence of myalgias did not influence the odds. Sensitivity was 60% in patients with the final diagnosis of polymyositis, dermatomyositis, or inclusion body myositis, and 70% in noninflammatory myopathies. Eight percent had false positive scintigrams. In individuals with biopsy-proven myopathy (51 subjects), the diagnostic sensitivity was 43%, and its specificity was 60%. Low positive and high negative likelihood ratios (5.0 and 0.65, respectively) document an only limited diagnostic efficiency of (99m)Tc-PYP scintigraphy in the evaluation of inflammatory and noninflammatory myopathies and suggest that the test is not helpful in the routine diagnostic workup of muscle complaints, even after a priori selection of patients for CK plus CRP abnormalities.

Adolescent↗

Cross-sectional study of 50 patients with calcium pyrophosphate dihydrate crystal arthropathy.

Calcium pyrophosphate dihydrate crystal arthropathy (CPPA) is a well known but heterogeneous disease with a variable presentation and course. We present a cross-sectional study undertaken in a Portuguese rheumatology unit with the aim of analysing clinical and radiological patterns of CPPA in our population. The study population included 50 patients, 34 (68%) women and 16 (32%) men. The mean age was 69.8 +/- 8.8 years. The onset features were acute arthritis in 19 (38%) patients and chronic joint complaints in 26 (52%); five (10%) patients were asymptomatic at the time of diagnosis, which was based only on radiological findings. The diagnosis was established in 37 (74%) cases by clinical and radiographic features, in eight (16%) by clinical, X-ray and synovial fluid analysis, and in five (10%) by clinical features and fluid analysis. The disease course was characterised by acute episodic arthritis in 16 (32%) patients and by persistent symptoms (with or without synovitis) in 34 (68%). The pattern of CPPA in 20 (40%) patients was pseudo-osteoarthritis with synovitis, pseudo-osteoarthritis without synovitis in nine (18%), pseudogout in nine (18%), monoarthropathy in eight (16%) and pseudorheumatoid arthritis in four (8%). The phosphocalcium balance was altered in nine (18%) cases: six patients had hypercalciuria two hyperphosphaturia, two hypocalciuria, one hypophosphaturia and one hypercalcemia. Five patients had abnormal thyroid hormone levels, but only one presented with clinical hypothyroidism. Four patients showed increased parathormone levels, but only one presented with clinical hyperparathyroidism. Radiographic findings showed that 43 (86%) patients had meniscus calcifications, 20 (40%) radiocarpal and 16 (32%) calcification of the symphysis pubis. The study confirms the clinical variability of the disease in a population of Portuguese patients. The knee meniscus calcifications were the most sensitive single finding for establishing the diagnosis of CPPA. Almost all our patients had sporadic idiopathic CPPA without associated pathological conditions.

Aged↗

Increased incidence and clinical correlation of persistently abnormal technetium pyrophosphate myocardial scintigrams following acute myocardial infarction in patients with diabetes mellitus.

"Persistently abnormal" technetium-99m stannous pyrophosphate myocardial scintigrams (PPi+) appear to be associated with a relatively poor prognosis after acute myocardial infarction (AMI). To assess the incidence and implications of PPi+, we performed a retrospective analysis in 29 patients with and 25 patients without diabetes mellitus who had abnormal myocardial scintigrams within 4 days of AMI and who had follow-up scintigrams at least 3 months after hospital discharge. There were no significant differences between patients with and without diabetes as regards age, incidence of transmural or nontransmural AMI, or degree of left ventricular dysfunction after AMI. Persistently abnormal PPi+ occurred more commonly in patients with diabetes than in nondiabetic patients (18 of 29, 62%, compared to 3 of 25, 12%; p less than 0.001). Patients with chronic PPi+ had more frequent cardiac complications following hospital discharge (p less than 0.005) including death, recurrent AMI, unstable angina, and intractable congestive heart failure. Postmortem analysis in two patients with diabetes and chronic PPi+ revealed marked myocytolysis. Thus, patients with diabetes mellitus have an increased incidence of post-AMI "persistently abnormal" technetium (PPi+) scintigrams and relatively poor prognosis following myocardial infarction.

Aged↗

Technetium-99m-pyrophosphate scintigraphy in patients with suspected acute myocardial infarction: impact of interobserver variability.

Technetium-99m-pyrophosphate (TcPYP) scintigraphy may have great value in patients with suspected acute myocardial infarction (AMI), but interobserver variability undoubtedly has adverse impact on predictive value. TcPYP scintigrams for 133 (80%) of 166 consecutive patients admitted for suspected AMI were interpreted independently by three experienced readers. Although there was complete agreement for 87 interpretations (65%), major discrepancies (i.e., at least one positive and one negative reading on the same scan) occurred for 28 scans (21%). To assess predictive accuracy, patients were categorized as follows: 36 had definite AMI manifest by new ECG Q waves and/or CK-MB evidence of AMI (group I), 56 were classified as possible AMI (group II), and 41 had AMI excluded (group III). Using only the definitive diagnostic categories (groups I and III), accuracy for each reader approximated 0.68, with no single reader being correct more often than any other.

Creatine Kinase↗

Relationship between Tl-201, Tc-99m (Sn) pyrophosphate and F-18 2-deoxyglucose uptake in ischemically injured dog myocardium.

We have previously demonstrated that enhanced glucose utilization in reperfused myocardium as assessed by F-18 2-deoxyglucose (FDG) and positron tomography predicts functional recovery. In this study, we compared segmental uptake of F-18 FDG with that of Tl-201 and Tc-99m (Sn) pyrophosphate (Tc-99m PPi) as conventional markers of tissue viability in seven dogs after a 3-hour intracoronary balloon occlusion and 20 hours of reperfusion. Myocardial blood flow was determined with microspheres. Regional retention fractions were calculated from tracer tissue concentrations, the arterial input function, and blood flow. Ischemic injury was assessed by triphenyltetrazolium chloride (TTC) staining and histologic analysis. At 24 hours, blood flow was 22% lower in reperfused than in control myocardium (p less than 0.05). Uptake of Tl-201 was related linearly to blood flow (r = 0.92), while glucose utilization and Tc-99m PPi were 2.9 (p less than 0.01) and 4.7 (p less than 0.05) times higher in reperfused than in control myocardium. Retention fractions of Tc-99m PPi increased with the degree of ischemic injury, while F-18 FDG uptake was highest in segments with mild cell injury. Thus, in ischemically injured myocardium, Tl-201 primarily reflects blood flow. F-18 FDG as a marker of glucose utilization identifies ischemically injured but viable tissue. The admixture of necrotic cells can be determined with Tc-99m PPi. Our results indicate that a dual tracer approach might best characterize the presence and extent of reversibly and of irreversibly injured tissue in a given myocardial region.

Animals↗

Clinical significance of early myocardial 99mTc-pyrophosphate uptake in patients with acute myocardial infarction.

Early 99mTc-pyrophosphate (PYP) scintigrams of 29 patients receiving coronary thrombolysis induced by urokinase, 3.9 +/- 1.2 hours after the onset of acute myocardial infarction (AMI), were evaluated. Intravenous 99mTc-PYP scintigraphy was performed 2.8 to 8.0 hours after the onset of AMI. All 19 patients with positive findings on early scintigrams had good recanalization, compared to only 3 of the 10 patients with negative findings. The seven patients with unsuccessful recanalization after coronary thrombolysis had total occlusion or subtotal occlusion with delayed washout of contrast material, and three of them had collaterals. The sensitivity, specificity, and predictive accuracy of positive results of early scintigraphy in predicting the presence of early reperfusion were 73%, 100%, and 90%, respectively. Patients with positive early scintigrams showed increasing regional ejection fraction and decreasing thallium defect scores from the acute stage to the chronic stage. These findings indicate that early 99mTc-PYP scintigraphy is a sensitive noninvasive technique for detecting early recanalization in infarcted vessels. The collateral flow or antegrade flow with delay is not enough to cause 99mTc-PYP uptake in a very early stage of AMI.

Aged↗

Measurement of infarct size in acute canine myocardial infarction by single-photon emission computed tomography with technetium-99m pyrophosphate.

The location and extent of myocardial infarction (MI) are important predictors of patient course. The current study tests the hypothesis that MI size could be measured accurately using rotating gamma camera single-photon emission computed tomography ( SPECT ) and technetium-99m pyrophosphate (PPi) and that the accuracy of these measurements was independent of MI location and transmural or nontransmural distribution. SPECT was performed in 38 dogs 48 hours after ligation of the left anterior descending coronary artery (14 dogs) or left circumflex coronary artery (LC) (24 dogs) at the mid-level or below. Projection images were corrected for center-of-rotation and field nonuniformity and processed with a 1-dimensional low-pass filter to diminish rib activity. Sixteen 0.5-cm-thick transverse sections, including the entire left ventricle, were reconstructed by filtered backprojection , low-pass filtered, contrast enhanced and processed with a 3-dimensional boundary enhancement operator. The boundary of PPi uptake in each slice was marked automatically using an algorithm that combined a directional derivative and a threshold, and required continuity of the boundary in 3 dimensions. The total number of volume elements that showed abnormal tracer uptake were summed, corrected to absolute volume, and multiplied by the specific weight of cardiac muscle. Scintigraphic MI weight was compared with pathologic MI weight. There was an excellent correlation between scintigraphic and pathologic MI weight. The poorer correlation for nontransmural compared with transmural MIs is most likely a function of size alone, since MIs that weighed less than 10 g (n = 12, range 1.3 to 9.5 g), both transmural and nontransmural, showed a similar correlation: S = 1.07 X P + 0.56 (r = 0.81, standard error of the slope = 0.245).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗