[Type II diabetes. Pathophysiology of insulin resistance, rules and goals of therapy].
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Animals↗
Biomedical subjects
E Ritz
Publications and source records attributed to E Ritz.
Effect of moxonidine on urinary electrolyte excretion and renal haemodynamics in man.
Moxonidine and related compounds have been recently introduced into antihypertensive therapy. It is thought that these drugs exert their blood pressure lowering effect through interaction with non-adrenergic receptors in the central nervous system, i.e. imidazoline receptors, although the contribution of specific interaction with alpha 2-receptors is still under debate. Imidazoline receptors have recently been documented in the renal proximal tubule. In experimental studies, interaction of imidazolines with these receptors decreased the activity of the Na+/H+ antiporter and induced natriuresis. To quantitate the effect of the imidazoline receptor agonist moxonidine on renal sodium handling and renal haemodynamics in man, we examined ten healthy normotensive males (age 25 +/- 4 years) in a double blind placebo-controlled study using a crossover design. Subjects were studied on a standardized salt intake (50 mmol per day). On the 7th and 10th study day they were randomly allocated to receive either i.v. placebo or i.v. 0.2 mg moxonidine. Urinary electrolyte excretion, lithium clearance (as an index of proximal tubular sodium handling), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial blood pressure (MAP), plasma renin activity (PRA) and plasma noradrenaline (NA) levels were assessed. Injection of moxonidine did not increase fractional sodium excretion or lithium clearance. Specifically, antinatriuresis was not observed after injection of moxonidine despite a significant decrease in MAP from 91 to 85 mmHg and a significant increase in PRA.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Decreased renal haemodynamic response to inhibition of nitric oxide synthase in subtotally nephrectomized rats.
To assess the renal haemodynamic response to manipulations of the nitric oxide (NO) system, we examined subtotally nephrectomized (SNX) rats and control rats (CON) 28 days after their operation. Bolus infusions of the NO synthase inhibitor NG-nitro-L-arginine (L-NA) were given intravenously at doses of 2 mg/kg and 10 mg/kg. Blood pressure was measured intra-arterially, glomerular filtration rate was measured by inulin clearance and fractional changes in renal blood flow (RBF) were determined by a Doppler flow probe. Both doses of L-NA caused a similar and dose-dependent increase in mean blood pressure in both SNX and CON rats. In contrast, the decrease in RBF and the increase in the renovascular resistance index (RVRI) was less in SNX rats as compared to CON rats (RBF = -70.1 +/- 2.2% of baseline vs -52.7 +/- 5.2%, P < 0.01; RVRI = +177 +/- 9% of baseline vs +243 +/- 24%, P < 0.05). These changes were not affected by autonomic blockade (hexamethonium), or by blockade of the angiotensin II receptor (Losartan). The exogenous NO donor sodium nitroprusside (0.5 and 1.5 micrograms.kg-1.min-1) lowered mean blood pressure to a similar degree in SNX and CON rats; in contrast, RVRI decreased less in SNX rats (86.9 +/- 9.2% of baseline) than in CON rats (68.2 +/- 4.6%, P < 0.05). We conclude that the reaction of the renal vasculature to manipulations of the NO system is altered in the SNX rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Oxidoreductases↗
Increased prevalence of salt sensitivity of blood pressure in IDDM with and without microalbuminuria.
In insulin-dependent diabetes mellitus (IDDM) elevated exchangeable sodium (Na) levels are found even in the absence of hypertension, but it is not known whether this is associated with increased sensitivity of blood pressure to sodium level. To clarify this issue we compared 30 patients with IDDM (19 without and 11 with microalbuminuria, i.e. more than 30 mg albumin/day) and 30 control subjects matched for age, gender and body mass index. The subjects were studied on the 4th day of a low-salt diet (20 mmol/day) under in-patient conditions and were subsequently changed to the same diet with a high-salt supplement, yielding a total daily intake of 220 mmol Na/day. Circadian blood pressure, plasma renin activity (PRA), plasma atrial natriuretic factor (p-ANF), plasma cyclic guanosine 5'-phosphate (p-cGMP) and urinary albumin were measured. The proportion of salt-sensitive subjects, i.e. showing increment of mean arterial pressure > or = 3 mmHg on high-salt diet, was 43% in diabetic patients (50% of diabetic patients with and 37% without microalbuminuria) and 17% in control subjects (p < 0.05). Lying and standing PRA levels on low- or high-salt diet were significantly lower in diabetic patients than in control subjects. Salt-sensitive diabetic patients had significantly higher lying ANF on high-salt (38.7 +/- 4.2 pmol/l vs 20.1 +/- 2.3 pmol/l, p < 0.005) than on low-salt diet. The results suggest that (i) the prevalence of sodium sensitivity is high in IDDM (ii) sodium sensitivity is found even in the absence of nephropathy as indicated by albuminuria.
Adult↗
L-fucose residues on cellulose-based dialysis membranes: quantification of membrane-associated L-fucose and analysis of specific lectin binding.
Contact of mononuclear human leukocytes with cellulose dialysis membranes may result in complement-independent cell activation, i.e. enhanced synthesis of cytokines, prostaglandins and an increase in beta 2-micro-globulin synthesis. Cellular contact activation is specifically inhibited by the monosaccharide L-fucose suggesting that dialysis membrane associated L-fucose residues are involved in leukocyte activation. In this study we have detected and quantitated L-fucose on commercially-available cellulose dialysis membranes using two approaches. A sensitive enzymatic fluorescence assay detected L-fucose after acid hydrolysis of flat sheet membranes. Values ranged from 79.3 +/- 3.6 to 90.2 +/- 5.0 pmol cm-2 for Hemophan or Cuprophan respectively. Enzymatic cleavage of terminal alpha-L-fucopyranoses with alpha-L-fucosidase yielded 7.7 +/- 3.3 pmol L-fucose per cm2 for Cuprophan. Enzymatic hydrolysis of the synthetic polymer membranes AN-69 and PC-PE did not yield detectable amounts of L-fucose. In a second approach, binding of the fucose specific lectins of Lotus tetragonolobus and Ulex europaeus (UEAI) demonstrated the presence of biologically accessible L-fucose on the surface of cellulose membranes. Specific binding was observed with Cuprophan, and up to 2.6 +/- 0.3 pmol L-fucose per cm2 was calculated to be present from Langmuir-type adsorption isotherms. The data presented are in line with the hypothesis that surface-associated L-fucose residues on cellulose dialysis membranes participate in leukocyte contact activation.
Acrylic Resins↗
Hemolytic uremic syndrome complicating postinfectious glomerulonephritis in the adult.
Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura is known to occur as a secondary complication of primary renal diseases, specifically of lupus nephritis, membranous glomerulonephritis, and focal segmental glomerulosclerosis. In a patient without a family history of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura we observed biopsy-confirmed postinfectious glomerulonephritis with humps, with simultaneous subendothelial hyaline deposits and fibrinoid thrombi in arterioles. The patient had a history of febrile pharyngitis with diarrhea 10 days prior to renal biopsy. He presented with transient elevation of serum creatinine, a nephritic sediment, and hypertension not exceeding 160/100 mm Hg. The patient also had purpura, transient thrombocytopenia, and signs of intravascular hemolysis. Results of verocytotoxin serology were negative. With the exception of isolated microhematuria, all findings reverted to normal within 8 weeks without any specific treatment. This case illustrates that hemolytic uremic syndrome/thrombotic thrombocytopenic purpura may complicate primary postinfectious glomerulonephritis in adults.
Adult↗
Low dialysate calcium in continuous ambulatory peritoneal dialysis: a randomized controlled multicenter trial. The Peritoneal Dialysis Multicenter Study Group.
Hypercalcemia is a common complication in continuous ambulatory peritoneal dialysis (CAPD) patients treated with calcium-containing phosphate binders and using the standard dialysate calcium concentration of 3.5 mEq/L (SCa). Lowering the dialysate calcium was proposed to overcome this problem. The current randomized controlled multicenter study was designed to investigate efficiency and safety of a low calcium dialysate (2.00 mEq/L; LCa) compared with SCa (3.5 mEq/L) in CAPD patients. After an 8-week run-in period, 103 stable CAPD patients, 68 men, 35 women, aged 54.5 years (range, 20 to 77)) were randomly allotted to treatment with either LCa or SCa. All patients received calcium carbonate as oral phosphate binder to achieve serum phosphate levels < 6.2 mg/dL. If persistent hypercalcemia arose, CaCO3 was replaced by Al(OH)3 until normocalcemia was achieved. All patients received 0.25 microgram calcitriol/d. Parameters monitored included total and ionized serum calcium, serum phosphate, phosphate binder intake, incidence of hypercalcemia, serum aluminium, intact parathyroid hormone (1,84PTH), osteocalcin, alkaline phosphatase, bone mineral density and hand skeletal x-ray. Primary end points were (a) number of hypercalcemic episodes, (b) tolerated doses of calcium-containing phosphate binders, and (c) 1,84PTH. After 6 months of therapy, total and ionized calcium were lower in LCa patients (total Ca:9.6 v 10.08 mEq/L, P = 0.005; iCa: 4.76 v 5.15 mg/dL; P = 0.013). In the LCa group, significantly fewer episodes of hypercalcemia were recorded (total S-calcium > 10.8 mg/dL: LCa 24 v SCa 86 episodes; P < 0.005). Use of LCa permitted the administration of more CaCO3 (mean daily tablet number: LCa, 5.9 v SCa, 4.2; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Alkaline Phosphatase↗
The role of the parathyroid glands in the uremic syndrome.
The genesis of hyperparathyroidism in uremia has turned out to be quite complex, involving low calcitriol, low ionized calcium, and possibly direct effects of high phosphate as well as the action of local factors and modifier genes determining the hyperplastic response of the gland. Growth is initially polyclonal and later monoclonal. In addition, the response of target tissues to parathyroid hormone (PTH) is attenuated ("PTH resistance"), and this may be due, at least in part, to diminished phenotypic expression of PTH receptors. In a series of elegant studies, it has been shown that PTH acts not only on the classical target organs of calcium homeostasis (ie, bone and kidney), but also on nonclassical. The role of PTH excess in the genesis of several features of the uremic syndrome, for example muscle dysfunction, cardiomyopathy, leukocyte and T-cell dysfunction or insulin secretion by pancreatic islet cells, has been established. These studies have borne out the prediction that PTH is a "uremic toxin."
Animals↗
Angiotensin-converting enzyme inhibitors may cause renal dysfunction in patients on long-term lithium treatment.
Anecdotal observations suggest that renal dysfunction may occur when unadjusted doses of angiotensin-converting enzyme inhibitors are administered to patients on long-term lithium treatment. Although no systematic experimental studies or controlled clinical observations are available, lithium is known to activate the renin angiotensin system through several mechanisms. In addition, direct interactions between lithium and angiotensin II may take place on a cellular level. We propose that (1) renal function should be closely monitored when patients on lithium treatment are given angiotensin-converting enzyme inhibitors and that (2) doses of both drugs should be chosen with caution to avoid serious drug interaction.
Acute Kidney Injury↗
Changes of vascular architecture independent of blood pressure in experimental uremia.
Striking alterations of the structure of arterial vessels of different caliber are a well-known feature of renal failure, but it is currently unknown to what extent they are a reflection of hypertension or of uremia per se. To address this issue further we studied subtotally nephrectomized rats, sham-operated and pair-fed with matched controls. After uremia of 14 days' duration, stereologic measurements were carried out on perfusion-fixed tissue. To eliminate a potential influence of hypertension, subgroups of animals received furosemide and hydralazine in the drinking fluid to yield daily doses of 15 mg/kg and 20 mg/kg, respectively. At the end of the experiment, systolic blood pressure (tail plethysmography) was 110 +/- 13.3 (mean +/- SD) mm Hg and 99.4 +/- 8.1 mm Hg in untreated and treated controls, respectively, and 132 +/- 20.7 mm Hg and 103 +/- 13.0 mm Hg in untreated and treated uremic animals, respectively (n = 5 to 10 animals per group). The wall:lumen ratio of intramyocardial small arteries was 0.056 +/- 0.011 and 0.052 +/- 0.006 in untreated and treated controls, respectively. In untreated and treated uremic animals, the corresponding values were 0.077 +/- 0.011 and 0.066 +/- 0.007 (P < .01; control v uremia, ANOVA). A similar increase, unaffected by blood pressure treatment, was found for wall thickness of intramyocardial arteries. Analogous changes were also noted in mesenteric arterioles and veins. Finally, aorta media thickness was significantly (P < .005) higher in uremic animals than in controls (138 +/- 29 micrometers v 103 +/- micrometers).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Are antihypertensive drugs similar in protecting the kidney?
Elevated systemic blood pressure is associated with more rapid progression of renal failure, as recently documented by prospective observations. Intervention studies with antihypertensive medication have clearly documented that progression can be attenuated by antihypertensive medication. Experimental studies and, more recently, controlled prospective trials in humans, have provided evidence that in this respect angiotensin converting enzyme (ACE) inhibitors are superior to equipotent doses of alternative antihypertensive agents, suggesting a specific nephroprotective action. Experimental studies suggest that this is not only due to hemodynamic, but also to nonhemodynamic, mechanisms. The effect of calcium channel blockers on this progression is less uniform and may depend on the model used, the percentage of blood pressure lowering, and possibly also the type of calcium channel blocker. Despite some discrepancies in experimental studies, recent controlled clinical trials show a similar slowing of progression with either ACE inhibitors or calcium channel blockers. Since combination therapy is required in most patients with advanced renal failure, recent experimental studies on development and glomerular sclerosis and clinical studies showing at least additive effects on reduction of proteinuria independent of blood pressure argue for combining ACE inhibitors and calcium antagonists.
Angiotensin-Converting Enzyme Inhibitors↗
Calbindin-D28K and -D9K and 1,25(OH)2 vitamin D3 receptor immunolocalization and mineralization induction in long-term primary cultures of rat epiphyseal chondrocytes.
Rat epiphyseal plat chondrocytes were grown on glass slides, as nonadhering monolayer cultures for up to 6 weeks. Chondrocyte growth, differentiation and maturation, matrix formation and mineralization, and the temporospatial distribution of the vitamin D-dependent calcium-binding proteins, calbindin-D9K and -D28K, and the 1,25(OH)2D3 receptor (VDR), were all monitored. Chondrocytes became confluent in 2.5 weeks, differentiated to acquire a chondrocyte (polygonal) morphology, produced extracellular matrix, and finally formed a true monolayer mineralizing cartilaginous tissue, with all the stages of chondrocyte development within a single culture. beta-Glycerophosphate promoted initial matrix mineralization in 4 weeks and accelerated cell differentiation. High nominal calcium and ascorbic acid were needed for abundant matrix formation. VDR occurred at all differentiation stages, in the nuclei and nucleoli and in the cytoplasm. Calbindin-D28K and -D9K were not coexpressed. Calbindin-D28K was found in prechondroblasts, chondroblasts, and in newly differentiated chondrocytes. It was cytoplasmic in prechondroblasts and subsequently also in the perinuclear region and in nuclei, suggesting migration to the nuclear chromatin. Calbindin-D28K was nuclear only in newly differentiated chondrocytes in vitro and was not found in mature chondrocytes. In contrast, calbindin-D9K was present in the cytoplasm of mature and hypertrophic chondrocytes only. It was first in the cell body and eventually migrated within and to the far end of long cell processes with a decreasing cytoplasmic concentration showed by decreased immunostaining intensity, and ultimately hypertrophy of chondrocytes in culture. These in vitro patterns of calbindins-D and VDR accurately reflect their in vivo distributions. The genomic action of vitamin D, in vitro, resulted in the synthesis of nuclear VDR and calbindins-D.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Vitamin D therapy in patients receiving dialysis.
Secondary hyperparathyroidism is found in a large proportion, but not all patients on dialysis. Calcitriol controls moderate hyperparathyroidism in most patients but only in a proportion of those with advanced hyperparathyroidism. Patients with nodular parathyroid hyperplasia respond less frequently, presumably because of monoclonal growth and diminished calcitriol-receptor expression by parathyroid cells. In patients with nodular parathyroid hyperplasia, parathyroidectomy is an important alternative to calcitriol treatment. A priori reasoning indicates that prophylactic administration of calcitriol (to prevent parathyroid hyperplasia) is a reasonable option, but currently no controlled evidence for long-term efficacy of this approach without side effects is available. Intermittent administration of calcitriol by intravenous or oral routes is effective and, at least in experimental studies, superior to continuous calcitriol. However, in clinical comparisons, no superiority of intravenous versus oral or daily versus intermittent calcitriol has been documented. Calcitriol treatment must be closely supervised to prevent hypercalcemia, hyperphosphatemia, and excessive suppression of parathyroid hormone. Because of an altered dose response relationship, parathyroid hormone levels should not be completely normalized so as to prevent low bone turnover (adynamic bone lesion).
Calcitriol↗
Association of ACE gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group.
In patients with type 1 diabetes an association has been found between an insertion/deletion (I/D) polymorphism in the gene for angiotensin I converting enzyme and the presence of diabetic nephropathy. Our objective was (i) to assess this association in a large cohort of patients with type 1 diabetes and (ii) to examine whether this finding also applies to type 2 diabetes. We examined 247 patients with type 1 diabetes of more than 10 years duration (135 patients > or = 20 years): Nephropathy was present in 114 and absent in 133 patients. Furthermore we separately analyzed 455 patients with type 2 diabetes of more than 10 years duration (158 patients > or = 20 years). Nephropathy was present in 247 and absent in 208 patients. Nephropathy was defined by confirmed presence of albuminuria > 30 mg/day (or > 20 micrograms/min). The I/D polymorphism was analyzed with PCR technique and alleles were visualized on 2% agarose gels after ethidium staining. Allele frequencies in the overall diabetic population did not differ significantly from the normal population. Distribution of genotypes was not significantly different between type 1 patients with and without nephropathy (P = 0.377). Also, no significant difference in genotype distribution was found between type 2 diabetic patients with and without nephropathy (P = 0.948). We conclude that no significant association between I/D polymorphism and nephropathy was demonstrable in either type 1 or type 2 diabetes, despite considerable statistical power of the patient sample and adequate duration of diabetes for nephropathy to become manifest.
Adult↗
PDGF and TGF-beta contribute to the natural course of human IgA glomerulonephritis.
PDGF and TGF-beta are known mediators of mesangial cell proliferation and matrix expansion. The presence of these regulatory factors was examined in 30 renal biopsies from patients with IgA glomerulonephritis (IgA-GN) at the mRNA and protein level. Normal renal tissue served as control. The mRNA expression of PDGF A/B chains, PDGF-beta R and TGF-beta 1 was evaluated by means of RT/PCR with subsequent Southern blot hybridization and/or non-radioactive in situ hybridization. In addition, PDGF-AB/BB, PDGF-beta R, TGF-beta isoforms (beta 1, beta 1 + 2, beta 2 + 3), the small TGF-beta 1 latency associated peptide (TGF-beta 1 LAP) and the extracellular matrix proteins tenascin and decorin were analyzed by immunocytochemistry. The expression of growth factors was correlated with light microscopic and clinical features. Compared to normal control kidneys, an increased expression of PDGF-BB/PDGF-beta R mRNAs and the corresponding proteins was observed in all biopsies with IgA-GN. Up-regulation was related to the degree of glomerular proliferation and the extent of fibrosing interstitial lesions. In contrast, there was a discordance between TGF-beta 1 mRNA and protein expression (evaluated by immunocytochemistry). In all biopsies, irrespective of the stage of the disease, abundant TGF-beta 1 transcripts were detected, whereas TGF-beta 1 immunoreactivity was expressed to a lesser degree and disclosed a more variable staining pattern. In patients with significant proliferative glomerular lesions and minor tubulointerstitial alterations, TGF-beta 1 positivity was confined to areas of glomerular proliferation, whereas in cases with more severe histology including sclerosing lesions TGF-beta 1 immunoreactivity was less prominent. The distribution and the intensity of TGF-beta 1 LAP staining commonly exceeded the positivity noted for TGF-beta 1, indicating only limited TGF-beta 1 activation. A decreased reactivity for tenascin accompanied the morphological features of glomerular sclerosis. The staining patterns and the fact that only very few inflammatory cells, particularly CD68 positive monocytes/macrophages, were detected in glomeruli confirm that predominantly resident glomerular cells (mesangial and endothelial cells) are the major source of up-regulated growth factor production in IgA-GN. Since the expression of PDGF-AB/BB paralleled the severity of proliferative glomerular changes, PDGF seems to represent a potential indicator of activity in this condition. It is suggested that an imbalance between PDGF and TGF-beta (by restricted translation and/or activation) production contribute to the progressive nature of IgA-GN.
Adult↗
Low-dose calcitriol prevents the rise in 1,84-iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial).
BACKGROUND: Higher doses of calcitriol are effective in lowering markedly elevated 1,84 PTH levels of patients with renal secondary hyperparathyroidism. It has not been established, however, whether prophylactic administration of low doses of calcitriol prevents an increase of 1,84 PTH without causing side-effects, i.e. hypercalcaemia, hypercalciuria, or hyperphosphataemia. STUDY DESIGN: We carried out a placebo-controlled, double-blind prospective multicentre trial over 12 months in 45 patients with mild to moderate renal failure. Criteria for inclusion were S-creatinine 1.4 mg/dl and 1,84 PTH > 6 pmol/l (normal 6). Calcitriol 0.125 microgram/day per os was compared with placebo. The patients received calcium carbonate per os if serum P exceeded 1.7 mmol/l. RESULTS: Baseline 1,84 iPTH concentrations were not significantly different, i.e. 14.0 pmol/l (6.7-63.3) on placebo vs 16.2 (6.85-82.0) on calcitriol. Intention to treat analysis revealed a significant difference of final 1,84 iPTH, i.e. 27.8 (4.2-68.5) on placebo vs 18.2 (4.45-75.5) on calcitriol. On post-hoc analysis the difference was even more pronounced at S-creatinine concentrations above 3 mg/dl. S-calcium, S-phosphate, and urinary excretion of calcium did not change significantly on either placebo or on calcitriol. There were no episodes of hypercalcaemia or hyperphosphataemia. There was no significant difference of final S-creatinine or change in S-creatinine between placebo and calcitriol. One patient on calcitriol and two on placebo progressed to terminal renal failure. Bone alkaline phosphatase as a non-invasive index of bone metabolism was not decreased to subnormal levels. CONCLUSION: The results document that a therapeutic window exists in patients with moderate renal failure and elevated of 1,84 iPTH, where low-dose calcitriol (0.125 microgram/day) prevents the increase in 1,84 iPTH without causing side-effects. This observation suggests that the parathyroid is more sensitive to calcitriol than intestine and bone.
Adult↗
The rising tide of endstage renal failure from diabetic nephropathy type II--an epidemiological analysis.
In recent years there has been a substantial increase in the proportion of patients requiring renal replacement therapy who suffer from diabetes mellitus. In the lower Neckar region, a survey has been made comprising all patients admitted for renal replacement therapy from 1.1.1993-30.6.1994. Out of a total of 225 patients admitted, 95 suffered from diabetes (10 type I, 85 type II). The estimated annual incidence of terminal renal failure with diabetes was 52/mio/year. At the same time, 79 patients who suffered from diabetes were admitted to the renal unit in Heidelberg (outpatient clinic and ward) for evaluation of de novo renal failure (approximately 176/mio/year); standard primary chronic renal disease was found in 19/79 of these diabetic patients (25%). The discrepancy between the annual incidence of (i) renal failure and of (ii) terminal renal failure suggests that a high proportion of patients with diabetes (mainly type II) and renal failure, dies prior to reaching terminal renal failure. Potential reasons for the increasing incidence of endstage renal failure from diabetes type II are (i) the increasing prevalence of type II diabetes in Germany in recent decades, (ii) aging of the population in view of the known greater prevalence of type II diabetes in older individuals and (iii) improved survival of patients with type II diabetes secondary to diminished cardiovascular mortality. Particularly because of the latter factor a further increase of endstage renal failure in patients with type II diabetes must be anticipated.
Diabetes Mellitus, Type 2↗
Genesis of disturbed vitamin D metabolism in renal failure.
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Animals↗