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J Segal

Publications and source records attributed to J Segal.

At least 91 records · Page 5Linked to original sources
PubMed1986

The effect of trypsinization on the plasma membrane binding and action of 3,5,3'-triiodothyronine in rat thymocytes.

We have previously demonstrated that in the rat thymocyte T3 produces a prompt, extranuclear effect to increase cellular cAMP concentration and 2-deoxyglucose (2-DG) uptake. We have also demonstrated the presence of specific receptors for T3 in the rat thymocyte plasma membrane. From these and other observations we have suggested that T3 initiates these actions by binding to its receptors on the surface of this cell. To test this hypothesis further we have now examined whether a decrease in the binding of T3 to the thymocyte plasma membrane, induced by mild trypsinization, attenuates the effect of T3 on thymocyte cAMP concentration and 2-DG uptake. Mild trypsin treatment of rat thymocytes in cell suspension did not cause appreciable nonspecific damage to the cells, since it did not change the ability of the cells to exclude either trypan blue or mannitol, a marker of extracellular water. Further, treatment with trypsin did not alter the ability of thymocytes to bind concanavalin A. It did produce, however, a dose-related decrease in the binding of T3 to its plasma membrane binding sites owing to a decrease in their number, but not their affinity. This was associated with a progressive decrease in the T3-induced increase in both 2-DG uptake and cAMP concentration. Thus, low concentrations of trypsin had no significant effect on 2-DG uptake in the absence of T3, but decreased significantly the increase in sugar uptake induced by T3, whereas a higher concentration of trypsin (5 mg/ml) decreased basal 2-DG uptake by only 23%, but abolished the response to T3 altogether. T3, epinephrine, and trypsin alone induced dose-related increases in cellular cAMP concentration, the response to trypsin exceeding that to T3 or epinephrine. Trypsinization also resulted in a progressive decrease in the response of cellular cAMP to both hormones, so that at a trypsin concentration of 5 mg/ml no further increase was produced by either hormone. The possibility that a maximum activation of adenylate cyclase by trypsin could explain these results was rendered unlikely by experiments with prostaglandin E1 (PGE1). The increase in cellular cAMP concentration induced by this agent was vastly greater than that produced by trypsin alone. Although the response to PGE1 was greatly inhibited by trypsin, cellular cAMP concentration in thymocytes incubated with trypsin (5 mg/ml) plus PGE1 was much higher than that in cells treated with trypsin alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Calmodulin mediates the stimulatory effect of 3,5,3'-triiodothyronine on adenylate cyclase activity in rat thymocyte plasma membranes.

We have previously demonstrated that T3 increases adenylate cyclase activity in rat thymocyte plasma membranes by a mechanism that is calcium dependent. In the present studies we have examined whether calmodulin participates in this response to T3. Initial experiments provided evidence that calmodulin is involved in regulating the activity of the guanyl nucleotide-dependent adenylate cyclase in this tissue. Thus, compared with findings in freshly prepared membranes, dialysis of thymocyte plasma membrane preparations for 20 h at 4 C decreased their calmodulin concentrations from an initial value of approximately 600 ng/100 micrograms protein by about 50% and decreased adenylate cyclase activity by approximately 80%. Although storage of the same preparations under comparable conditions resulted in no change in calmodulin content, it caused an approximate 30% decrease in adenylate cyclase activity. Addition of calmodulin had no effect on adenylate cyclase activity in fresh or stored membrane preparations, but produced a dose-dependent increase in enzyme activity in preparations that had been dialyzed. Further, when added to freshly isolated membranes, three calmodulin antagonists, trifluoperazine, calmidazolium, and calmodulin antibodies, all produced a concentration-dependent inhibition of adenylate cyclase activity, and this was completely reversed in all cases by the addition of high concentrations of exogenous calmodulin. The stimulation of guanyl nucleotide-dependent adenylate cyclase activity that T3 induced in fresh membrane preparations was present in membranes that had been stored, but was absent in those that had been dialyzed. In addition, the response to T3 in fresh membranes was inhibited or abolished by all three calmodulin antagonists. Both in dialyzed membranes and in the presence of antagonists, the response to T3 was restored by the addition of exogenous calmodulin. We conclude that calmodulin influences the activity of the guanyl nucleotide-dependent adenylate cyclase in rat thymocytes and ultimately mediates the stimulation of enzyme activity that T3 produces. Such mediation very likely explains the calcium-dependent nature of the stimulatory effect of T3 on thymocyte adenylate cyclase activity.

Adenylyl Cyclases↗
PubMed1986

Effect of age on the 3,5,3'-tri-iodothyronine-induced increase in sugar uptake in rat thymocytes.

The effect of age on the responsiveness of rat thymocytes to 3,5,3'-tri-iodothyronine (T3) was studied. It has been demonstrated previously that the plasma membrane-mediated effect of T3 to increase sugar uptake by rat thymocytes is influenced by age and sex. In both sexes, T3 given in vitro stimulated sugar uptake in cells from animals of 15 days of age, had no effect at 21 days and was again effective at 26 days. In the male, thymocytes from animals of 40 days of age and older were refractory to T3. However, in the female, T3, although less effective than in cells from 26-day-old animals, remained stimulatory in cells from 40- and 60-day-old rats. T3 had no effect in cells from animals of 90 days of age and older. In in-vivo studies in which female rats of 26, 60 and 90 days of age were first injected with T3 and 1 h later with [3H]2-deoxyglucose, the responsiveness of thymocytes to T3 also declined progressively with advancing age; T3 was most effective in cells from 26-day-old animals, less stimulatory in 60-day-old and essentially without effect in cells from 90-day-old animals. From these observations we have concluded that in both male and female rats the responsiveness of thymocytes to T3 declines progressively with age, and that this decline occurs at an earlier age in cells obtained from males.

Aging↗
PubMed1986

Cation chelators and their utilization in the preparation of low concentrations of calcium. Caution of use in biological systems with high affinity to calcium.

Ethylene glycol bis (beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA)-calcium buffer is widely used in various calcium-dependent reactions where free calcium concentrations of 1 microM or less are desirable. The free calcium concentration is calculated from the association constant of EGTA . Ca2- and serves as the true available calcium in systems devoid of a constituent with high affinity to Ca2+ other than EGTA. But, it is conceivable that in systems with high affinity to Ca2+ (comparable to that of EGTA) this is not the case, because such systems will compete with EGTA for the total calcium content in the medium, so that the true available calcium for these systems is greater than that calculated from the EGTA buffer. This hypothesis was tested in three different Ca+-modulated systems: Quin 2 fluorescence, Ca2+-ATPase, and adenylate cyclase, in which the response of the system to calcium was compared between EGTA-free media, containing known amounts of added calcium, and the EGTA-Ca2+ buffer media. In all three systems, the amount of available calcium in the EGTA-Ca2+ buffer medium was much greater than the calculated free Ca2+ concentration. This indicates that in systems with high affinity to Ca2+, preparation of available Ca2+ in concentrations of 1 microM or less must account for both the EGTA and the system capacities for calcium.

Adenylyl Cyclases↗
PubMed1985

In vivo stimulation of sugar uptake in rat thymocytes. An extranuclear action of 3,5,3'-triiodothyronine.

In previous studies we have demonstrated that 3,5,3'-triiodothyronine (T3) in vitro produces a prompt increase in the uptake of the sugar analogue 2-deoxyglucose (2-DG) by freshly isolated rat thymocytes. This effect is prompt, being evident at 20 min after addition of T3, is independent of new protein synthesis, and can be elicited by physiologic concentrations of the hormone. In the present studies, we have sought to determine whether physiologic doses of T3 are capable of inducing an increase in 2-DG uptake in the thymocytes of the living animal. Therefore, 26-28-d-old female rats were injected with increasing doses of i.v. T3, followed 60 min later by 3H-labeled 2-DG. 30 min later, animals were killed, thymocytes were isolated, and their 3H content determined. Uptake of [3H]2-DG was increased by T3 in a dose-dependent manner. The lowest effective dose was 10 ng/100 g of body weight (30% above control) and the maximally effective dose 1 microgram/100 g of body weight (116% above control). The effect of T3 was independent of new protein synthesis in that it was not blocked by a dose of cycloheximide that inhibited the incorporation of [3H]leucine into thymocyte protein by 92-95%. Comparable studies with various thyronine analogues revealed the following rank order of potency: L-T3 greater than L-3,5,3'5'-tetraiodothyronine (L-T4) greater than D-T3 greater than or equal to D-T4 greater than L-3,3'5'-triiodothyronine greater than 3'-isopropyl-3,5-L-diiodothyronine (T2) = 3,5-L-T2. DL-thyronine was without effect. These studies indicate that T3 in physiologic doses acts in vivo to increase the uptake of sugar by rat thymocytes by a mechanism that is extranuclear in origin, in that it is independent of new protein synthesis. The findings support the conclusion that the previously demonstrated effects of T3 on thymocyte sugar uptake in vitro, which seem clearly to be mediated at the level of the plasma membrane, have physiologic relevance.

Animals↗
PubMed1985

The effect of thyroid status on the calmodulin content of several tissues in the rat.

The present studies represent an initial effort to evaluate a possible relationship between thyroid status and calmodulin and were undertaken because of evidence that some actions of the thyroid hormones are calmodulin mediated. To this end, the effects of hypothyroidism and of thyroid hormone excess on the concentration of calmodulin in several tissues of the rat were evaluated. In thymocytes, liver, heart, and brain, but not in skeletal muscle, calmodulin concentrations were markedly increased in the thyrotoxic rat (140-203% of values in normal controls); values were unchanged in hypothyroid animals. These changes were evident regardless of whether calmodulin concentrations were expressed per cell (thymocytes), or in relation to either the wet wt or protein content of the tissues. These findings are apparently the first to demonstrate that thyroid hormone, unlike other hormones tested thus far, can influence tissue calmodulin content. In view of the fact that many metabolic systems that are influenced by calmodulin are similarly affected by thyroid hormones, the findings support the possibility that some actions of thyroid hormone are calmodulin mediated.

Animals↗
PubMed1985

Stimulation of adenylate cyclase activity in rat thymocytes in vitro by 3,5,3'-triiodothyronine.

In view of our previous demonstration that T3 promptly increases the cAMP concentration in freshly isolated rat thymocytes in vitro, we studied the effects of T3 on adenylate cyclase activity in a crude thymocyte plasma membrane preparation. In common with adenylate cyclase in other tissues, the enzyme in rat thymocytes was activated by NaF, GTP, 5'-guanylylimidodiphosphate, and beta-adrenergic agonists and was inhibited by high concentrations of calcium. In the presence of 1 microM Ca+2, T3 induced a time-dependent increase in adenylate cyclase activity that was statistically significant between 1 and 2 min and maximum between 2 and 5 min after hormone addition. As judged from observations made at 5 min, the effect of T3 was dose dependent over the range 1 nM to 1 microM. The stimulatory effect of T3 was calcium dependent, since it was abolished by EGTA at a concentration (0.5 mM) that did not alter basal enzyme activity, and the effect of T3 in the presence of EGTA was restored by the addition of either 0.1 or 1 mM Ca+2. As judged from the lack of hydrolysis of added cAMP, phosphodiesterase activity in the assay mixture was nil in both the presence and absence of T3. Both epinephrine and the specific beta-adrenergic agonist isoproterenol, but not the alpha-agonist phenylephrine, increased adenylate cyclase activity, and their effects appeared to be additive to that of T3. The beta-adrenergic antagonist L-alprenolol, in doses that did not influence basal adenylate cyclase activity, produced a dose-related inhibition of the stimulatory effect of T3 and of the effects of epinephrine and isoproterenol as well. Neither D-alprenolol nor the alpha-antagonist phentolamine had any effect. Various thyronine analogs displayed a rank order of potency in stimulating adenylate cyclase activity very similar to their relative potencies in increasing cAMP concentration in the intact thymocyte. These findings reveal that T3 stimulates adenylate cyclase activity in rat thymocyte plasma membrane preparations. With respect to calcium dependence, inhibition by alprenolol, and response to thyronine analogs, this effect has properties similar to those of the increase in cellular cAMP concentration induced by T3 in the intact thymocyte. It can be concluded, therefore, that the effect of T3 to increase 2-deoxyglucose uptake by the rat thymocyte in vitro, a response consequent to an increase in thymocyte cAMP concentration, derives from a stimulatory effect of the hormone on adenylate cyclase itself.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Effects of age and sex on certain metabolic functions and mitogenic activity in rat thymocytes.

In female and male Sprague-Dawley CD rats, both total mass and thymocyte content of thymus gland peaked during the second month of life and then declined with age. Values of both 2-deoxyglucose (2-DG) uptake and thymidine incorporation in thymocytes were higher in cells from females than from males in all age groups studied, these differences being significant only at 3 months of age and onward. In cells from both sexes, thymocyte 2-DG uptake and thymidine incorporation were at maximum at the first and second months of age, respectively. Thereafter, in cells from males, 2-DG uptake and thymidine incorporation declined rapidly with advancing age; whereas in cells from females, these functions started to decline only after 6 months. In both freshly isolated and cultured cells, the concanavalin A (Con A)-induced increase in thymidine incorporation was also affected by age, peaking at about 3 months. The proportionate effect of Con A on thymidine incorporation was similar in cells of both sexes, but because of differences in basal values, the absolute increase in thymidine incorporation produced by Con A was higher in cells from females than from males. Since thymocytes are the progenitors of T-cells, these changes in the number and function of thymocytes may be the forerunner of similar functional abnormalities that are seen in circulating T-cells, but at a later age.

Age Factors↗
PubMed1985

Fourth pharyngeal pouch sinus.

This is the first description and documentation of an extremely rare developmental anomaly of the pharyngeal apparatus in a 15-year-old female. The clinical, radiological, histological, and anatomical findings indicated that the anomaly originated in the pharyngeal fourth pouch. It presented as a recurrent lateral neck abscess which was due to a paratracheal sinus. This sinus penetrated the larynx and after a translaryngeal course ended in the pyriform sinus. It was caudad to the superior laryngeal nerve and external to the recurrent laryngeal nerve. Its penetration into the larynx at the cricothyroid joint region could serve as a useful surgical landmark.

Abscess↗
PubMed1984

An immediate increase in calcium accumulation by rat thymocytes induced by triiodothyronine: its role in the subsequent metabolic responses.

In previous studies we have shown that the thyroid hormone T3 induces a prompt increase in the cAMP concentration of rat thymocytes in vitro. This is followed by and very likely leads to an increase in cellular uptake of the glucose analog 2-deoxyglucose (2-DG). Since these effects of T3 were shown to require the presence of Ca2+ in the suspending medium, it seemed reasonable to determine whether T3 would influence the metabolism of calcium itself. In standard medium containing 1 mM Ca2+ and 45Ca as a tracer, T3 induced a very prompt, dose-related, but transient, increase in thymocyte calcium accumulation. This effect was evident within the first minute after the addition of T3 (including processing time) and is to our knowledge the most rapid effect of T3 yet demonstrated. The effect reached a maximum very shortly thereafter and then abated within a few minutes. Uptake of 45Ca from Ca2+-free medium (5 microM Ca2+ as a contaminant) was also increased by T3, but under these conditions, the increase was sustained for the entire 120-min period of study. At a concentration of 25 microM, lanthanum (La3+) unexpectedly produced a rapid and marked (4- to 6-fold) increase in 45Ca accumulation in the thymocytes. The increase in cellular calcium accumulation produced by La3+ was not associated with any effect on thymocyte cAMP concentration or 2-deoxyglucose (2-DG) uptake. However, La3+ potentiated the response of the cell to T3 in respect to calcium accumulation, cAMP concentration, and 2-DG uptake, shifting the dose-response curve of the latter two effects to the left. In view of the calcium dependence of the T3 effect on thymocyte cAMP concentration and 2-DG uptake, and the effect of La3+ to concomitantly enhance the sensitivity of the cell to the effects of T3 on calcium accumulation and cAMP and 2-DG metabolism, we suggest that the prompt increase in cellular Ca2+ uptake induced by T3 that we demonstrated is causally related to its subsequent effect on cellular cAMP concentration and 2-DG uptake.

Animals↗
PubMed1983

Bacterial colonization of the nose and external ear canal in newborn infants.

The bacterial flora of the nose and external ear canal of 132 newborn infants, aged 3 days and 4 to 7 days, was examined. Cultures taken from the nose showed the following pattern of bacterial colonization: normal flora (39%); potentially pathologic gram-positive microorganisms (23%); gram-negative enteric rods (16%); and sterile cultures (22%). The most frequent bacterial cultures from nostrils were Staphylococcus epidermidis (39%); Staph. aureus (11%) and Escherichia coli (8%). The cultures from the external ear canal showed normal flora (37%); potentially pathologic gram-positive microorganisms (5%); gram-negative enteric rods (24%); and sterile cultures (34%). The most frequent bacteria cultured from the ear canal were: Staph. epidermidis (37%); E. coli (8%); and Klebsiella pneumoniae (7.5%). Of several factors studied, the type of delivery, Apgar score and the duration of hospitalization were found to have a significant influence on the pattern of bacterial colonization.

Apgar Score↗
PubMed1982

A postulated mechanism for the coordinate effects of ionophore A23187 on calcium uptake and cell viability in rat thymocytes.

At the physiological concentration of Ca2+, the presumed calcium ionophore A23187 produced dose-related increases in 45Ca uptake by rat thymocytes and decreases in cell viability, effects that displayed a strong linear correlation. In media containing a very low concentration of Ca2+ (7.10(-6) M), in contrast, ionophore A23187 had no specific effect on either 45Ca uptake or cell viability. The calcium-dependent cytotoxicity of ionophore A23187 resembles that of other agents that are not ionophores, but that are known to perturb the plasma membrane. Consequently, we suggest that, in the rat thymocyte, ionophore, ionophore A23187 may not act as a true ionophore, but may perturb the cell membrane, allowing Ca2+ to pass freely through the membrane along its electrochemical gradient.

Animals↗
PubMed1982

Specific binding sites for the triiodothyronine in the plasma membrane of rat thymocytes. Correlation with biochemical responses.

As a prerequisite to studies of whether the plasma membrane of the rat thymocyte contains specific, saturable binding sites for the thyroid hormone 3,5,3'-triiodothyronine (T(3)), a method was developed for the isolation of a plasma membrane fraction from these cells. As judged from both electron microscopic and marker enzyme studies, the fraction was composed principally of plasma membrane vesicles, was free of nuclear contaminants, and was only slightly contaminated with other subcellular components. At 37 degrees C and pH 7.4, binding of [(125)I]T(3) by the fresh membrane preparation was rapid, reaching a maximum at 5 min and then declining with time, so that by 60 min binding was virtually nil. Decreased binding with time was due to a loss of functional binding sites, but did not reflect desensitization, since the decrease in binding activity with time was independent of the presence or absence of T(3). Scatchard analysis of saturation studies revealed the presence of two binding sites, one with an apparent dissociation constant (K(d)) of 0.95 nM and a maximum capacity of 5.3 x 10(10) sites/100 mug protein, and the other with an apparent K(d) of 25 nM and a binding capacity of 1.4 x 10(12) sites/100 mug protein. Measurement of the ability of several thyronine analogues to inhibit the binding of [(125)I]T(3) revealed the following rank order of potency: l-T(3) > l-T(4) > d-T(3) = d-T(4) > l-3,5-T(2) > rT(3) > d,l-thyronine. Binding of T(3) was inhibited by the omission of calcium from the medium or by the addition of the beta adrenergic antagonist alprenolol. As judged from studies of the lower affinity binding site, these manipulations decreased the affinity, but not the number, of binding sites for T(3). The relative potencies of thyronine analogues to inhibit the binding of [(125)I]T(3) were generally parallel to their previously reported potencies in stimulating the uptake of the sugar analogue 2-deoxy-glucose (2-DG) in intact rat thymocytes in vitro. Further, the inhibition of T(3)-binding produced by l-alprenolol or by excluding calcium from the medium resembled the previously reported inhibition that these manipulations produce with respect to T(3)-induced enhancement of 2-DG uptake. These findings suggest that the binding sites for T(3) present in the plasma membrane of rat thymocytes act as functional receptors linked to the stimulation of 2-DG uptake that T(3) induces in these cells.

Alprenolol↗
PubMed1982

Influence of age and sex on the concentrations of thyroid hormone in serum in the rat.

Studies of the influence of age and sex on the concentrations of total thyroxine (T4) and 3,5,3'-tri-iodothyronine (T3) in serum and on the free T4 and free T3 indices, were conducted in Sprague-Dawley rats of the CD strain varying in age between 10 days and 12 months. Both sex- and age-related differences were found. In all age-groups studied, serum T4 concentrations were higher in the male than in the female, whereas serum T3 concentrations were higher in the female. In both sexes, concentrations of T4 and T3 in serum reached a peak early in life, between the first and second month of age, and declined thereafter. In addition, in both sexes the intensity of thyroid hormone binding, as judged from values of the in-vitro uptake of T3, did not change with age, suggesting that free T4 and T3 concentrations in the serum display the same sex differences and age-related changes as do the concentrations of total T4 and T3. It remains to be determined whether these sex- and age-related alterations in serum thyroid hormone concentration are expressed in differences in the activity of various thyroid hormone-dependent processes.

Aging↗
PubMed1981

Studies of the mechanism by which 3,5,3'- triiodothyronine stimulates 2-deoxyglucose uptake in rat thymocytes in vitro. Role of calcium and adenosine 3':5'-monophosphate.

The present experiments were designed to explore the mechanism whereby 3,5,3'-triiodothyronine (T3) stimulates the uptake of 2-deoxy-D-glucose (2-DG) in rat thymocytes in vitro. Addition of T3 evoked a transient, dose-related increase in cellular cyclic (c) AMP concentrations, evident within 5 min. followed soon by an increase in 2-DG uptake. The effects of T3 on both cAMP concentration and 2-DG uptake were dependent upon the presence of extracellular calcium. Epinephrine also induced a sequential increase in thymocyte cAMP concentration and 2-DG uptake. These responses were more prompt than those to T3, but were calcium independent. As with their combined effects on 2-DG uptake, T3 and epinephrine produced synergistic or additive effects on cellular cAMP concentration. Dibutyryl cAMP also stimulated 2-DG uptake, an effect that was more prompt than that of epinephrine, and like that of epinephrine, was calcium independent. Prior or simultaneous addition of L-alprenolol (10 microM), which, we have previously shown, blocks the effect of both T3 and epinephrine on 2-DG uptake, also blocked the increase in thymocyte cAMP concentration induced by these agents. In contrast, L-alprenolol failed to block the increase in 2-DG uptake produced by dibutyryl cAMP. On the basis of these observations we suggest that T3 increases 2-DC uptake in the rat thymocyte by increasing the cellular concentration of cAMP, which then acts to enhance sugar transport. The increase in 2-DC uptake induced by epinephrine is also mediated by an increase in cAMP concentration. The greater response of cellular cAMP concentration to T3 and epinephrine when added together than to either agent added alone may explain their synergistic action to increase 2-DG uptake. We suggest that these actions of T3 and epinephrine are both initiated at the level of the plasma membrane.

Alprenolol↗
PubMed1981

The triage experiment in coordinated care for the elderly.

Triage is a model project designed to overcome the organizational and financial barriers inhibiting the provision of appropriate care to the elderly. Teams made up of a nurse clinician and a social worker performed assessment, service coordination, and monitoring functions. Services arranged by the teams were financed through a series of waivers on the use of the Medicare Trust Fund. Three hundred and seven Triage clients were followed and compared to a group of 195 elderly in a two year quasi-experimental study of functioning status outcomes, use of services, and health care costs. Triage clients had slightly better mental functioning outcomes than comparison clients; results of physical and social functioning outcomes were inconclusive. Both service utilization and costs were somewhat higher for Triage clients; the proportional difference in utilization was greater than the proportional difference in costs.

Aged↗
PubMed1981

Cimetidine-benzodiazepine drug interaction.

The effect of cimetidine on the metabolism of benzodiazepines is discussed. Studies of cimetidine's inhibition of benzodiazepine metabolism by liver microsomal enzyme pathways are described. Cimetidine is known to have this effect on the metabolism of diazepam and chlordiazepoxide, and because chlorazepate and prazepam are similarly metabolized, cimetidine is likely to have the same effect on the metabolism of these drugs. Oxazepam and lorazepam are two benzodiazepines not metabolized by liver microsomal enzymes, but are thought to be glucuronidated in peripheral tissue by glucuronyl transferase. Cimetidine has been shown not to alter the pharmacokinetics of lorazepam or oxazepam when administered concurrently with either of these benzodiazepines. When it is necessary to treat a patients receiving cimetidine with a benzodiazepine, oxazepam or lorazepam may be the drug of choice.

Animals↗