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Biomedical subjects

A Bergstrand

Publications and source records attributed to A Bergstrand.

At least 19 recordsLinked to original sources
PubMed2001

Renal lesions in Baltic grey seals (Halichoerus grypus) and ringed seals (Phoca hispida botnica).

A severe reduction in the populations of grey and ringed seals in the Baltic occurred during the 1960s and 1970s. Adult animals showed (and still show) a series of lesions inter alia in the female reproductive organs, intestines, integument, kidneys, adrenals, and skulls (the Baltic seal disease complex). The morphology and prevalence of light microscopic changes in the kidneys of 76 grey seals and 29 ringed seals collected in the Baltic proper and the Gulf of Bothnia during 1977-1996 are presented in this report. Specific changes in the glomeruli were diffuse thickening of the capillary walls and the presence of large, rounded, hyaline bodies in the capillary or capsular walls. Specific changes in the distal convoluted tubules and the collecting ducts included focal replacement of the normal epithelium by multilayered cell proliferations. The prevalence and extent of the changes were age-related and thus correlated with the time of exposure to environmental toxicants. The lesions were more conspicuous in Baltic grey seals than in Baltic ringed seals. Similar findings were recorded in 5 grey seals from Swedish zoological gardens. These animals had been fed Baltic fish for most of their lives. Electron microscopy was performed on 5 of the Baltic grey seals and on one of the grey seals from zoological gardens. Electron microscopy results mainly based on findings in one of the Baltic grey seals, included mesangial inter-position in the glomerular capillary walls and the characteristics of intercalated cells in cell proliferations in the distal parts of the nephrons. Eleven grey seals from the Scottish coast and 23 ringed seals from Svalbard served as reference material. None of the reference seals showed the specific lesions described above. The authors propose that organochlorine pollution of the Baltic environment is a factor in the cause of these kidney changes.

Animal Diseases↗
PubMed2000

Antidepressant-induced lipidosis with special reference to tricyclic compounds.

Cationic amphiphilic drugs, in general, induce phospholipid disturbances. Tricyclic, as well as other antidepressants belong to this group. In experimental animals, antidepressants induce lipid storage disorders in cells of most organs, a so-called generalized phospholipidosis. This disorder is conveniently detected by electron microscopic examination revealing myelin figures. Myelin figures or myeloid bodies are subcellular organelles containing unicentric lamellar layers. The lipidotic induction potency during in vivo is related to the apolarity of the compound. Metabolism of phospholipids takes place within the cell continuously. Several underlying mechanisms may be responsible for the induction of the phospholipid disturbance. For instance, it has been suggested that the compounds bind to phospholipids and such binding may alter the phospholipid's suitability as a substrate for phospholipases. Free TCA or metabolites thereof may also inhibit phospholipases directly, as has been demonstrated for sphingomyelinase in glioma and neuroblastoma cells. Both these mechanisms might result in phospholipidosis. Interaction between drug and phospholipid bilayer has been investigated by nuclear magnetic resonance technique. There seems to be large differences in the sensitivities amongst different organs. Steroid-producing cells of the adrenal cortex, testis and ovaries are in particular susceptible to drug-induced lipidosis. The so-called foam cells are lung macrophages located in the interstitium which become densely packed with myelin figures during TCA exposure. It requires about 3-6 weeks of treatment to develop this converted cell. In cell cultures however, phospholipidosis is demonstrated already after 24 h only. It appears that the cells that undergo TCA-induced lipidosis may recover after withdrawal of the drug. The time required to achieve complete recovery ranges from 3-4 weeks to several months, depending on the organ affected. Little is known about the functional significance of lipidosis. Even if TCA and other antidepressants show other effects, it has not been possible to exclusively relate it to phospholipidosis. However, few attempts have been made to correlate the physiological effects of TCAs in experimental animals to the morphological changes associated with phospholipidosis. There is an increasing evidence however, that cationic amphiphilic drugs may have effects on immune function, signal transduction and receptor-mediated events, effects that to some extent might be related to disturbances in phospholipid metabolism.

Animals↗
PubMed1999

Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X(L).

In order to investigate the molecular mechanism of the antineoplastic effects exerted by the antidepressive agents imipramine, clomipramine, and citalopram, we examined the effects of these compounds on cell viability, generation of reactive oxygen species (ROS), and mitochondrial membrane potential (DeltaPsi(m)) in human acute myeloid leukemia HL-60 cells. Our results indicate that exposure to these compounds causes a loss in cell viability by activating the apoptotic process, as identified by electron microscopy, DNA gel electrophoresis, and flow cytometry. The increased generation of ROS induced by these drugs was a relatively early event and preceded the loss of DeltaPsi(m). Overexpression of the antiapoptotic protein Bcl-2 or Bcl-X(L) prevents antidepressant-induced apoptosis, as well as loss of DeltaPsi(m), but does not affect the generation of ROS.

Antidepressive Agents↗
PubMed1999

The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation.

Some widely used antidepressants such as imipramine, clomipramine, and citalopram have been found to possess antineoplastic effects. In the present study, these compounds were found to induce apoptotic cell death in human acute myeloid leukemia HL-60 cells. Apoptosis induced by the antidepressants was identified by electron microscopy and conventional agarose gel electrophoresis and was quantitated by propodium iodide staining and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) via flow cytometry. Treatment with apoptosis-inducing concentrations of the antidepressants (80 microM imipramine, 35 microM clomipramine, or 220 microM citalopram) caused induction of caspase-3/caspase-3-like activity, which was monitored by the cleavage of poly(ADP-ribose) polymerase (PARP), the loss of the 32 kD caspase-3 (CPP32) precursor, and the cleavage of the fluorescent CPP32-like substrate PhiPhiLux. Pretreatment with a potent caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (zVAD-fmk) inhibited antidepressant-induced CPP32/CPP32-like activity and apoptosis. Furthermore, activation of caspase induced by the antidepressants was preceded by the hypergeneration of intracellular reactive oxygen species (ROS). These results suggested that the antidepressants may induce apoptosis via a caspase-3-dependent pathway, and induction of apoptosis by the antidepressants may provide a clue for the mechanism of their antineoplastic effects.

Antidepressive Agents↗
PubMed1999

Effects of the rodent peroxisome proliferator and hepatocarcinogen, perfluorooctanoic acid, on apoptosis in human hepatoma HepG2 cells.

The effects of perfluorooctanoic acid (PFOA), a potent hepatocarcinogen and peroxisome proliferator in rodents, on human cells have not yet been examined. In the present study we demonstrate that treatment of human hepatoblastoma HepG2 cells with PFOA induces apoptosis, as well as perturbs the cell cycle. This apoptosis was characterized by electron microscopy, which revealed typical nucleosomal fragmentation (also observed as a 'DNA ladder' upon electrophoresis on agarose) and was quantitated using propidium iodide staining of cellular DNA and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. This process was dose- and time-dependent: apoptosis became manifest with 200 microM and maximal (45% of the cells) upon exposure to 450 microM PFOA for 24 h. Electrophoresis of the DNA from HepG2 cells exposed to 500 microM PFOA for 24 h or to 400 microM PFOA for 48 h revealed a smear typical of non-specific degradation. These findings indicate that in the presence of high concentrations of PFOA for long times, HepG2 cells undergo primary and secondary necrosis. Quantitation of trypan blue exclusion supported this conclusion. Flow cytometric analysis revealed that the cell cycle of HepG2 cells was perturbed by exposure to 50-150 microM PFOA. A 50 microM concentration resulted in a significant increase in the proportion of G(2)/M cells and, simultaneously, a decrease in the number of cells in the S phase, whereas treatment with 100 or 150 microM PFOA increased the proportion of cells in the G(0)/G(1) phase and decreased the number of cells in the G(2)/M and S phases. Simultaneous flow cytometric analysis of apoptosis-associated DNA strand breaks using the TUNEL procedure and of propidium iodide staining of cellular DNA revealed DNA breaks in HepG2 cells exposed to 150 microM PFOA, prior to nuclear fragmentation.

Apoptosis↗
PubMed1996

Hepatic peroxisome proliferation in vitamin A-deficient mice without a simultaneous increase in peroxisomal acyl-CoA oxidase activity.

Vitamin A-adequate and vitamin A-deficient C57B1/6 mice were treated for ten days with 0.02% (w/w) perfluorooctanoic acid (PFOA) in their diet. Treated vitamin A- adequate and -deficient mice demonstrated approximately the same increases in liver somatic index (g liver/g body weight) (somewhat more than 2-fold) and mitochondrial protein content (5-fold). PFOA treatment resulted in a 26-fold increase in hepatic peroxisomal lauroyl-CoA oxidase activity in vitamin A-adequate mice, whereas the same activity was unchanged in vitamin A-deficient mice. Vitamin deficiency itself caused a 3- to 4- fold increase in cytosolic catalase activity and a smaller increase in the activity of microsomal cytochrome P-450 IVA (lauric acid omega- and omega-1 hydroxylase) in this same organ. The induction of the activities of these enzymes was less prominent in vitamin A-deficient mice compared with the effect caused by PFOA in vitamin A-adequate mice, resulting in approximately the same maximal values for these parameters in both groups (i.e approx 21 micromol/g liver - min and 350 nanomol/g liver - min, respectively). A 70 kDa protein, presumable the multifunction protein, was shown by Commassie blue staining of SDS-polyacrylamide gels and by immunoblotting (with antibodies towards the multifunctional protein) to be induced to approximately the same degree in vitamin A-adequate and deficient mice. A morphometric study revealed that PFOA causes the same extent of hepatic peroxisome proliferation in vitamin A-deficient as in vitamin A-adequate mice. The possibility that PFOA exerts its effect in vivo through at least two different mechanisms is discussed.

Acyl-CoA Oxidase↗
PubMed1996

[The man on the portrait].

Marie Curie was awarded the Nobel Prize in chemistry 1911. During the preceding year a rumour had circulated in Stockholm that she had had an affaire with one of her assistants. She received a letter, in which she was told that there had been strong opposition to her election not on scientific but moral grounds, and that she should not go to Stockholm, because nobody could forsee what reactions her appearance at the prize ceremony could evoke. Emil Kleen, a man of violent temper and radical opinions, reacted strongly to these rumours. He wrote a paper, with a violent attack on Gustaf Retzius, previous professor of Histology at Karolinska Institutet. Rightly or wrongly he suspected him to be the author of the infamous letter. Retzius is described as a dilletant in scientific matters, as a "sexual hyena" and a garroulus old man. This portrait of Retzius is of course most unfair, but the portrait of Emil Kleen by the famous swedish artist Bruno Liljefors is a masterpiece and one of the most valuable of the Swedish Medical Association.

History, 20th Century↗
PubMed1994

Effects of perfluorooctanoic acid--a potent peroxisome proliferator in rat--on Morris hepatoma 7800C1 cells, a rat cell line.

In this study, Morris hepatoma 7800C1 cells (from rat) were exposed to 500 microM perfluorooctanoic acid (PFOA) in the culture medium for 7 days. This treatment resulted in inductions of catalase, lauroyl-CoA oxidase (which catalyzes the first step in peroxisomal beta-oxidation) and of cytochrome P-450IVA (specialized for omega- and omega-1 hydroxylation of fatty acids). Northern blot analysis revealed that the level of mRNA for peroxisomal fatty acyl-CoA oxidase was enhanced in cells treated with PFOA. Inductions of the enzymes mentioned above are generally connected with peroxisome proliferation in vivo. This work also includes a comparison between the activities of catalase, lauroyl-CoA oxidase, DT-diaphorase and glutathione transferase in rat liver homogenate and 7800C1 cells in order to investigate to what extent this cell line differs from the situation in vivo. The findings suggest that the cells selectively lost most of their peroxisomes during transformation into a cell line and subsequent propagation. The control activities of catalase and lauroyl-CoA oxidase (marker enzymes for peroxisomes) were only about 2% of the corresponding enzyme activities in rat liver. In addition, a morphological study revealed that the frequency of peroxisomes in 7800C1 cells is very low. The control activity of glutathione transferase in 7800C1 cells was 11% of the corresponding activity in rat liver homogenate, whereas the level of DT-diaphorase was virtually the same in 7800C1 cells as in rat liver. Electron microscopic investigation of the control cultures revealed all signs of viable cells, with well-developed cell organelles. Treatment of 7800C1 cells with 500 microM PFOA has little effect on cellular morphology.

Acyl-CoA Oxidase↗
PubMed1992

The involvement of selenium in peroxisome proliferation caused by dietary administration of clofibrate to rats.

The effects of dietary treatment with clofibrate (0.5% w/w for 10 days) on the livers of selenium-deficient male rats were examined. The peroxisome proliferation (as determined by electron microscopy) in the livers of selenium-deficient animals was much less pronounced than in the case of selenium-adequate rats and no increase in peroxisomal fatty acid beta-oxidation (assayed both as antimycin-insensitive palmitoyl-CoA oxidation and lauroyl-CoA oxidase activity) was observed in the deficient animals. On the other hand, in selenium-deficient rats clofibrate caused increases in the specific activity of microsomal lauric acid omega- and omega-1-hydroxylation and an apparent change in mitochondrial size, seen as a redistribution of mitochondria from the 600 x g(av) pellet to the 10,000 x g(av) pellet, which were approximately 50% as great as the corresponding effects on control animals. Obviously, then, these three different effects of clofibrate are not strictly coupled and may involve at least partially distinct underlying mechanisms. Initial experiments demonstrated that peroxisome proliferation could be obtained by exposing primary hepatocyte cultures derived from selenium-deficient rats to clofibric acid (an in vivo hydrolysis product of clofibrate which is the proximate peroxisome proliferator), nafenopin or mono(2-ethylhexyl)phthalate. This finding suggests that selenium deficiency does not have a direct influence on the basic process(es) underlying peroxisome proliferation, but rather has indirect effects, influencing, for example, the pharmacokinetics of clofibrate and/or hormonal factors.

Animals↗
PubMed1991

Distribution of 125I-galanin binding sites, immunoreactive galanin, and its coexistence with 5-hydroxytryptamine in the cat spinal cord: biochemical, histochemical, and experimental studies at the light and electron microscopic level.

The distribution of galanin-like immunoreactivity (GAL-LI) in the spinal cord of the cat was studied by use of indirect histochemistry and the peroxidase-antiperoxidase (PAP) technique. In the ventral horn GAL-immunoreactive (IR) axonal fibers and terminals were most frequent in the ventral part of the motor nucleus. The GAL-IR axons also contained 5-hydroxytryptamine (5-HT)-LI, and they disappeared after spinal cord transection. It was concluded that these GAL-IR fibers belong to the serotoninergic bublospinal pathway. In the medulla oblongata from normal cats, scattered GAL-IR cell bodies were encountered within the nucleus raphe obscurus and nucleus raphe pallidus. Electron microscopic observations revealed that the fine structure of the GAL-IR axonal boutons in the motor nucleus was similar to that of 5-HT-IR boutons with a varying number of immunoreactive large dense core vesicles. The postsynaptic element in all cases studied was a dendrite. A dense GAL-IR axonal plexus was found in the superficial laminae I-II of the dorsal horn. Coexistence was found between the GAL- and substance P-LI in fibers within the dorsal horn plexus. Spinal cord transection did not alter the pattern of GAL-LI in the dorsal horn, while the vast majority of GAL-IR axonal swellings disappeared following dorsal root sectioning. Electron microscopic observations in lamina II (substantia gelatinosa) revealed that the GAL-IR axonal terminals could be divided into two main groups. One with small to medium-sized axonal boutons formed synaptic contacts with both dendritic and axonal profiles. The other formed the central axon terminals of glomeruli, suggesting that GAL-LI may be present in C-type primary afferents. Numerous small GAL-IR cell bodies were encountered in laminae II and III. GAL-IR cell bodies were also observed in lamina X. The dorsal root ganglia contained a low but consistent number of small to medium-sized GAL-IR cell bodies, which all contained immunoreactive calcitonin gene-related peptide (CGRP). Following peripheral sciatic nerve transection, the number and the labeling intensity of GAL-IR cell bodies in the corresponding dorsal root ganglia showed a moderate increase. Radioimmunoassay revealed that the concentration of GAL-LI increased along the rostrocaudal axis of the normal spinal cord, and was about three times higher in the dorsal than in the ventral regions. The concentration in the dorsal root ganglia was intermediate to those seen in the corresponding dorsal and ventral cord regions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Deterioration of GFR in IgA nephropathy as measured by 51Cr-EDTA clearance.

In 191 patients with mesangial IgA nephropathy, GFR was determined as clearance of 51Cr-EDTA. 86 (45%) of them had subnormal renal function 7.3 +/- 4.6 years after renal biopsy. The change in GFR was followed in 153 patients with repeated determinations of 51Cr-EDTA clearance. 50.3% of the patients had a loss of more than 1.1 ml/min/year, which we regard as pathological. The markers of progressive disease were: male sex, high output of urinary protein, severe histological lesions and presence of hypertension. Even patients lacking these markers had a significantly increased incidence of progressive disease. Of 93 patients, with initially normal GFR, 32% will have a subnormal GFR within five years and 25% will develop end-stage renal failure within 20 years. In 38 patients with six or more determinations of 51Cr-EDTA clearance, the predictive value of the first four determinations was calculated. Of 26 with a decrease of more than 1.1 ml/min/year, 13 (50%) developed subnormal GFR during follow-up, while 11 of 12 (91.7%) with a decrease of less than 1.1 ml/min/year (P less than 0.05) remained normal. This shows that repeated determinations of GFR with an accurate method will predict the final outcome early in the disease. We also confirmed that single or repeated determinations of clearance of creatinine are of little value in separating a normal GFR from a slightly decreased one, but more reliable in detecting a markedly reduced GFR.

Adult↗
PubMed1991

Deterioration rate in hypertensive IgA nephropathy: comparison of a converting enzyme inhibitor and beta-blocking agents.

The effect of beta-blocking agents and enalapril as antihypertensive drugs has been compared in 47 patients with IgA nephropathy. The deterioration rate was calculated from the regression line of 51Cr-EDTA clearance and expressed in ml/min/year. The annual loss in glomerular filtration rate (GFR) was greater in patients treated with different beta-blocking agents (-4.9 +/- 6.8 ml/min/year) compared to patients treated with Enalapril (1.7 +/- 7.4 ml/min/year), in spite of the fact that these patients had a lower initial GFR. Nine patients were initially treated with beta-blocking agents (-9.5 +/- 9.3 ml/min/year) and then with an angiotensin-converting enzyme inhibitor (5.5 +/- 11.2 ml/min/year). Angiotensin-converting enzyme inhibitors should therefore be preferred in the treatment of hypertension in IgA nephropathy.

Adrenergic beta-Antagonists↗
PubMed1991

An electron and fluorescence microscopic study of LLC-PK1 cells, a kidney epithelial cell line: normal morphology and cyclosporin A- and cremophor-induced alterations.

The present study demonstrates the following: (I) At high concentrations cyclosporin A is toxic to LLC-PK1 cells and at intermediate concentrations also alters intracellular morphology in this same system. Even though these cells differ morphologically from renal cortex in a number of ways, the morphological changes in this system caused by cyclosporin A resembled in certain respects its reported morphological effects in vivo. Thus, LLC-PK1 cells may provide a suitable system for investigating certain aspects of the nephrotoxicity of cyclosporin A and its underlying mechanism. (2) The cytotoxic effects of cyclosporin A on LLC-PK1 cells demonstrated a relatively distinct threshold concentration, suggesting that a threshold for in-vivo nephrotoxicity might also exist. (3) Cremophor, an oil used clinically as the vehicle for cyclosporin A, was also found to be cytotoxic towards LLC-PK1 cells at high concentrations, as well as to alter the morphology of these cells at lower concentrations. This finding supports previous suggestions that cremophor itself may have a nephrotoxic effect. (4) Finally, we have found that Nile red can be used as a fluorescent probe for the rapid and simple detection of drug-induced, lipid-rich structures in cell cultures. In addition to its use in experimental systems, Nile red might also be employed to examine biopsy material and/or to look for the occurrence of lipid-rich structures (released from disrupted cells of, e.g. the renal cortex) in urine.

Animals↗
PubMed1990

Effects of dietary treatment with clofibrate, nafenopin or WY-14.643 on mitochondria and DNA in mouse liver.

Male C57bl/6 mice were administered clofibrate (0.5%, w/w), nafenopin (0.125%, w/w) or WY-14.643 (0.125%, w/w) in their diet for 4 days. Assay of eight mitochondrial marker enzymes, -i.e., malate and glutamate dehydrogenases (matrix markers), cytochrome oxidase and cytochromes c + c1 and a (inner membrane), adenylate kinase (intermembrane space) and monoamine oxidase and microsomal glutathione transferase (outer membrane)--and morphometric analysis of electron micrographs was used to examine hepatic mitochondria after treatment with these peroxisome proliferators. A moderate increase in the number of hepatic mitochondrial profiles, with a simultaneous decrease in the average size of these organelles, was observed. The total mitochondrial volume is apparently unchanged during this process. An important experimental consequence of the apparent decrease in mitochondrial size is the redistribution of a large portion of the total hepatic mitochondria from the 'nuclear' to the mitochondrial fraction. A similar effect was seen with rats.

Animals↗
PubMed1990

Intracellular distribution of gentamicin within the rat kidney cortex: a cell fractionation study.

The present study demonstrates that during the first 1.5-3 min after a single intraperitoneal administration of [3H]gentamicin to rats, most of the radioactivity in the kidney cortex is recovered in the cytosolic and microsomal fractions upon subcellular fractionation. Subsequently, the level of radioactivity recovered in the cytosolic fraction decreases markedly, whereas this level remains relatively unchanged in microsomes and increases somewhat in the nuclear and mitochondrial fractions. A steady state is apparently reached 13 hr after the injection. The high initial concentration of gentamicin in the cytosol may indicate that this substance is taken up to a large extent by diffusion. Such uptake is somewhat surprising, because of the polar nature of gentamicin. The small size of this drug may, however, allow it to diffuse through so-called pores and/or interaction with negatively charged phospholipids may be involved in the uptake of gentamicin. The initial total level of radioactivity recovered in microsomes after in vivo administration of [3H]gentamicin was considerably higher than in the nuclear and mitochondrial-lysosomal fractions. Furthermore, when gentamicin was added directly to kidney homogenate prepared from untreated rats, instead of being administered in vivo, this substance was still recovered in highest amounts in the total microsomal fraction. This observation may indicate that enrichment of gentamicin in the endoplasmic reticulum (or fragments thereof) reflects a special affinity of this drug for these membranes and is probably not the result of a particular in vivo process. There was no difference in the levels of radioactivity recovered in smooth and rough microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Development of hypertension in IgA nephropathy as a marker of a poor prognosis.

We have studied 209 patients with IgA nephropathy. 26 were hypertensive at the time of renal biopsy, and 59 patients developed hypertension during follow-up. Survival statistics show that only 45% of the patients will remain normotensive 10 years after renal biopsy. The presence of hypertension at renal biopsy correlated well with the usual parameters of a poor prognosis. The same markers predicted a later development of hypertension in patients who were normotensive at the time of renal biopsy. When hypertension is established, the prognosis is poor. Three years after diagnosis of hypertension, the renal survival was found to be 70% in the 59 patients we have followed. It is also possible that the markers of a poor prognosis actually predict the progression rate rather than the prognosis, because in time, some patients with initially mild manifestations of the disease will progress to end-stage renal failure.

Actuarial Analysis↗
PubMed1989

Isolation of myelin bodies from the kidney cortex of gentamicin-treated rats.

Myelin bodies have been isolated from the kidney cortex of gentamicin-treated rats (100 mg gentamicin sulfate/kg body weight i.p. twice daily for 3 days) by a simple procedure involving differential centrifugation followed by equilibrium density centrifugation on a discontinuous sucrose gradient. Electron microscopy and assay of acid phosphatase suggest that the myelin bodies were obtained in virtually quantitative yield, essentially uncontaminated by other cellular structures and relatively intact. The method developed here may also prove applicable for the isolation of myelin bodies arising in connection with other drug treatments and may provide information on a number of toxic side-effects of clinical importance.

Acid Phosphatase↗