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  • 1 Sumy State University, Ukraine
  • | 2 Sumy State University, Ukraine
  • | 3 Sumy State University, Ukraine
  • | 4 Sumy State University, Ukraine
Open access

Purpose

The article is devoted to study the structural changes in the skeletal muscles caused by heavy metal salts.

Materials and methods

The study was conducted on 72 mature male rats. The experimental groups were given to drink water with combinations of heavy metal salts for one, two and three months. This type of water is typical for the water basins in the northern districts of the Sumy region. The study of morphological changes in the striated muscles was concluded using light and scanning electron microscopy.

Results

The data analysis revealed that a prolonged duration of negative factor could intensify sclerotic and edematous processes. The structure of muscle fibers was destroyed, nuclei were deformed and placed irregularly, and many petechial hemorrhages occurred. Besides, cross-striation was irregular, I and A bands were deformed and destroyed, H band was hardly visualized. The inner mitochondrial membrane and cristae become deformed. The symplastic nuclei were placed irregularly within sarcoplasm. Besides, they were swollen. Against swollen and enlarged symplastic nuclei, pyknotic nuclei were also found. The structures of sarcoplasmic reticulum were mainly dilated with deformed and ruptured areas.

Conclusion

Our study approves that high concentrations of heavy metal salts have a destructive influence on the skeletal striated muscles.

Abstract

Purpose

The article is devoted to study the structural changes in the skeletal muscles caused by heavy metal salts.

Materials and methods

The study was conducted on 72 mature male rats. The experimental groups were given to drink water with combinations of heavy metal salts for one, two and three months. This type of water is typical for the water basins in the northern districts of the Sumy region. The study of morphological changes in the striated muscles was concluded using light and scanning electron microscopy.

Results

The data analysis revealed that a prolonged duration of negative factor could intensify sclerotic and edematous processes. The structure of muscle fibers was destroyed, nuclei were deformed and placed irregularly, and many petechial hemorrhages occurred. Besides, cross-striation was irregular, I and A bands were deformed and destroyed, H band was hardly visualized. The inner mitochondrial membrane and cristae become deformed. The symplastic nuclei were placed irregularly within sarcoplasm. Besides, they were swollen. Against swollen and enlarged symplastic nuclei, pyknotic nuclei were also found. The structures of sarcoplasmic reticulum were mainly dilated with deformed and ruptured areas.

Conclusion

Our study approves that high concentrations of heavy metal salts have a destructive influence on the skeletal striated muscles.

Introduction

Modern extent of pollution becomes threatening. The modern state of the industry and increasing technical pressure of biosphere cause widespread soil, water, and atmosphere contamination, which have a dramatic effect on all biological species [1]. Direct or indirect intake of different contaminants can cause a disease or become a reason for the development of related disorders [2, 3].

Heavy metals are considered to be terribly dangerous for their toxicity and prevalent in both Ukraine and other countries. An increase in contents of chromium, lead, zinc, iron, copper, and manganese contained in the water of the northern districts of the Sumy region, has reached a critical level and exceeded the maximum permissible level ten times [4].

In the last decades, international scientists have concluded an in-depth research on various pathogenic mechanisms, caused by heavy metals and their salts on organisms in general, and on functioning and structure of certain tissues, organs, and systems in particular [5–7]. It is well known that the negative effect of heavy metals is detected in their direct damaging effects on the structures of biological membranes [8, 9].

Nowadays, the effect of heavy metals on the respiratory, skeletal, endocrine, cardiovascular, nervous, and urogenital systems is thoroughly researched [10, 11]. At the same time, there is limited information concerning the pathogenic effect of heavy metals on the skeletal striated muscles [12–14]. Besides, available information is often controversial and required further justification. This is the reason for writing this article.

The objectives of this paper are as follows: the investigation at the micro- and ultrastructural levels and the morphological remodeling features of the striated muscles of rats after the influence of heavy metals.

Materials and Methods

The study was conducted on 72 matured male rats. The animals were divided into two groups: experimental and control (36 rats). The experimental groups were given water to drink with combinations of heavy metal salts for 1, 2, and 3 months. It is typical water for the basins in the northern districts of the Sumy region [zinc salts (ZnSO4 × 7H2O), 5 mg/L; copper salts (CuSO4 × 5H2O), 5 mg/L; iron salts (FeSO4), 10 mg/L; lead (Pb(NO3)2), 3 mg/L; manganese (MnSO4 × 4H2O), 1 mg/L; and chromium (K2Cr2O7), 10 mg/L] [4]. The control group was given standard drinking water. The 12 rats from each group were killed every 30 days by decapitation under ether anesthesia, followed by the study of the specimens: the skeletal striated muscles (the lateral head of the triceps surae muscle).

Animals kept under vivarium conditions (the vivarium of Medical Institute of Sumy State University). Experiments were carried out in accordance with the European convention for the protection of vertebrate animals used for experimental and other scientific purposes (Strasburg, 1986); Directive 2010/63/EU of the European Parliament and of the Council of the Protection of Animals on September 22, 2010 used for scientific purposes; and The General Ethical Principles for Experiments on Animals, which were accepted by the First Bioethics National Congress.

Histological specimens were stained with hematoxylin and eosin. The specimens were analyzed using a light microscope “OLYMPUS” with a digital camera (Baumer Optronic Typ: CX 05 with lenses 4, 10 × 40 and binocular 10). The ultramicroscopic study was performed using a scanning electron microscope (SEM-125K), manufactured by JCK Selmi (Sumy, Ukraine), with the acceleration voltage of 75–100 kV. The magnified (2700–13,600) images were processed by the Kappa Image program and with the digital camera Baumer/Optronic Typ: CX 05c.

We had conducted the study with the following parameters: diameter of muscle fiber (DMF), width of endomysium (WE), width of perimysium (WP), square of the nucleus (SN), square of the mitochondria (SM), volume of the nucleus (VN), and volume of the mitochondria (VM). Determining the reliability of differences was performed using Student’s t-test (t). The value of P < 0.05 was considered as significant. All statistical analyses were performed using the Statistical Package for Social Science Program (SPSS for Windows, version 15.0, SPSS Inc., Chicago, IL, USA).

Results

A month later, the study of the lateral head of the triceps surae muscle of mature rats revealed significant changes in micro- and ultrastructural levels comparing with the controls.

Deformed muscle fibers with multiple small dark nuclei, placed irregularly, were noted on the histological specimens (Fig. 1B). The fibers were mostly similar in length and diameter. On cross-sections, blood vessels differed in shape – from a circle to an elongated ellipse. On longitudinal sections, capillaries and muscle fibers ran parallel. Venules were placed at a sharp angle to myosymplast. On cross-sections, we noted small edema. Fascicles of muscle fibers, separated by pronounced and slightly extended perimysium, were detected clearly on the specimens (Fig. 2B).

Fig. 1.
Fig. 1.

(A) The striated muscle of a mature rat, which was drinking standard water. (B) The striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for a month. Tortuous of muscle fibers. (C) The striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for 2 months. Deformation of a muscle fibers. (D) The striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for 3 months. Atrophic and sclerotic changes. Longitudinal section. H&E staining

Citation: Interventional Medicine and Applied Science Interventional Medicine and Applied Science 8, 2; 10.1556/1646.8.2016.2.7

Fig. 2.
Fig. 2.

(A) The striated muscle of a mature rat, which was drinking standard water. (B) The striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for a month. Exceeded layer of connective tissue. (C) The striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for 2 months. Enlarged and swollen elements of connective tissue. (D) The striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for 3 months. Placement of nuclei in the cytoplasm, the deformation of the muscle fibers, expressed endomysial development. Cross-section. H&E staining

Citation: Interventional Medicine and Applied Science Interventional Medicine and Applied Science 8, 2; 10.1556/1646.8.2016.2.7

After 3 months, the ultramicroscopic investigation of the lateral head of the triceps surae muscle of mature rats revealed often but not massive deformations of myofibrils, violation of their parallel arrangement (Fig. 3B). Places of fibrils gap were absent. Endoplasmic reticulum, nuclei, and mitochondria mostly appeared swollen and their internal structures were hardly affected.

Fig. 3.
Fig. 3.

(A) The ultrastructure of the striated muscle of a mature rat, which was drinking standard water. (B) The ultrastructure of the striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for a month. Violation of myofibrils parallel arrangement. (C) The ultrastructure of the striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for 2 months. Destructive changes in muscle fibers, swollen of sarcoplasmic reticulum. (D) The ultrastructure of the striated muscle of a mature rat, which was drinking water with salts (Pb, Cu, Fe, Cr, Zn, and Mn) for 3 months. Extension and deformation of elements of the sarcoplasmic reticulum and mitochondria

Citation: Interventional Medicine and Applied Science Interventional Medicine and Applied Science 8, 2; 10.1556/1646.8.2016.2.7

Morphometric parameters after a month of experience had the following changes. DMF in experimental group increased by 4.25% (P = 0.081), WE at 7.17% (P = 0.218), WP at 4.19% (P = 0.011), SN at 4.53% (P = 0.139), SM at 4.57% (P = 0.306), VN at 6.81% (P = 0.001), and VM at 6.16% (P = 0.035) compared with the control (Table I).

Table I

Morphometric parameters of skeletal muscles of comparison groups (Mean ± SEM)

1 month2 months3 months
ParametersControl group (n = 12)Study group (n = 12)Control group (n = 12)Study group (n = 12)Control group (n = 12)Study group (n = 12)
DMF, μm17.61 ± 0.2618.35 ± 0.2318.33 ± 0.3119.57 ± 0.34*19.05 ± 0.2920.99 ± 0.35*
WE, μm2.77 ± 0.092.96 ± 0.122.89 ± 0.123.31 ± 0.14*3.01 ± 0.123.61 ± 0.19*
WP, μm33.12 ± 0.3734.51 ± 0.34*34.21 ± 0.3836.65 ± 0.41*34.99 ± 0.2939.03 ± 0.34*
SN, μm211.33 ± 0.2211.84 ± 0.2512.24 ± 0.2513.28 ± 0.31*13.09 ± 0.2314.86 ± 0.29*
SM, μm21.82 ± 0.071.91 ± 0.052.21 ± 0.072.41 ± 0.06*2.74 ± 0.063.08 ± 0.06*
VN, μm325.01 ± 0.3126.71 ± 0.34*28.41 ± 0.3731.92 ± 0.41*31.77 ± 0.3638.28 ± 0.42*
VM, μm30.81 ± 0.020.86 ± 0.01*1.07 ± 0.031.21 ± 0.03*1.41 ± 0.031.66 ± 0.03*

DMF = diameter of muscle fiber; WE = width of endomysium; WP = width of perimysium; SN = square of the nucleus; SM = square of the mitochondria; VN = volume of the nucleus; VM = volume of the mitochondria

P < 0.05 (exact P values are indicated in the text)

After 2 months, changes were more notable. Fragmentation of myosymplast, rare destruction of fibers, and deformation of shape occurred at the histological level of the microscopic structure of skeletal muscles of mature rats (Fig. 1C). Certain pathological abnormalities (sclerotic and swelling processes) progressed. Myosymplasts were separated from each other by a greatly expanded endomysium. We observed certain changes: undulated shape of muscle fibers, destruction and chaotic arrangement of nuclei, and numerous dot hemorrhages. Nevertheless, striated appearance preserved. The elements of connective tissue were enlarged and swollen (Fig. 2C).

The SEM study of skeletal muscles of mature rats, which were intoxicated by heavy metal salts for 2 months, revealed destruction progression of muscle fibers. It is characterized by undulated myofibrils and areas of pronounced irregular placement and destruction (Fig. 3C). Nuclei and mitochondria were greatly enlarged similar to the previous experimental period. Satellite cells were situated under the basement membrane, sometimes they were noted at the intracellular layers. Perhaps, satellite cells migrated there through a rupture in the basement membrane of muscle fibers. They were a little bit smaller in size with enlightened matrix. Cytoplasm contained a great number of polysomes and vacuoles.

After 2 months of experiments, the DMF of study group increased by 6.78% (P = 0.013), WE at 14.23% (P = 0.032), WP at 7.16% (P < 0.001), SN at 8.51% (P = 0.016), SM at 8.73% (P = 0.041), VN at 12.41% (P < 0.001), VM at 12.49% (P = 0.003), compared with the control the group (Table I).

After a month, the ultramicroscopic investigation of the lateral head of the triceps surae muscle of mature rats revealed significant changes in the shape of myosymplast fibers, their destruction, and even destroyed areas (Fig. 1D). Nuclei of muscle fibers were placed irregularly throughout the area of the sarcoplasm and characterized by various shapes: from small circles to extended swollen ellipses and triangles. Fibers were separated by pronounced layers of endomysium, whereas fascicles were surrounded by massive perimysium. The layers of connective tissues exceeded significantly and enclosed by dot hemorrhages (Fig. 2D). Vessels in the microcirculation were full-blooded, connective tissue privileged in the structure of vascular walls.

The SEM study of skeletal muscles of mature rats, which were intoxicated by heavy metal salts for 3 months, revealed multiple foci with irregular cross-striation. Quite often, myofibrils were fully contracted, I and A bands were deformed and destroyed, and H band was hardly visualized. The arrangement of some filaments was directed to the sarcoplasmic reticulum lumen unlike others. On the specimens, mitochondria were hydropic, inner membrane was destroyed, cristae were deformed or completely absent. Symplastic nuclei were placed irregularly within sarcoplasm. They were swollen. Against swollen and enlarged symplastic nuclei, pyknotic nuclei were also found. The structures of sarcoplasmic reticulum were mainly dilated with deformed and ruptured areas (Fig. 3D).

After a 3‐month experiment, all desired morphometric parameters changed statistically significant when compared with the control series (Fig. 4). DMF increased by 10.22% (P < 0.001), WE at 20.11% (P = 0.014), WP at 11.56% (P = 0.001). Swelling nuclei has led to an increase in their square to 13.55% (P < 0.001), volume at 20.49% (P < 0.001). SM increased by 12.28% (P < 0.001), VM at 17.82% (P <0.001) (Table I).

Fig. 4.
Fig. 4.

Percentage correlation of morphometric parameters of the lateral head of the triceps surae muscle of mature rats in condition of using the salts of Pb, Cu, Fe, Cr, Zn, and Mn after 1, 2, and 3 months of experiment. For an explanation of abbreviations see legend in Table I. *parameters, whose values in rats of the experimental group, were significantly different than intact animals

Citation: Interventional Medicine and Applied Science Interventional Medicine and Applied Science 8, 2; 10.1556/1646.8.2016.2.7

Discussion

Analyzing the nature of pathological changes that occurred in the structure of mature rat skeletal muscles at the cellular and subcellular levels against the background of a constant receipt to organism of heavy metal salts, we can say that the action of these salts proved swelling, deformity and destruction of muscle fibers, and subcellular structures and enhanced the development of connective tissue elements.

Similar results were obtained in the works of other authors. Thus, Ciamarro et al. [15] found a significant increase of the diameter of individual fibers in white pectoral muscle of fish Astyanax altiparanae, which were exposed to water from the urban lake with a high content of heavy metals during 7 and 30 days. Research of Ismail et al. [16] showed marked changes in the structure of skeletal muscle of fish that were in water for a long time with a high content of heavy metals (Cr, Zn, Cu, Pb, Cd, Hg, and Fe). The histological study demonstrated the fragmentation of the muscle fibers, degeneration in muscle bundles accompanied with focal areas of deep myolysis. Also, many muscle fibers ended by a pointed end and distinguished by wide extracellular spaces occupied by connective tissue. Ultrastructural analysis showed that the nuclei increased in size, contained more peripheral heterochromatin aggregations and became highly electron-dense. In some regions, discrete and incomplete myofibrils were observed.

The leading pathogenetic mechanism of heavy metals’ toxic affinity is their ability to start oxidative stress [5, 10, 13]. Under the influence of heavy metals, onset of oxidative stress occurs on the account of two different pathways operating simultaneously; first comes the generation of reactive oxygen species, like hydroperoxides (HO2), singlet oxygen and hydrogen peroxide (H2O2), and the second, the antioxidant reserves become depleted [17].

Heavy metals show electron sharing capability that results in the formation of covalent attachments. These attachments are formed between the metals moiety and the sulfhydryl groups present in antioxidant enzymes, which are the most susceptible targets for them and which eventually get inactivated. Heavy metals inactivate glutathione by binding to sulfhydryl groups present in it. This results in synthesis of glutathione from cysteine via the γ-glutamyl cycle, which is usually not effective in replenishing the supply of glutathione [18]. Similarly, heavy metals inactivate enzymes like δ-amino levulinic acid dehydratase, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase, which further depress the glutathione levels [19]. A few other notable antioxidant enzymes that are rendered inactive by heavy metals include superoxide dismutase (SOD) and catalase (CAT). Decrease in the SOD concentration reduces the disposal of superoxide radical, whereas the reduction in CAT impairs scavenging of superoxide radical (O2–•). Apart from targeting the sulfhydryl groups, different heavy metals can also replace the zinc ions that serve as important cofactors for these antioxidant enzymes and inactivate them [20].

Thus, we can assume that the free radical lesion of lipids of cellular membranes and intracellular organelles membranes lead first to the ion imbalance and edema, and ultimately to the rupture of membranes and their complete destruction.

Along with that, injury of various proteins of the skeletal muscle cells by free radicals also occurs. We suggest that oxidative injury of proteins, such as metallothioneins, may lead to loss of their ability to bind heavy metals, which in turn increases the toxicity of these exopollutants. In addition, the work of Buchheim et al. [21] have made the assumption that the development of fibrotic–sclerotic changes in the skeletal muscles of monkeys, who have been subjected to lead intoxication, is realized through inhibition of matrix metalloprotease, which are aimed at the degradation of collagen. Thus, damage of the matrix metalloproteinases, which are mostly synthesized in skeletal muscles by satellite cells, can enhance connective tissue development in the striated muscle.

There are a number of works devoted to the ionic mechanism of the toxic effects of heavy metals [20, 22, 23]. It is reported that heavy metals are capable of inhibiting divalent and monovalent cations, especially Ca2+, Mg2+, Fe2+, and Na+, thus inhibiting the process of intracellular signal transduction, holding proteins, regulating of enzymes, ion transport, and release of transmitters.

We hypothesize that heavy metals increase swelling in cells and organelles by the inhibition of electrolyte transport and lead to significant dysfunction of muscle fibers and atrophic changes in them by inhibition of intracellular fundamental processes. General scheme, showing the basic ways of pathological effects of heavy metals on skeletal muscle structure, is shown in Fig. 5.

Fig. 5.
Fig. 5.

The scheme of heavy metals influence on the striated muscle cells. The leading pathogenetic mechanism of heavy metals’ toxic affinity is their ability to inhibit the antioxidant protection. The formation of covalent bonds with SH-groups of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) and non-enzymatic antioxidants (glutathione) leads to inactivation of antioxidant protection in cells, free radicals formation (reactive oxygen and nitrogen species) and oxidative stress. As a result, a free-radical affection of cells and organelles membranes takes place, leading first to the ionic imbalance and edema changes and ultimately second to the membranes rupture and destruction. Free radicals affection of the proteins, such as metallothionein leads to loss of their ability to bind heavy metal ions, which also increases the toxic effects of heavy metals. Inhibition of matrix metalloproteinases activity, which is aimed at the collagen degradation, can cause intensive growth of connective tissue layers. Also heavy metals are capable of inducing divalent and monovalent cations, thus inhibiting basic intracellular processes that lead to swelling and atrophic processes

Citation: Interventional Medicine and Applied Science Interventional Medicine and Applied Science 8, 2; 10.1556/1646.8.2016.2.7

The question of protecting the cells of living organisms from the toxic effects of heavy metals currently remains open. Given that the main mechanism of pathogenic influence of heavy metals is the launch of oxidative stress, the main mechanism for fight against this effect is the use of substances, which are directed at or inhibiting the formation of reactive oxygen and nitrogen species, or strengthening of intracellular antioxidant. These substances include vitamins C and E and drugs from the group of antioxidants (2-ethyl-6-methyl-3-hydroxypyridine succinate).

Vitamins C and E are natural non-enzymatic antioxidants that are able to scavenge free radicals and decrease lipid peroxidation. Many studies on the effects of vitamins C and E on Cd and Pb intoxication have been performed. Vitamin C attenuates the oxidative damage and histopathological changes induced by CdCl2 in the lungs and brain of rats [24]. It has similar protective effects in the liver, kidney, brain, and the testes of Pb-exposed rats [25].

2-ethyl-6-methyl-3-hydroxypyridine succinate reduces the manifestations of oxidative stress, inhibits free radical peroxidation of lipids, and increases the activity of antioxidant system enzymes. Hence, we have proved the effectiveness of 2-ethyl-6-methyl-3-hydroxypyridine succinate for the correction of poisoning by some toxic substances [26]. Our subsequent work will focus on research opportunities of protecting skeletal muscles from damaging action of heavy metals and correction capabilities of their pathogenic effect using the above listed substance.

Conclusions

Significantly, high concentrations of Cu, Pb, Fe, Zn, Cr, and Mn cause swelling, activation of sclerotic and atrophic processes in the striated muscles of mature rats: enlarged muscle fibers and layers of connective tissue, deformation of their shapes, homogenous sarcoplasma, and hypochromic nuclei.

The ultramicroscopic study revealed multiple dot hemorrhages with irregular cross-striation, deformed myofibril; with respect to mitochondria, they were hydropic, swollen with destroyed inner membrane and deformed cristae. Symplastic nuclei were placed irregularly within sarcoplasm. They were swollen. The structures of sarcoplasmic reticulum were mainly dilated with deformed and ruptured areas.

Authors’ contribution

AT, VS, and IS made the critical review, GT prepared the article and figures, VB prepared the manuscript, ML and AM made the literature review and prepared figures. All authors read and approved the final form.

Conflict of interest

The authors declare that they have no conflict of interest.

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  • 1.

    Claassen CD (2001): Toxicology. The Basic Science of Poisons (6th ed.). McGraw-Hill, New York, Chicago, Toronto, London

  • 2.

    Dewanjee S , Sahu R , Karmakar S , Gangopadhyay M : Toxic effects of lead exposure in Wistar rats: Involvement of oxidative stress and the beneficial role of edible jute (Corchorus olitorius) leaves. Food Chem Toxicol 55, 7891 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Lavery TJ , Kemper CM , Sanderson K , Schultz CG , Coyle P , Mitchell JG , Seuront L : Heavy metal toxicity of kidney and bone tissues in South Australian adult bottlenose dolphins (Tursiops aduncus). Mar Environ Res 67, 17 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Vashkulat NP : Establish levels of heavy metals in soils in Ukraine. Environ Health 2, 4446 (2002)

  • 5.

    Wang YP , Shi JY , Lin Q , Chen XC , Chen YX : Heavy metal availability and impact on activity of soil microorganisms along a Cu/Zn contamination gradient. J Environ Sci (China) 19, 848853 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Holmes AL , Wise SS , Sandwick SJ , Lingle WL , Negron VC , Thompson WD , Wise JP : Chronic exposure to lead chromate causes centrosome abnormalities and aneuploidy in human lung cells. Cancer Res 66, 40414048 (2006)

    • Crossref
    • Search Google Scholar
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2019  
Scimago
H-index
11
Scimago
Journal Rank
0,220
Scimago
Quartile Score
Medicine (miscellaneous) Q3
Scopus
Cite Score
155/133=1,2
Scopus
Cite Score Rank
General Medicine 199/529 (Q2)
Scopus
SNIP
0,343
Scopus
Cites
206
Scopus
Documents
23

 

Interventional Medicine and Applied Science
Language English
Size  
Year of
Foundation
2009
Publication
Programme
changed title
Volumes
per Year
 
Issues
per Year
 
Founder Akadémiai Kiadó
Founder's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2061-1617 (Print)
ISSN 2061-5094 (Online)

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