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Article ; Online: Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?

Gohar, Eman Y / Cook, Anthony K / Pollock, David M / Inscho, Edward W

2019 Volume 10, Issue 1, Page(s) 1

Abstract: Background: The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation ... ...

Abstract	Background: The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ET Methods: Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery (n = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ET Results: Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10 Conclusion: These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ET
MeSH term(s)	Animals ; Arterioles/drug effects ; Arterioles/physiology ; Castration ; Endothelin-1/pharmacology ; Female ; Male ; Microcirculation/drug effects ; Rats, Sprague-Dawley ; Receptor, Endothelin A/agonists ; Receptor, Endothelin A/physiology ; Receptor, Endothelin B/agonists ; Receptor, Endothelin B/physiology ; Sex Characteristics ; Vasoconstriction/drug effects ; Vasoconstrictor Agents/pharmacology ; Viper Venoms/pharmacology
Chemical Substances	Endothelin-1 ; Receptor, Endothelin A ; Receptor, Endothelin B ; Vasoconstrictor Agents ; Viper Venoms ; sarafotoxins s6
Language	English
Publishing date	2019-01-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2587352-0
ISSN	2042-6410 ; 2042-6410
ISSN (online)	2042-6410
ISSN	2042-6410
DOI	10.1186/s13293-018-0218-2
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Article ; Online: Purinoceptor regulation of renal tubular transport is coming of age.

Inscho, Edward W

American journal of physiology. Renal physiology

2009 Volume 297, Issue 5, Page(s) F1166–7

MeSH term(s)	Adenosine Triphosphate/physiology ; Animals ; Biological Transport, Active/physiology ; Humans ; Kidney Tubules/cytology ; Kidney Tubules/physiology ; Loop of Henle/physiology ; Rats ; Receptors, Purinergic/physiology
Chemical Substances	Receptors, Purinergic ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2009-09-09
Publishing country	United States
Document type	Comment ; Editorial ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00506.2009
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Article ; Online: A novel functional role for the classic CNS neurotransmitters, GABA, glycine, and glutamate, in the kidney: potent and opposing regulators of the renal vasculature.

Wildman, Scott S / Dunn, Kadeshia / Van Beusecum, Justin P / Inscho, Edward W / Kelley, Stephen / Lilley, Rebecca J / Cook, Anthony K / Taylor, Kirsti D / Peppiatt-Wildman, Claire M

American journal of physiology. Renal physiology

2023 Volume 325, Issue 1, Page(s) F38–F49

Abstract: The presence of a renal GABA/glutamate system has previously been described; however, its functional significance in the kidney remains undefined. We hypothesized, given its extensive presence in the kidney, that activation of this GABA/glutamate system ... ...

Abstract	The presence of a renal GABA/glutamate system has previously been described; however, its functional significance in the kidney remains undefined. We hypothesized, given its extensive presence in the kidney, that activation of this GABA/glutamate system would elicit a vasoactive response from the renal microvessels. The functional data here demonstrate, for the first time, that activation of endogenous GABA and glutamate receptors in the kidney significantly alters microvessel diameter with important implications for influencing renal blood flow. Renal blood flow is regulated in both the renal cortical and medullary microcirculatory beds via diverse signaling pathways. GABA- and glutamate-mediated effects on renal capillaries are strikingly similar to those central to the regulation of central nervous system capillaries, that is, exposing renal tissue to physiological concentrations of GABA, glutamate, and glycine led to alterations in the way that contractile cells, pericytes, and smooth muscle cells, regulate microvessel diameter in the kidney. Since dysregulated renal blood flow is linked to chronic renal disease, alterations in the renal GABA/glutamate system, possibly through prescription drugs, could significantly impact long-term kidney function.
MeSH term(s)	Glutamic Acid/pharmacology ; Microcirculation ; Glycine/pharmacology ; Kidney/blood supply ; gamma-Aminobutyric Acid/pharmacology ; Central Nervous System ; Neurotransmitter Agents/pharmacology
Chemical Substances	Glutamic Acid (3KX376GY7L) ; Glycine (TE7660XO1C) ; gamma-Aminobutyric Acid (56-12-2) ; Neurotransmitter Agents
Language	English
Publishing date	2023-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00425.2021
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Article: Endothelial Histone Deacetylase 1 Activity Impairs Kidney Microvascular NO Signaling in Rats fed a High Salt Diet.

Dunaway, Luke S / Cook, Anthony K / Botta, Davide / Molina, Patrick A / d'Uscio, Livius V / Katusic, Zvonimir S / Pollock, David M / Inscho, Edward W / Pollock, Jennifer S

bioRxiv : the preprint server for biology

2023

Abstract: Aim: We aimed to identify new mechanisms by which a high salt diet (HS) decreases NO production in kidney microvascular endothelial cells. Specifically, we hypothesized HS impairs NO signaling through a histone deacetylase 1 (HDAC1)-dependent mechanism.! ...

Abstract	Aim: We aimed to identify new mechanisms by which a high salt diet (HS) decreases NO production in kidney microvascular endothelial cells. Specifically, we hypothesized HS impairs NO signaling through a histone deacetylase 1 (HDAC1)-dependent mechanism. Methods: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or high salt diet (4% NaCl) for two weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. Results: We found that HS impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS fed rats to be sufficient to induce dysfunction suggesting a humoral factor, we termed Plasma Derived Endothelial-dysfunction Mediator (PDEM), mediates the endothelial dysfunction. The antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. Conclusion: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.
Language	English
Publishing date	2023-03-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.08.531731
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Article ; Online: ATP, P2 receptors and the renal microcirculation.

Inscho, Edward W

Purinergic signalling

2009 Volume 5, Issue 4, Page(s) 447–460

Abstract: Purinoceptors are rapidly becoming recognised as important regulators of tissue and organ function. Renal expression of P2 receptors is broad and diverse, as reflected by the fact that P2 receptors have been identified in virtually every major tubular/ ... ...

Abstract	Purinoceptors are rapidly becoming recognised as important regulators of tissue and organ function. Renal expression of P2 receptors is broad and diverse, as reflected by the fact that P2 receptors have been identified in virtually every major tubular/vascular element. While P2 receptor expression by these renal structures is recognised, the physiological functions that they serve remains to be clarified. Renal vascular P2 receptor expression is complex and poorly understood. Evidence suggests that different complements of P2 receptors are expressed by individual renal vascular segments. This unique distribution has given rise to the postulate that P2 receptors are important for renal vascular function, including regulation of preglomerular resistance and autoregulatory behaviour. More recent studies have also uncovered evidence that hypertension reduces renal vascular reactivity to P2 receptor stimulation in concert with compromised autoregulatory capability. This review will consolidate findings related to the role of P2 receptors in regulating renal microvascular function and will present areas of controversy related to the respective roles of ATP and adenosine in autoregulatory resistance adjustments.
Language	English
Publishing date	2009-03-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2172143-9
ISSN	1573-9546 ; 1573-9538
ISSN (online)	1573-9546
ISSN	1573-9538
DOI	10.1007/s11302-009-9147-1
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Article ; Online: Role for ovarian hormones in purinoceptor-dependent natriuresis.

Gohar, Eman Y / Kasztan, Malgorzata / Zhang, Shali / Inscho, Edward W / Pollock, David M

Biology of sex differences

2020 Volume 11, Issue 1, Page(s) 52

Abstract: Background: Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y: Methods: To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) ...

Abstract	Background: Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y Methods: To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na Results: Acute P2 inhibition attenuated urinary Na Conclusion: These data suggest that ovary-intact females have enhanced P2Y
MeSH term(s)	Animals ; Cell Line ; Dose-Response Relationship, Drug ; Epithelial Sodium Channels/genetics ; Epithelial Sodium Channels/metabolism ; Estradiol/metabolism ; Female ; Gene Expression Regulation/drug effects ; Kidney Medulla/physiology ; Male ; Natriuresis/physiology ; Ovariectomy ; Ovary/physiology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2/genetics ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2Y2/genetics ; Receptors, Purinergic P2Y2/metabolism ; Sex Factors ; Suramin/pharmacology ; Type C Phospholipases/genetics ; Type C Phospholipases/metabolism
Chemical Substances	Epithelial Sodium Channels ; RNA, Messenger ; Receptors, Purinergic P2 ; Receptors, Purinergic P2Y2 ; purinoceptor P2Y4 ; Estradiol (4TI98Z838E) ; Suramin (6032D45BEM) ; Type C Phospholipases (EC 3.1.4.-)
Language	English
Publishing date	2020-09-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2587352-0
ISSN	2042-6410 ; 2042-6410
ISSN (online)	2042-6410
ISSN	2042-6410
DOI	10.1186/s13293-020-00329-0
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Article ; Online: Lewis K. Dahl Memorial Lecture. Mysteries of renal autoregulation.

Inscho, Edward W

Hypertension (Dallas, Tex. : 1979)

2008 Volume 53, Issue 2, Page(s) 299–306

MeSH term(s)	Animals ; Disease Models, Animal ; Hemodynamics/physiology ; Homeostasis/physiology ; Humans ; Hypertension/physiopathology ; Kidney/blood supply ; Kidney/physiology ; Kidney Glomerulus/blood supply ; Kidney Glomerulus/physiology ; Signal Transduction/physiology
Language	English
Publishing date	2008-12-08
Publishing country	United States
Document type	Lecture ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.108.119982
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Article ; Online: Restoration of afferent arteriolar autoregulatory behavior in ischemia-reperfusion injury in rat kidneys.

Feng, Wenguang / Remedies, Colton E / Obi, Ijeoma E / Aldous, Stephen R / Meera, Samia I / Sanders, Paul W / Inscho, Edward W / Guan, Zhengrong

American journal of physiology. Renal physiology

2021 Volume 320, Issue 3, Page(s) F429–F441

Abstract: Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal ... ...

Abstract	Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60 min of bilateral renal artery occlusion followed by 24 h of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65 ± 3% of baseline diameter (13.2 ± 0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7 ± 0.5 µm and remained between 90% and 101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (tempol or apocynin) to IR kidneys for 20 min increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, the addition of polyethylene glycol superoxide dismutase or polyethylene glycol-catalase to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating the involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and monocyte chemoattractant protein-1 in renal tissue homogenates, and this was prevented by tempol pretreatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion.
MeSH term(s)	Animals ; Arterioles/metabolism ; Blood Pressure/physiology ; Glomerular Filtration Rate/physiology ; Homeostasis/physiology ; NADPH Oxidases/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Renal Circulation/physiology ; Renal Insufficiency, Chronic/metabolism ; Reperfusion Injury/metabolism
Chemical Substances	Reactive Oxygen Species ; NADPH Oxidases (EC 1.6.3.-)
Language	English
Publishing date	2021-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00500.2020
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Article ; Online: Rho kinase inhibitors reduce voltage-dependent Ca

Guan, Zhengrong / Baty, Joshua J / Zhang, Shali / Remedies, Colton E / Inscho, Edward W

American journal of physiology. Renal physiology

2019 Volume 317, Issue 5, Page(s) F1132–F1141

Abstract: Voltage-dependent L-type ... ...

Abstract	Voltage-dependent L-type Ca
MeSH term(s)	3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology ; Amides/pharmacology ; Animals ; Aorta/cytology ; Arterioles/drug effects ; Bacterial Proteins ; Calcium Channels/metabolism ; Cell Line ; Kidney/blood supply ; Male ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Potassium Chloride/pharmacology ; Pyridines/pharmacology ; Rats ; Repressor Proteins ; Signal Transduction/physiology ; Thiazoles/pharmacology ; Urea/analogs & derivatives ; Urea/pharmacology ; Vasoconstriction/drug effects ; rho-Associated Kinases/antagonists & inhibitors
Chemical Substances	Amides ; Bacterial Proteins ; Calcium Channels ; Pyridines ; RKI-1447 ; Repressor Proteins ; SprA protein, Salmonella typhimurium ; Thiazoles ; Y 27632 (138381-45-0) ; Potassium Chloride (660YQ98I10) ; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester (71145-03-4) ; Urea (8W8T17847W) ; rho-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2019-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00212.2018
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Article ; Online: Extracellular Nucleotides and P2 Receptors in Renal Function.

Vallon, Volker / Unwin, Robert / Inscho, Edward W / Leipziger, Jens / Kishore, Bellamkonda K

Physiological reviews

2019 Volume 100, Issue 1, Page(s) 211–269

Abstract: The understanding of the nucleotide/P2 receptor system in the regulation of renal hemodynamics and transport function has grown exponentially over the last 20 yr. This review attempts to integrate the available data while also identifying areas of ... ...

Abstract	The understanding of the nucleotide/P2 receptor system in the regulation of renal hemodynamics and transport function has grown exponentially over the last 20 yr. This review attempts to integrate the available data while also identifying areas of missing information. First, the determinants of nucleotide concentrations in the interstitial and tubular fluids of the kidney are described, including mechanisms of cellular release of nucleotides and their extracellular breakdown. Then the renal cell membrane expression of P2X and P2Y receptors is discussed in the context of their effects on renal vascular and tubular functions. Attention is paid to effects on the cortical vasculature and intraglomerular structures, autoregulation of renal blood flow, tubuloglomerular feedback, and the control of medullary blood flow. The role of the nucleotide/P2 receptor system in the autocrine/paracrine regulation of sodium and fluid transport in the tubular and collecting duct system is outlined together with its role in integrative sodium and fluid homeostasis and blood pressure control. The final section summarizes the rapidly growing evidence indicating a prominent role of the extracellular nucleotide/P2 receptor system in the pathophysiology of the kidney and aims to identify potential therapeutic opportunities, including hypertension, lithium-induced nephropathy, polycystic kidney disease, and kidney inflammation. We are only beginning to unravel the distinct physiological and pathophysiological influences of the extracellular nucleotide/P2 receptor system and the associated therapeutic perspectives.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Humans ; Kidney/metabolism ; Kidney/physiology ; Nucleotides/metabolism ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2/physiology ; Signal Transduction
Chemical Substances	Nucleotides ; Receptors, Purinergic P2 ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2019-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	209902-0
ISSN	1522-1210 ; 0031-9333
ISSN (online)	1522-1210
ISSN	0031-9333
DOI	10.1152/physrev.00038.2018
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