Ivan Ćavar

The effect of glucagon and cyclic adenosine monophosphate on acute liver damage induced by acetaminophen

Recent investigations suggest that glucagon might have a potentially important hepatoprotective activity. We investigated the effect of glucagon in a model of acetaminophen-induced liver injury. CBA male mice were injected intraperitoneally with a lethal (300 mg/kg) or sublethal (150 mg/kg) dose of acetaminophen. The liver injury was assessed by observing the survival of mice, by liver histology and by measuring the concentration of alanine-aminotransferase (ALT). Inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB) protein expressions were determined immunohistochemically. Hepatic levels of reduced glutathione (GSH) and cyclic adenosine monophosphate (cAMP) were also measured. Results show that glucagon, dose and time dependently, protects against acetaminophen-induced hepatotoxicity. This protection was achieved with a dose of 0.5 mg/kg of glucagon given intraperitoneally 15 min before or 1 h after acetaminophen. Treatment of animals with acetaminophen elevated ALT and nitrite/nitrate concentration in the plasma, enhanced iNOS and NF-κB expression and reduced GSH and cAMP concentration in the liver. Animals treated with glucagon had higher hepatic cAMP level, lower ALT and nitrite/nitrate concentration in plasma and lower expression of iNOS in liver cells than animals in control group, whereas there was no difference in the expression of NF-κB. Glucagon did not prevent the loss of GSH content caused by acetaminophen. Our investigation indicates that glucagon has a moderately protective effect against acetaminophen-induced liver injury, which is, at least partially, mediated through the downregulation of iNOS and through the increase in hepatic cAMP content, but it is not mediated through the modulation of NF-κB activity.

Hepatoprotective action of Panaxatriol saponins against acetaminophen‐induced liver injury: what is the mechanism?

To the Editor: We read with great interest a recent article published in Liver International by Wang et al., who reported on the powerful protective effect of Panaxatriol saponins (ginsenosides) extracted from Panax notoginseng against acetaminophen hepatotoxicity. The authors concluded that the protection is mediated through suppression of tumour necrosis factor alpha (TNF-a) and upregulation of thioredoxin-1 (TRX1) (1). However, a review of the published literature suggests a more plausible mechanism of protection. Toxicity of acetaminophen depends on its metabolic activation to N-acetyl-p-benzoquinoneimine (NAPQI) by cytochrome P450 enzymes. It is well known that many substances exert powerful protective effect against acetaminophen hepatotoxicity by inhibiting its cytochrome P450mediated biotransformation (2). Therefore, when performing a study on a hepatoprotective substance, it is critical to investigate its effect on acetaminophen activation, at least by monitoring the dynamic of GSH liver content loss or, in more precise way, by monitoring the levels of acetaminophen metabolites. The authors did not provide such data, although the literature suggests that ginsenosides might have inhibitory effect on several CYP isoforms, including the CYP1A2, CYP3A4 and CYP2E1 (3, 4), important for acetaminophen bioactivation (5). Therefore, treatment with Panaxatriol saponins could suppress the production of NAPQI and subsequently acetaminophen toxicity. Since NAPQI overproduction leads to oxidative stress and increases TNF-a production (6), the differences in levels of TRX1 and TNF-a between the control and Panaxatriol saponins-treated group might have been caused by differences in NAPQI production. Furthermore, literature data do not support authors’ conclusions regarding the role of TNF-a and TRX1 in acetaminophen hepatotoxicity:

Effect of nitric oxide donors S-nitroso-N-acetyl-DL-penicillamine, spermine NONOate and propylamine propylamine NONOate on intracellular pH in cardiomyocytes.

Previous studies suggest that exogenous nitric oxide (NO) and NO‐dependent signalling pathways modulate intracellular pH (pHi) in different cell types, but the role of NO in pHi regulation in the heart is poorly understood. Therefore, in the present study we investigated the effect of the NO donors S‐nitroso‐N‐acetyl‐dl‐penicillamine, spermine NONOate and propylamine propylamine NONOate on pHi in rat isolated ventricular myocytes. Cells were isolated from the hearts of adult Wistar rats and pHi was monitored using the pH‐sensitive fluorescent indicator 5‐(and‐6)‐carboxy seminaphtharhodafluor (SNARF)‐1 (10 μmol/L) and a confocal microscope. To test the effect of NO donors on the Na+/H+ exchanger (NHE), basal pHi in Na+‐free buffer and pHi recovery from intracellular acidosis after an ammonium chloride (10 mmol/L) prepulse were monitored. The role of carbonic anhydrase was tested using acetazolamide (50 μmol/L). 4,4‐Diisothiocyanatostilbene‐2,2′‐disulphonic acid (0.5 mmol/L; DIDS) was used to inhibit the Cl−/OH− and Cl−/ HCO3− exchangers. Acetazolamide and DIDS were applied via the superfusion system 1 and 5 min before the NO donors. All three NO donors acutely decreased pHi and this effect persisted until the NO donor was removed. In Na+‐free buffer, the decrease in basal pHi was increased, whereas inhibition of carbonic anhydrase and Cl−/OH− and Cl−/ HCO3− exchangers did not alter the effects of the NO donors on pHi. After an ammonium preload, pHi recovery was accelerated in the presence of the NO donors. In conclusion, exogenous NO decreases basal pHi, leading to increased NHE activity. Carbonic anhydrase and chloride‐dependent sarcolemmal HCO3− and OH− transporters are not involved in the NO‐induced decrease in pHi in rat isolated ventricular myocytes.

Body Composition and Inflammation in Hemodialysis Patients

The volume state of dialysis patients is important in guiding the dialysis process. Volume overload in these patients is associated with inflammation. The objectives of the present study were to assess the body composition of patients on hemodialysis; to determine the concentrations of B‐type natriuretic peptide (BNP) in plasma and evaluate the association of BNP concentrations with volume overload; to determine the concentrations of C‐reactive protein (CRP), albumin and superoxide dismutase (SOD) activities as indicators of inflammatory or antioxidant processes. The study included 79 maintenance hemodialysis patients. Assessment of body compartments was carried out using a body composition monitor (BCM). After BCM measurements, blood samples were taken from the patients for laboratory tests. There were 40 (50.6%) volume‐overloaded patients (relative overhydration >15%). These patients had a higher prevalence of arterial hypertension (P < 0.05), significantly higher concentrations of BNP (P = 0.01), lower body mass index (P < 0.05) and lower fat tissue index (P < 0.05). There was a positive correlation between plasma BNP and CRP concentrations (ρ = 0.231; P < 0.05), and a negative correlation between (log) BNP and albumin (r = −0.021; P < 0.05), as well as (log) CRP and albumin concentrations (r = −3; P < 0.01). SOD activity was positively correlated with albumin concentrations (r = 0.254; P < 0.05). The concentrations of BNP in this study were associated with volume overload and inflammatory markers. Patients with a higher albumin concentration had higher SOD activity.

Transient cortical blindness in posterior reversible encephalopathy syndrome after postpartum eclampsia

Posterior reversible encephalopathy syndrome (PRES) is a clinical condition that can cause different ophthalmological and neurological symptoms. Preeclampsia toxemia or eclampsia is one of the leading causes of PRES. Herein, we present a study of a 35-year old woman who gave birth to healthy twins at 35 weeks of gestation by cesarean section because of threatened preterm delivery. On the 1st postoperative day, the woman developed a severe headache, arterial hypertension, tachycardia, generalized tonic–clonic seizures, and loss of consciousness that persisted for about 2 min. A provisional diagnosis of eclampsia was made, and the woman was then quickly transferred to the intensive care unit where she was treated with antihypertensive therapy, magnesium sulphate, and diazepam. Following stabilization of the general condition, the patient noticed sudden bilateral blindness. An ophthalmological examination revealed significant bilateral loss of vision at the level of insecured light perception, normal pupillary responses to a light stimulus, and normal fundus findings. On this basis, an ophthalmologist made the diagnosis to cortical blindness. Radiographic analysis showed an edematous change in the occipital and parietal brain regions, thus suggesting a diagnosis of PRES. In conclusion, cortical blindness is a clinically striking ophthalmic disorder that may occur in PRES associated with postpartum eclampsia.

HALLUCINATORY EXPERIENCES IN VISUALLY IMPAIRED INDIVIDUALS: CHARLES BONNET SYNDROME – IMPLICATIONS FOR RESEARCH AND CLINICAL PRACTICE

BACKGROUND Charles Bonnet syndrome (CBS) refers to visual hallucinations that occur in individuals with preserved cognitive functions associated with visual impairment. METHODS This article reviews occurence of visual hallucinations in subjects with CBS by journals published in English in the Pubmed database in the period 1992-2018. Criteria for selection of appropriate papers were sufficient information and perspicuous view on pathogenesis, epidemiology, clinical presentation and treatment possibilities of CBS. RESULTS Most commonly, visual hallucinations in patients with CBS are complex, repetitive and stereotyped. Such individuals have preserved insight that those percepts are not real, and there is an absence of secondary explanatory delusions and hallucinations within other modalities. Seeing as the aforementioned percepts do not share all the characteristics of hallucinations, it remains unresolved how they should be referred to. Terms as release hallucinations, one that is reflecting its underlying pathogenesis, or confabulatory hallucinatory experiences have been proposed. Moreover, CBS has also been referred to as phantom vision syndrome and may occur in any ophthalmological disease. It is not particularly connected with loss of function along any level of the visual pathway. Although this syndrome is mostly associated with age-related macular degeneration, glaucoma and cataract, it could be related to almost any other ophthalmological conditions. The incidence of CBS alongside with mostly other ocular pathology is rising as population is ageing. CONCLUSIONS Nonetheless, CBS remains commonly underreported, under recognized and/or misrecognized. Albeit the treatment recommendations and guidelines are not yet fully established, it is important to raise awareness of this specific and distinct condition, which inevitably implicates many differential diagnostic deliberations.