Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs as protectants against anthracycline-induced cardiotoxicity

The risk of cardiotoxicity is the main drawback of anthracycline antibiotics. However, these drugs remain among the most effective and frequently used anti cancer drugs. In this study we aimed to assess the cardioprotective effects of aroylhydrazone iron (FE) chelators: pyridoxal isonicotinoyl hydrazone (PIH) and its two analogs: salicyladehyde isonicotinoyl hydrazone (SIH) and pyridoxal o-chlorbenzoyl hydrazone (o-108). In rabbits, chronic treatment with daunorubicin (DAU) (3 mg/kg weekly for 10 weeks) induced mortality (33%) as well as left ventricular (LV) dysfunction. Co-administrations of PIH (25 mg/kg, i.p.), SIH hydrochloride [1 mg/kg, iv] as well as o-108 (10 mg/kg, i.p.), fully prevented premature deaths and most of the DAU-induced functional impairments were significantly suppressed. However, when 2- to 2.5-fold higher doses of the chelators were used, they led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality.     

Effect of Pentylenetetrazole on Ethanol Intake, Ethanol Kinetics, and Social Behavior in Male Wistar Rats

Stress and anxiety are often implicated in excessive alcohol use. The nature of this interaction, however, is not understood. The aim of this study was to examine the effect of the anxiogenic agent, pentylenetetrazole (PTZ), on the acquisition and maintenance of ethanol drinking behavior in male Wistar rats. In rats maintained on a limited access procedure, with a choice between a 12% w/v ethanol (ETOH) solution and water available for 30 min each day, acute PTZ administration (1.5 to 15.0 mg/kg) did not modify ETOH intake. Chronic PTZ administration elicited a significant suppression in ETOH intake; however, this effect developed gradually over time. During the acquisition phase, chronic PTZ treatment also suppressed ETOH consumption. Chronic, but not acute, treatment with PTZ seemed to enhance water consumption. To assess whether the effect of PTZ on ETOH intake was due to either alterations in ETOH kinetics or behavior, blood ETOH levels and social interaction behaviour were examined. PTZ (15.0 mg/kg) produced a significant suppression in social interaction behavior, although tolerance developed to this effect on chronic PTZ administration. Both acute and chronic PTZ treatment (15 mg/kg) resulted in lower blood ETOH levels achieved after administration of 1.0 g/kg po of ETOH. Because the anxiogenic effect of PTZ was not maintained on repeated administration, yet the suppression of ETOH intake was only observed after chronic treatment, this suggests a dissociation between the processes regulating these behaviors.     

EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion‐Almeida type

Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion‐Almeida type (MFDGA). MFDGA‐associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss‐of‐function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss‐of‐function are self‐evident, the mechanisms by which missense variants are disease‐causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss‐of‐function. Only four of 19 assessed missense variants cause EFTUD2 loss‐of‐function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre‐messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory‐based validation of bioinformatic predictions for EFTUD2 missense variants.     

Effect of isolated proximal coronary stenotic lesions on distal myocardial perfusion during exercise

This study tested the hypothesis that the absolute dimension of a coronary stenotic lesion is a more important determinant of its hemodynamic effect on regional myocardial perfusion during exercise than is relative percent stenosis. In 31 patients with an isolated lesion of the left anterior descending coronary artery, regional myocardial perfusion was determined from thallium-201 scans recorded in the left anterior oblique projection after symptom-limited treadmill exercise. Thallium-201 uptake in the distribution of the left anterior descending coronary artery was expressed as a ratio of thallium-201 uptake in the left circumflex artery distribution. Percent area stenosis, minimal cross-sectional area and mean diameter of each stenotic lesion were measured by computer-assisted cinevideodensitometric analysis of projected coronary arteriograms digitized in a 512 X 512 pixel matrix with 256 gray levels. Thallium-201 uptake in the left anterior descending coronary artery distribution, expressed as a ratio, correlated poorly (r = 0.65) with relative percent stenosis, but correlated significantly (r = 0.83; p less than 0.05) with absolute lesion area. For all 16 patients with reduced regional perfusion in the left anterior descending coronary artery distribution during exercise, lesion cross-sectional area was less than 1.8 mm2 (mean 0.9 +/- 0.6); for 13 of the 15 patients with normal distal perfusion, the area of the stenotic lesion was greater than 1.8 mm2 (mean 2.7 +/- 0.7; p less than 0.001). Percent coronary stenosis failed to predict flow-limiting lesions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of chronic toxic effects of daunorubicin and doxorubicin in rabbits

This study compares the chronic toxicity of two anthracyclines--daunorubicin and doxorubicin, commonly used for induction of anthracycline cardiomyopathy in the rabbit model. Such a comparative study has not been published until now. Both drugs were administered intravenously to male Chinchilla rabbits in doses at 3 mg/kg (50 mg/m2) once weekly for 10 weeks. Selected biochemical, haematological and cardiovascular parameters and body weights were regularly monitored; additionally, a histological evaluation of heart, kidney and liver was performed at the end of the experiment. In the daunorubicin group, there were marked signs of the progressive development of heart failure, like the significant increases of the pre-ejection period/left ventricular ejection time index values (up to 134%)--and histological changes within the myocardium were also observed. On the other hand, the 10-week doxorubicin administration did not cause these changes that are typical for heart injury. Haematotoxicity, manifested particularly by aplastic anaemia, was apparent in both the experimental groups. Significant body weight loss (by 45.2%) and high premature mortality (100% versus 36.4%) reflected a greater general toxicity, especially nephrotoxicity of doxorubicin in comparison with daunorubicin. Further studies are necessary to find a possible explanation for these findings.     

Spontaneous tumor lysis syndrome in solid tumors: really a rare condition?

Acute tumor lysis syndrome (ATLS), which occurs spontaneously, without cytotoxic therapy, is a rare condition. Spontaneous TLS (STLS) has been seen most commonly in lymphoma and leukemia. We report a series of 3 cases of STLS in patients with solid tumors who were hospitalized in our department during a 9-month period and suggest that STLS is probably more frequent than previously thought.     

Troponin as a marker of myocardiac damage in drug-induced cardiotoxicity

Cardiac troponins T and I (cTnT and cTnI) are becoming the serum biomarkers of choice for monitoring potential drug-induced myocardial injury in both clinical and preclinical studies. The utility of cardiac troponins has been mainly demonstrated following the administration of antineoplastic drugs and beta-sympathomimetics, although the routine use of these markers in the monitoring in patients who received anthracyclines therapy is far from settled. Unlike the previous markers, which suffered from numerous shortages, the main advantages of cardiac troponins are their high specificity and sensitivity, wide diagnostic window and the possibility to use commercially available assays in clinical settings as well as in a broad range of laboratory animals. Nevertheless, in spite of vigorous research in this area, a number of questions are still unanswered and these are discussed in this review. The main problems seem to be the lack of standardisation of variety of troponin immunoassays, the assessment of suitable cutoff for drug-induced cardiotoxicity and determination of critical diagnostic window related to the optimal timing of sample collection, which may be drug-dependent.     

Adequacy of laboratory simulation of in-line skater falls

PURPOSE: Currently most laboratory simulation of distal radius fractures and wrist injuries has been with axial limb loading or vertical drop technique. To better assess the contribution of horizontal velocity in momentum in the development of wrist injury and wrist fracture we have compared forces and fracture patterns for fall simulations involving strictly vertical impacts with those that incorporated horizontal momentum in fresh-frozen upper extremities. METHODS: The premise for testing was based on a forward fall onto the palmar surface of an outstretched arm. A 45 degrees-incline impact device was used to model the horizontal and vertical velocity components of a skater fall at a representative speed. Sled mass was 26.2 kg. A 45.5-kg vertical impact system furnished contrasting data and represented prior state-of-the-art technology. Drop heights were adjusted to compensate for discrepancy in sled mass. Measurements from either impact system included vertical and horizontal forces and kinetic energy at impact. Fracture patterns were assessed radiographically. Nine trials were conducted with the incline device and 11 trials were conducted with the vertical impact system. RESULTS: The fracture rate was substantially higher for vertical impacts versus incline impacts (82% vs 33%). The rate of carpal fractures also was higher. Vertical and horizontal forces were similar statistically although slightly greater for vertical impacts. Kinetic energy, however, was 3 times greater for incline impacts than for vertical impacts. These kinetic parameters support the argument that the incline impacts should have resulted in far greater injury. CONCLUSIONS: The data suggest horizontal momentum changes limb loading. We submit that published methods for modeling skater falls have failed to provide a true simulation of the event in question.