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Harshad Chaudhari, Smita Mahendrakar, Stuart E Baskin, Alluru S Reddi Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USACorrespondence: Harshad Chaudhari, Email hc835@njms.rutgers.eduAbstract: The role of contrast-induced nephropathy (CIN) remains controversial. Many experts contend that CIN does not exist or is extremely rare. The diagnosis was previously made too frequently and inappropriately in the presence of coexisting and confounding comorbidities and risk factors making it difficult to singularly isolate the etiologic role of intravenous contrast media in acute kidney injury (AKI). It is probable that many patients were denied important diagnostic information from radiocontrast studies for fear of CIN. Recently, a new terminology for CIN was introduced, and the term CIN was replaced by two interrelated new terms: one is contrast-associated acute kidney injury (CA-AKI), and the second one is contrast-induced acute kidney injury (CI-AKI). CA-AKI occurs in association with risk factors or comorbidities, therefore, it is a correlative diagnosis. On the other hand, CI-AKI is a subtype of CA-AKI that results directly from iodinated contrast media. In this review, we present evidence from various studies that argue against CI-AKI and also those that suggest its existence but with much lower frequency. We will also provide the current status of the pathophysiology and management of CA-AKI/CI-AKI.Keywords: contrast agents, contrast-induced acute kidney injury, contrast-associated acute kidney injury, pathophysiology, prevention, propensity score matching

Repetitive elements (RE) and transposons (TE) can comprise up to 80% of some plant genomes and may be essential for regulating their evolution and adaptation. The "repeatome" information is often unavailable in assembled genomes because genomic areas of repeats are challenging to assemble and are often missing from final assembly. However, raw genomic sequencing data contain rich information about RE/TEs. Here, raw genomic NGS reads of 10 gymnosperm species were studied for the content and abundance patterns of their "repeatome". We utilized a combination of alignment on databases of repetitive elements and de novo assembly of highly repetitive sequences from genomic sequencing reads to characterize and calculate the abundance of known and putative repetitive elements in the genomes of 10 conifer plants: Pinus taeda , Pinus sylvestris , Pinus sibirica , Picea glauca , Picea abies , Abies sibirica , Larix sibirica , Juniperus communis , Taxus baccata , and Gnetum gnemon . We found that genome abundances of known and newly discovered putative repeats are specific to phylogenetically close groups of species and match biological taxa. The grouping of species based on abundances of known repeats closely matches the grouping based on abundances of newly discovered putative repeats ( kChains ) and matches the known taxonomic relations.

Background: Patients undergoing liver transplantation (LT) can develop acute heart failure (HF) in the postoperative period despite having had a normal cardiac evaluation prior to surgery. End-stage liver disease is often associated with underlying cardiac dysfunction which, while not identified during preoperative testing, manifests itself during or immediately after surgery., Case Presentation: We describe three cases of non-ischemic acute HF developing shortly after LT in patients who had a normal preoperative cardiac evaluation. The challenges associated with both diagnosis and management of acute HF in the setting of a newly implanted graft will be discussed., Conclusions: Diastolic dysfunction, QTc interval prolongation, and an increase in BNP may be predictive of postoperative HF. Current recommendations for preoperative cardiovascular evaluation of transplant candidates does not include studies examining these risk factors and should be revised. Further investigations are necessary to evaluate these findings.

Chronic hepatitis C virus (HCV) infection is a complex, multi-organ disorder, not just limited to the liver. Mixed cryoglobulinemia (MC) type 2 is a common extrahepatic complication, in which immunoglobulin complexes deposit in vascular endothelium. This in turn creates a diffuse inflammatory reaction, leading to a variety of disorders involving multiple systems. We report the rare case of a patient with cryoglobulinemia, cutaneous vasculitis, membroproliferative glomerulonephritis, and B cell lymphoma with a variant t(6;10) translocation in the setting of an untreated, chronic HCV infection. This case highlights the challenge associated with diagnosing and managing such a complex presentation., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Many substances that form methemoglobin (MHb) effectively counter cyanide (CN) toxicity. Although MHb formers are generally applied as treatments for CN poisoning, it has been proposed that a stable, long-acting MHb former could serve as a CN pretreatment. Using this rationale, the 8-aminoquinoline WR242511, a potent long-lasting MHb former in rodents and beagle dogs, was studied in the rhesus monkey for advanced development as a potential CN pretreatment., Methods: In this study, WR242511 was administered intravenously (IV) in 2 female and 4 male rhesus monkeys in doses of 3.5 and/or 7.0 mg/kg; a single male also received WR242511 orally (PO) at 7.0 mg/kg. Health status and MHb levels were monitored following exposure., Results: The selected doses of WR242511, which produced significant methemoglobinemia in beagle dogs in earlier studies conducted elsewhere, produced very little MHb (mean < 2.0%) in the rhesus monkey. Furthermore, transient hemoglobinuria was noted approximately 60 minutes postinjection of WR242511 (3.5 or 7.0 mg/kg), and 2 lethalities occurred (one IV and one PO) following the 7.0 mg/kg dose. Myoglobinuria was also observed following the 7.0 mg/kg dose. Histopathology analyses in the 2 animals that died revealed liver and kidney toxicity, with greater severity in the orally-treated animal., Conclusions: These data demonstrate direct and/or indirect drug-induced toxicity. It is concluded that WR242511 should not be pursued as a pretreatment for CN poisoning unless the anti-CN characteristics of this compound can be successfully dissociated from those producing undesirable toxicity.

The IGF-1R is a genetic determinant of oxidative stress and longevity. Hyperglycemia induces an exponential increase in the production of a key danger signal, reactive oxygen intermediates, which target genomic DNA. Here, we report for the first time that ligand activation of the IGF-1R prevents hyperglycemia-induced genotoxic stress and enhances DNA repair, maintaining genomic integrity and cell viability. We performed single gel electrophoresis (comet assay) to evaluate DNA damage in serum-starved SV40 murine mesangial cells (MMC) and normal human mesangial cells (NHMC), maintained at high ambient glucose concentration. Hyperglycemia inflicted an impressive array of DNA damage in the form of single-strand breaks (SSBs) and double-strand breaks (DSBs). The inclusion of IGF-1 to culture media of MMC and NHMC prevented hyperglycemia-induced DNA damage. To determine whether DNA damage was mediated by reactive oxygen species (ROS), ROS generation was evaluated, in the presence of IGF-1, or the free radical scavenger n-acetyl-cysteine (NAC). IGF-1 and NAC inhibited hyperglycemic-induced ROS production and hyperglycemia-induced DNA damage. We next asked whether IGF-1 promotes the repair of DSB under hyperglycemic conditions, by homologous recombination (HRR) or nonhomologous end joining (NHEJ). Repair of DSB by NHEJ and HRR was operative in MMC maintained under hyperglycemic conditions. IGF-1 increased HRR by nearly twofold, whereas IGF-1 did not affect DNA repair by NHEJ. IGF-1R enhancement of HRR correlated with the translocation of Rad51 to foci of DNA damage. Inhibition of Rad51 expression by short interfering RNA experiments markedly decreased percentage of MMC positive for Rad51 nuclear foci and increased hyperglycemic DNA damage. We conclude that the activated IGF-1R rescues mesangial cells from hyperglycemia-induced danger signals that target genomic DNA by suppressing ROS and enhancing DNA repair by HRR.

The activated insulin-like growth factor-1 receptor (IGF-1R) protects cells from a wide range of apoptotic stimuli. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide, both of which have been linked to the activation of the mitochondrial apoptosis program. Here, we report for the first time that ligand activation of the IGF-1R protects normal human mesangial cells and SV40 murine mesangial cells from the glycol-oxidant-induced apoptosis program. The IGF-1R antiapoptosis program was dependent on the recruitment of both Akt/PKB and the ERK subfamily of mitogen-activated protein kinases. IGF-1 treatment also protected the redox potential of mesangial cells maintained at high ambient glucose concentration, by inhibiting the generation of reactive oxygen intermediates and preserving mitochondrial transmembrane potential. IGF-1R survival signals targeted the Bcl-2 family of proteins to protect against glucose-induced apoptosis and oxidative stress. IGF-1-treated cells exhibited a decrease in the Bax/Bcl-2 ratio; increased phosphorylation/inactivation of Bad at Ser112 and Ser136; inhibition of cytochrome c release; perturbations directionally opposed to the initiation of the apoptosis program. In addition, we demonstrate IGF-1R-activated ERK signaling modules phosphorylate Ser112 of the mitochondrial Bad protein, establishing a direct link between surface IGF-1R and the survival program in mitochondria. Our findings indicate that in mesangial cells maintained at high ambient glucose concentration, IGF-1 activates a survival program that maintains the integrity of mitochondria and prevents the expression of the genetic program for apoptosis.

A single dose of radioactive copper ((64)Cu or new Cu) was infused into the stomach of rainbow trout (Oncorhynchus mykiss) to model dietary copper (Cu) uptake under conditions of a normal nutritional dose and optimum environmental temperature (16 degrees C, 0.117 microg Cu g(-)(1 )body mass). The distribution of new Cu to the gut and internal organs occurred in two phases: rapid uptake by the gut tissues (almost complete by 24 h post-infusion) followed by slower uptake by the internal organs. By 72 h, 60 % of the dose had been excreted, 19 % was still retained in the gut tissue, 10 % remained in the lumen and 12 % had been absorbed across the gut and partitioned amongst the internal organs. A reduction in water temperature of 10 degrees C (to 6 degrees C) significantly retarded components of new Cu distribution (movement of the bolus along the gut and excretion); nonetheless, by 72 h, the fraction absorbed by all the internal organs was similar to that at 16 degrees C. An increase in water temperature of 3 degrees C (to 19 degrees C) caused a pronounced increase in internal organ uptake by 24 h to approximately double the uptake occurring at 16 degrees C. The uptake of new Cu by the gut tissue had a low temperature coefficient (Q(10)<1) consistent with simple diffusion, while the temperature coefficient for transfer of new Cu from gut tissue to the internal organs was high (Q(10)>2), consistent with facilitated transport. Internally, the liver and gall bladder (including bile) were the target organs for dietary Cu partitioning since they were the only organs that concentrated new Cu from the plasma. Individual tissues differed in terms of the exchange of their background Cu pools with new Cu. The background Cu in the walls of the gastrointestinal tract (excluding stomach) exchanged 45-94 % with new Cu from the gut lumen, while tissues such as the stomach, gills, kidney, carcass and fat had 5-7 % exchangeable background Cu. The liver, heart, spleen, ovary, bile and plasma had only 0.2-0.8 % exchangeable background Cu. The gastrointestinal tissues appear to act as a homeostatic organ, regulating the absorption of nutritional (non-toxic) doses of Cu (0. 117 microg g(-)(1 )body mass day(-)(1)) by the internal organs. Within the dose range we used and at optimal temperature (16 degrees C), the new Cu content of the gut tissues fluctuated, but absorption of new Cu by the internal organs remained relatively constant. For example, predosing the fish with non-radioactive Cu caused new Cu absorption by the gut tissues to double and decreased new Cu excretion from 38 to 1.5 %, but had no effect on new Cu uptake by the internal organs. Feeding fish after application of the normal liquid dose of new Cu also had no effect on new Cu uptake by the internal organs, even though the presence of food in the digestive tract reduced the binding of new Cu to the gut tissues and assisted with the excretion of new Cu. The gut was therefore able to regulate new Cu internalization at this dosage. Higher new Cu doses (10, 100 and 1000 times the normal dose), however, evoked regurgitation and increased new Cu excretion within 4 h of application but did not elevate new Cu levels in gut tissue beyond a threshold of approximately 40 microg of new Cu. Only at the highest dose (1000 times the normal dose, 192 microg g(-)(1 )body mass), equivalent to toxic concentrations in the daily diet (7000 microg Cu g(-)(1 )dry mass food), was the buffering capacity of the gut overwhelmed, resulting in an increase in internal new Cu uptake.

Controlled methemoglobin (MHb) formation is one strategy employed to counter cyanide (CN) toxicity. Currently available MHb formers present certain drawbacks and limitations. The purpose of this study was to characterize, in mice, the hematologic effects of the MHb-forming compound p-aminopropiophenone (PAPP), and two structurally-related p-aminophenones, p-aminoheptanoylphenone (PAHP) and p-aminooctanoylphenone (PAOP). Although these three p-aminophenones have been shown previously to be efficacious as pretreatments against CN, a more complete understanding of their hematologic effects is lacking. In addition, because the active form of PAPP has been shown to be its N-hydroxy metabolite, the N-hydroxy metabolites of PAPP, PAHP and PAOP were also tested. Using a hemoximeter, blood samples obtained -2 to +180 min relative to intramuscular (i.m.) or intraperitoneal (i.p.) drug injections were evaluated. Sodium nitrite (NaNO(2)) and the appropriate solvents served as the positive and negative controls, respectively. Dose-, time-, route-, and compound-related effects were observed. MHb and sulfhemoglobin levels increased, whereas levels of those parameters related to oxygen-carrying capacity of the blood, such as, oxygen saturation and oxyhemoglobin decreased. In general, the effects of PAHP and PAOP were longer lasting than those of PAPP and NaNO(2). Furthermore, PAPP and NaNO(2) were equally effective with either route of administration. Conversely, PAHP and PAOP showed larger effects when administered i.p. versus i.m. The animals treated with N-hydroxy metabolites of the p-aminophenones also showed similar changes in the hematological parameters measured. N-hydroxy PAPP was shown to be the most rapidly acting MHb-forming compound examined in this series. It could achieve therapeutic concentrations of MHb within 2 min and thus may be considered as a treatment for CN intoxication. Although additional work is needed, these data provide information that will be useful for the successful development of improved anti-CN MHb formers.

It was proposed that the diminished renal function observed with advancing age could be due to a lower concentration of essential ions within the organ or an accumulation of ions which could produce cellular toxicity. This investigation reports the effect of age (3, 6, 12, 24 and 28 months) on the concentrations of magnesium, calcium, zinc, copper and iron in renal homogenates of Fischer 344 strain rats. Samples of renal tissues were homogenized in a solution containing 5 p. 100 La + 25 p. 100 HNO3. The samples were digested, centrifuged and assayed by atomic absorption spectrophotometry. With age, the magnesium concentration decreased (P less than 0.05) while the calcium and copper concentrations remained unchanged, and the zinc concentration decreased slightly while the iron concentration markedly increased (P less than 0.05). In summary, these data and other data obtained from similar studies of the brain and heart, suggest that the changes observed with age are unique to the kidney. Our results suggest that changes in ionic concentration in the kidney with respect to age could contribute to the diminished function observed in that organ with senescence.

A patient with syphilitic glomerulonephritis had a renal biopsy and was treated for secondary syphilis. Light, electron, and immunofluorescence microscopic studies revealed an acute proliferative glomerulonephritis with subepithelial, intramembranous, and subendothelial immune complex deposits containing IgG, IgA, IgM, C4, and C3. Similar local deposits containing predominantly IgM were noted in areas of mesangial proliferation. Indirect fluorescent antibody studies employing rabbit treponemal antibody and sheep antirabbit globulin conjugate revealed the presence of treponemal antigen in the glomerular deposits. This finding provides strong evidence for the immunopathogenesis of the glomerular lesion as well as a causal link with Treponema pallidum.

This study determined whether the protective action of bretylium against ouabain-induced ventricular arrhythmia in the cat is related to an action of bretylium on the adrenergic nerve terminal. Bretylium pretreatment (20 mg/kg, i.v.) administered 2 h prior to ouabain (2 micrograms/kg/min, i.v. until death) increased the dose of ouabain to produce premature ventricular contraction, ventricular tachycardia, and death from 77.2 +/- 5.2 to 107.7 +/- 6.7 micrograms/kg; from 84.9 +/- 5.2 to 113.9 +/- 7.1 micrograms/kg; and from 108.8 +/- 4.0 to 146.7 +/- 5.7 micrograms/kg, respectively (p less than 0.05). Surgical denervation 2 weeks prior to the experiment or 6-hydroxydopamine (6OH dopamine), 20 mg/kg, i.v., administered 3 or 14 days prior to the ouabain infusion did not protect against the arrhythmogenic effects of ouabain. When bretylium was administered to cats pretreated with 6OH dopamine 3 days prior to the ouabain infusion or to surgically denervated cats, the protective action against ouabain-induced arrhythmia did not develop. Since 6OH dopamine and surgical denervation prevented the action of bretylium on ouabain-induced ventricular arrhythmia, it appears that bretylium is acting on the adrenergic nerve terminal. Thus, agents like bretylium that act on the adrenergic nerve terminal, leaving it structurally intact but not functional, are effective against ouabain-induced ventricular arrhythmia while procedures which cause the degeneration of the adrenergic nerve terminal, such as 6OH dopamine and surgical denervation, are not. These observations indicate that for the protective effect of sympathectomy against ouabain-induced arrhythmia to develop, the adrenergic nerve terminal must be present, although not functional as far as adrenergic neurotransmission is concerned. Changes in the heart rate or blood pressure did not appear to be a factor in the protective effect of bretylium.