Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines

Pediatric heart failure (HF) is an important cause of morbidity and mortality in childhood. This article presents guidelines for the recognition, diagnosis, and early medical management of HF in infancy, childhood, and adolescence. The guidelines are intended to assist practitioners in office-based or emergency room practice, who encounter children with undiagnosed heart disease and symptoms of possible HF, rather than those who have already received surgical palliation. The guidelines have been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and are accompanied by practical Recommendations for their application in the clinical setting, supplemented by online material. This work does not include Recommendations for advanced management involving ventricular assist devices, or other device therapies.

Effects of fluidized gas desulfurization (FGD) gypsum on non-target freshwater and sediment dwelling organisms.

Fluidized gas desulfurization gypsum is a popular agricultural soil amendment used to increase calcium and sulfur contents, and reduce aluminum toxicity. Due to its surface application in conservation tillage systems and high solubility, the soluble components of gypsum may be transferred with agricultural runoff into receiving waters. The current study measured toxicity of gypsum to Ceriodaphnia dubia, Pimephales promelas, Chironomus dilutus, and Hyalella azteca. Solutions at 2,400 mg gypsum/L (maximum solubility) produced no observable toxicity to C. dubia and P. promelas. Mixtures of a control sediment and gypsum indicated no observed toxicity effects for H. azteca, although effects were noted at 25% dilution for C. dilutus. Data suggest gypsum is not harmful to freshwater organisms at concentrations expected in the agricultural environment.

Assessing caffeine as an emerging environmental concern using conventional approaches.

Organic wastewater contaminants, including pharmaceuticals, caffeine, and nicotine, have received increased scrutiny because of their detection in water bodies receiving wastewater discharge. Despite recent measurement in United States streams, caffeine's effect on freshwater organisms is not well documented. The present study measured caffeine's lethal and sublethal effects on the freshwater species, Ceriodaphnia dubia, Pimephales promelas, and Chironomus dilutus. These organisms, which are used in standard testing or effluent monitoring, were exposed to aqueous caffeine solutions under static exposure for 48 hours and daily renewed static exposure for 7 days. Averaged responses of 48-hour acute end points indicated that C. dubia was more sensitive to caffeine exposures (LC50 = 60 mg/L) than either P. promelas (LC50 = 100 mg/L) or C. dilutus (LC50 = 1,230 mg/L). Exposure-response slopes confirmed these findings (3% mortality/mg/L for C. dubia; 0.5% mortality/mg/L for P. promelas; and 0.07% mortality/mg/L for C. dilutus). Comparative 7-day responses between C. dubia and P. promelas (LC50 = 46 and 55 mg/L, respectively) were more similar than the broad range of acute values. Sublethal effects measured for caffeine exposure included impaired C. dubia reproduction (IC50 = 44 mg/L) and inhibited P. promelas growth (IC50 = 71 mg/L). According to the results of this study, combined with earlier studies reporting environmental concentrations and product half-lives, caffeine should pose negligible risk for most aquatic vertebrate and invertebrate organisms.

The use of carvedilol in pediatric heart failure.

Chronic congestive heart failure has become a significant medical burden in the adult and a growing problem in the pediatric age group. While the etiologies of heart failure differ between children and adults, applied medical therapies are generally the same. In this regard, over the last decade, beta-adrenergic receptor blockade has become an important component in drug therapy of congestive heart failure in the adult population. A third-generation beta-blocker, carvedilol, has now been shown in adult trials to be efficacious in the treatment of heart failure and has been shown to be superior to other similarly used beta-blockers. Carvedilol use has been adapted into pediatric heart failure practice although data supporting its efficacy in infants and children are scarce. This review will describe the application of carvedilol in the adult, as it pertains to pediatric practice, review the existing pediatric literature and describe our institution's experience with carvedilol in heart failure therapy.

Mitogen-activated protein kinases and anoxia tolerance in turtles.

The response of two vertebrate mitogen-activated protein kinase (MAPK) family members, the extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), to anoxia exposure in vivo was examined in organs (liver, heart, kidney, brain, spleen) of the anoxia-tolerant adult turtle, Trachemys scripta elegans. ERKs activities rose during anoxia only in spleen (a 2.8-fold increase). JNK activity showed a significant increase only in liver (4-fold increase) after 5 hr of anoxic submergence but declined thereafter. Levels of the transcription factor c-Fos were strongly suppressed in liver, heart, and kidney of anoxia-exposed turtles, whereas levels increased 2-fold in anoxic brain. The effect of anoxia on c-Myc was organ-specific and variable with 2- and 1.5-fold increases in protein expression in kidney and brain, respectively, and a 60% decrease in anoxic spleen. These results for an anoxia-tolerant animal suggest the potential importance of the MAPKs and of the immediate-early genes (c-fos, c-myc) in mediating adaptive responses to oxygen deprivation.

Activation of mitogen-activated protein kinases during natural freezing and thawing in the wood frog.

The responses of mitogen-activated protein kinase (MAPK) family members, including ERK (extracellular signal-regulated kinase), JNK (c-Jun NH2-terminal kinase), and p38, in the metabolic responses to whole animal freezing (up to 24 h frozen at -2.5 degrees C) and thawing (up to 4 h at 5 degrees C after a 12 h freeze) were examined in four organs (liver, kidney, heart, brain) of the freeze-tolerant wood frog Rana sylvatica. Levels of the active phosphorylated form of p38 increased within 20 min as an early response to freezing in liver and kidney but rose later (after 12 h) in heart. Both JNK and p38 were activated during thawing in liver, kidney and heart with temporally-distinct patterns in each organ. The only MAPK response to freeze/thaw in frog brain was a transient elevation of p38 after 90 min thawing. ERK activity did not respond to freeze/thaw in any organ. The levels of c-Fos increased during freezing in kidney and brain whereas c-Jun was unaffected by freeze/thaw. Organ-specific responses by MAPKs, particularly p38, suggest that these may have roles in regulating metabolic or gene expression responses that may be adaptive in dealing with freezing stress or metabolic recovery during thawing.

Seasonal change and prolonged anoxia affect the kinetic properties of phosphofructokinase and pyruvate kinase in oysters.

The effects of seasonal change, November versus July, and prolonged anoxia (96 h under N2 gas) on the properties of phosphofructokinase and pyruvate kinase from five tissues (gill, mantle, hepatopancreas, phasic adductor, catch adductor) of the oyster, Crassostrea virginica were investigated. Both enzymes showed tissue-specific and season-specific changes in kinetic properties; for pyruvate kinase this correlated with seasonal differences in enzyme elution patterns on hydroxylapatite chromatography. Kinetic properties of both enzymes in winter were consistent with primarily catabolic roles in glycolysis with responsiveness to cellular energy demands, whereas in summer these enzymes may be more closely regulated with respect to the biosynthetic and gluconeogenic functions of the tissues. Anoxia-induced changes in phosphofructokinase properties were relatively minor but anoxia stimulated changes in pyruvate kinase properties and elution profiles on hydroxylapatite in all tissues except mantle, with much greater effects seen for the enzyme from winter versus summer animals. For example, anoxia-induced changes in pyruvate kinase from winter gill included a fourfold rise in the substrate affinity constant for phosphoenolpyruvate, a sevenfold increase in the concentration of fructose-1,6-bisphosphate needed to activate the enzyme by 50%, and a 50% decrease in the concentration of L-alanine that inhibits activity by 50%. Changes in pyruvate kinase kinetics and hydroxylapatite elution patterns during prolonged anoxia are consistent with covalent modification of pyruvate kinase but contrary to results for many other mollusc species, anoxia exposure appears to induce a dephosphorylation of the enzyme.

Effects of nitrobenzylthioinosine on neuronal injury, adenosine levels, and adenosine receptor activity in rat forebrain ischemia.

Adenosine levels increase in brain during cerebral ischemia, and adenosine has receptor-mediated neuroprotective effects. This study was performed to test the hypothesis that nitrobenzylthioinosine (NBMPR), a selective and potent inhibitor of one adenosine transporter subtype termed ENT1, or es, can protect against ischemic neuronal injury by enhancing adenosine levels and potentiating adenosine receptor-mediated effects, including attenuation of the cellular production and release of tumor necrosis factor-alpha (TNF-alpha). In rats, the phosphorylated prodrug form of NBMPR, NBMPR-phosphate, or saline was administered by intracerebroventricular injection 30 min before forebrain ischemia. Seven days following the ischemic episode, rats were killed, and neuronal damage in the CA1 region of the hippocampus was assessed. The number of pyramidal neurons was significantly (p < 0.001) greater in the NBMPR-P treatment group. A trend toward protection was still evident at 28 days postreperfusion. Adenosine increased significantly during ischemia to levels eight- to 85-fold above basal. NBMPR-P treatment did not cause statistically significant increases in ischemic adenosine levels; however, this treatment tended to increase adenosine levels in all brain regions at 7 min postreperfusion. Ischemia-induced expression of TNF-alpha was not altered by NBMPR-P treatment, and the nonselective adenosine receptor antagonist 8-(p-sulfophenyl) theophylline did not abolish the neuroprotective effects of NBMPR-P treatment. These data indicate that NBMPR can protect CA1 pyramidal neurons from ischemic death without statistically significant effects on adenosine levels or adenosine receptor-mediated inhibition of the proinflammatory cytokine TNF-alpha.

Root surface caries: a complication of the jejunoileal bypass.

BACKGROUND: A patient developed root surface caries and loss of teeth following the jejunoileal (JI) bypass. We attempted to confirm the association of root surface caries with the JI bypass and explore the mechanisms by which it occurs. METHODS: The number of root surface caries per year after, and an equal period of time before, a JI bypass was determined in 18 patients. These 18 patients and 5 normal controls gave stimulated saliva samples for measurement of chloride, bicarbonate and pH. 4 JI bypass patients and 4 normal controls gave timed stimulated saliva samples for measurements of volume. RESULTS: 7 of 18 JI bypass patients had >0.5 root surface caries per year after the operation but none before (p<.01). Salivary chloride was > 12 meq/l in 3 of the 18 JI bypass patients but in none of 5 controls (p<.05). The salivary pH and bicarbonate were 6.38+/-0.48 vs 6.92+/-0.21 and 2.81+/-2.1 meq/l vs 5.8+/-1.2 meq/l in the JI bypass group and the control group respectively (p<.05). The stimulated saliva was 2.3+/-1.2 vs 4.5+/-1.4 cc/min in the JI bypass group and control group, respectively (p<.02). CONCLUSIONS: Root surface caries are more frequent after JI bypass. This may be due to decreased saliva flow and a reduced salivary buffering capacity.

Discordant responses of mitogen-activated protein kinases to anoxia and freezing exposures in hatchling turtles.

The role of two vertebrate mitogen-activated protein kinases (MAPKs) in mediating responses to in vivo anoxia or freezing exposures was examined in four organs (liver, heart, kidney and brain) of hatchling red-eared turtles, Trachemys scripta elegans, which are naturally tolerant of these stresses. The extracellular signal-regulated kinases were not stress-activated except in brain of frozen turtles. The c-Jun NH2-terminal kinases (JNKs) were transiently activated by anoxia exposure in all four organs (after 1 h in brain or 5 h in other organs) but activity was suppressed during freezing except in brain which showed a transient activation of JNK after 1 h. Changes in the concentrations of the transcription factors, c-Fos and c-Myc, were also stress- and organ-specific. The patterns of MAPK activation in a stress-tolerant animal suggest the relative importance of these kinase pathways in cellular adaptation to oxygen deprivation or freezing and identify novel natural activators of MAPKs in vivo. The specificity of the signaling pathways is also emphasized here as the general whole-body stresses, anoxia and freezing, activated individual MAPKs in a tissue-, time-, and stress-dependent manner.

Clinical subtypes of Crohn's disease according to surgical outcome.

Patients with Crohn's disease are typically classified into perforator or nonperforator groups. The perforator group includes those who present with acute perforation, fistulas, or abscess formation. The nonperforator group presents with stricture, obstruction, or unresponsiveness to medical therapy. Our purpose was to investigate whether perianal disease constitutes a separate predictor of surgical outcome. The form of presentation was classified as perforator, nonperforator, or perianal disease in 91 patients undergoing 232 operations for Crohn's disease. Those with perforating complications presented with the highest Crohn's Disease Activity Index, followed by those with nonperforating complications, and then the perianal disease group. However, the perianal disease group appeared to have the most rapid rate of recurrence and subsequent surgery, followed next by the perforator, and then the nonperforator group. Recurrence rate and subsequent operation intervals for the perforator group appeared to lengthen when those patients were treated with steroids and/or immunosuppressants, as compared to nonsteroidal and/or antimicrobial agents. Recurrence rate and subsequent operation intervals appeared to lengthen for the nonperforator and perianal disease groups when they were treated with nonsteroidal and/or antimicrobial therapy, as compared to steroids and/or immunosuppressants. Our data indicate that perianal disease, as a form of presentation of Crohn's disease, has independent predictive value, although this is not accurately reflected by the Crohn's Disease Activity Index.

Topical insulin in wound healing: a randomised, double-blind, placebo-controlled trial.

Two studies were carried out to assess the relative roles of insulin and zinc in the acceleration of wound healing. In the first study, six diabetic and five non-diabetic human volunteers had two uniform cuts created, one on each forearm. One forearm wound was treated with topical regular insulin (Iletin-II) and the other with normal saline four times a day until healed. Treatment was double-blind and forearms were assigned randomly. The wounds treated with insulin healed 2.4 +/- 0.8 days faster than the wounds treated with saline (P < 0.001 by paired t-test). Zinc is used to crystallise insulin. When wounds are treated with insulin, they are therefore also being treated with zinc. If insulin accelerates wound healing, it is not clear if the increase in the rate of healing would be due to insulin (a known growth factor), the zinc it contains, or a combination of the two. The second study used a randomised, double-blind, placebo-controlled design to compare the efficacy of insulin with that of a solution containing the same amount of zinc in accelerating the healing of standardised wounds in rats and humans. Although these pilot investigations did not have the power to define the relative roles of insulin and zinc with accuracy, the results suggest that zinc does play a role in the wound healing process. It is concluded that topical insulin accelerates wound healing in humans. More importantly, however, this study describes a method of creating uniform wounds in humans acceptable to an institutional review board, thus solving one of the major impediments to the scientific evaluation of human wound healing.

Temporal expression of TGF-beta1, EGF, and PDGF-BB in a model of colonic wound healing.

BACKGROUND: Dehiscence of colonic anastomoses is a multifactorial phenomenon. One mechanism by which this can occur is a deficiency of colonic submucosal collagen. Peptide growth factors (PGFs) have been shown to play a role in the synthesis, deposition, and maturation of collagen. Specifically, in tissues other than the colon, the transforming growth factor-beta (TGF-beta1) gene has been shown to be temporally associated with expression of the procollagen gene. This study examines the temporal expression of the TGF-beta1, epidermal growth factor (EGF), and platelet-derived growth factor B (PDGF-BB) genes and their temporal relationship to the expression of the procollagen type 1 (PROC I) gene. MATERIALS AND METHODS: Forty-eight Sprague-Dawley rats underwent transection of the descending colon with primary anastomosis. Perianastomotic colonic tissue was harvested on Day 0 and postoperative days 3, 5, 6, 7, and 14. Colonic tissue was analyzed using semiquantitative reverse transcriptase-polymerase chain reaction and primers specific for the TGF-beta1, EGF, and PDGF-B growth factors. Relative expression ratios of PGFs and PROC I genes were calculated versus a constitutive gene. RESULTS: The data show that although all three of the PGFs genes were expressed in healing postoperative colonic tissue, only TGF-beta1 showed a significant increase in its level of expression versus a constitutive gene from a mean ratio of 0.4 +/- 0. 08 on Day 0 to a mean ratio of 1.9 +/- 0.27 on Day 7 (P < 0.0001 by ANOVA). The PROC I gene also showed a significant increase in expression (P < 0.001 by ANOVA) in the postoperative period which temporally correlated with the increase in the expression of the TGF-beta1 gene (r = 0.89, P < 0.05). CONCLUSIONS: The temporal correlation between an increase in the gene expression of TGF-beta1 and PROC I is initial evidence that that TGF-beta1 plays a significant role in collagen metabolism in a healing colonic anastomosis.

Expression of ryanodine receptors in human embryonic kidney (HEK293) cells.

It has been shown previously that mobilization of caffeine-sensitive intracellular calcium (Ca2+i) stores increased the release of amyloid beta-peptide (Abeta) from transfected human embryonic kidney cells (HEK293) [Querfurth, Jiang, Geiger and Selkoe (1997) J. Neurochem. 69, 1580-1591]. The present study was to test the hypothesis that the caffeine/Abeta responses were due to interactions with specific subtypes of ryanodine receptors (RyR) using [3H]ryanodine receptor binding, epifluorescence imaging of Ca2+i, immunocytofluorescence, immunoprecipitation and PCR techniques. [3H]Ryanodine bound to a single class of high-affinity caffeine-sensitive sites (Kd=9.9+/-1.6 nM, Bmax=25+/-4 fmol/mg of protein). RyRs were immuno-decorated in a punctate reticulo-linear pattern. Results from SDS/PAGE and reverse transcriptase-PCR demonstrated endogenous expression of type 1 (skeletal) and type 2 (cardiac) RyRs. HEK293 cell RyRs were functionally active, because (i) [Ca2+]i increased 2.8-fold over baseline following applications of 5-15 mM caffeine, (ii) repetitive spiked increases in [Ca2+]i were observed, and (iii) evidence for a use-dependent block was obtained. Some of these findings were extended to include HeLa and human fibroblast cell lines, suggesting a broader applicability to cells of epithelioid lineage. Implications for the processing of the beta-amyloid precursor protein in Alzheimer's disease and for calcium channel research using transfected HEK293 cells are discussed.

Differential regulation of the mitochondrial ADP/ATP translocase gene in wood frogs under freezing stress.

The gene Aat coding for ADP/ATP translocase (AAT) was cloned from liver of the freeze-tolerant wood frog, Rana sylvatica, via differential screening of a cDNA library from liver of frozen frogs and using probes from control versus frozen frogs. Sequence analysis showed that clone pBfFR07 bearing the AAT cDNA contained a 1318-bp insert with one full-length open reading frame. The deduced amino acid sequence included 317 residues, with 81-86% identities to mammalian AAT. A 1750-nt transcript from the Aat gene was detected using pBfFR07 probe and a putative frog AAT of over 30 kDa was visualized by immunoblotting using a polyclonal antibody raised against chicken AAT. Analysis of liver samples from a time course of freezing showed a maximal 4.5-fold increase in mRNA after 8 h with AAT protein peaking in 24-h frozen frogs. Freezing also induced Aat expression in bladder and lung. In liver, mRNA expression also responded positively to anoxia stress but not to experimental dehydration of the animals. These results suggest that AAT induction during freezing may be stimulated by the ischemia that develops when plasma freezes; changes in AAT may contribute to stabilizing energetics in mitochondrial versus cytosolic pools over freeze/thaw cycles.

Ethanol added to resuscitation improves survival in an experimental model of hemorrhagic shock.

Ethyl alcohol induces systemic vasodilation, decreases platelet aggregation, and inhibits neutrophil activation in vivo. Alcohol may thus be of potential benefit in resuscitation from shock by improving microcirculation. The purpose of this study was to test the effects of ethanol (ETOH) in resuscitation from hemorrhagic shock. Blood pressure, tissue pO2, white blood cell (WBC) and platelet adhesiveness, and survival were measured for 60 male Sprague-Dawley rats in a blinded and randomized study. Anesthetized animals were phlebotomized to 60 per cent of their blood volume, and maintained in shock for 45 minutes. Resuscitation was by continuous infusion of Lactated Ringers (LR) at 2 x shed blood volume over 1 hour. The experimental group received LR and ETOH (1.25 mL/kg). Control rats received LR and placebo. Mean arterial pressure was not significantly different, nor was WBC adhesiveness index different. However, postresuscitation platelet adhesiveness index was significantly higher in control rats than in ETOH rats. Postresuscitation total platelet arterial-venous difference was also greater in controls than in ETOH rats. Average tissue pO2 for ETOH rats (47 +/- 8.2 mm Hg) was significantly higher than controls (39.0 +/- 9.8 mm Hg) during resuscitation (P = 0.0001). Survival for ETOH rats (70%) was significantly higher than controls (20%) (P = 0.003). Our data suggests that ETOH added to resuscitation from shock improves survival by inhibiting platelet activation and increasing tissue perfusion.

Treatment of depression with cyproheptadine.

We evaluated the antidepressant activity of cyproheptadine HCl in six patients diagnosed with major depression. This was a double-blind, placebo-controlled, crossover trial with treatment order balanced and randomly assigned. The patients received 4 weeks of treatment with cyproheptadine HCl 4 mg 4 times/day or placebo, followed by 4 weeks of cryproheptadine HCl 8 mg 4 times/day or placebo, followed by a crossover to cyproheptadine HCl or placebo. Each subject had a Hamilton Depression Rating Scale assessment and a 1-mg dexamethasone suppression test completed immediately before treatment and at 4-week intervals throughout the study. Two patients had nonsuppressible dexamethasone suppression tests and could not tolerate cyproheptadine due to anxiety and irritability. Four patients had suppressible dexamethasone suppression tests and had lower scores on the Hamilton Depression Rating Scale during treatment with cyproheptadine (p < 0.01, Student's t test for paired observations). Cyproheptadine HCl may be useful in treating a subset of patients with major depression who have a suppressible dexamethasone suppression test.

Developmental biochemistry of cottonseed embryogenesis and germination: changing messenger ribonucleic acid populations as shown by in vitro and in vivo protein synthesis.

Changes in messenger ribonucleic acid (mRNA) populations during embryogenesis of cottonseed have been followed by cataloging (a) extant proteins, (b) proteins synthesized in vivo, and (c) proteins synthesized in vitro from extracted RNA, all at specific stages of embryogenesis. Evidence is presented for the existence of five mRNA subsets, all apparently under different regulatory regimes, that produce the abundant proteins of embryogenesis. One of these functions principally during the cell division phase of embryogenesis and encodes among its products the seed storage proteins whose mRNA is superabundant during this period. This subset has disappeared from the abundant group by the mature seed stage. Two other subsets appear in late embryogenesis, one of which may result from the removal of the embryo from the maternal environment, since it is inducible by excision of the young embryo from the seed. The other appears to be induced by the plant growth regulator abscisic acid, whose endogenous concentration increases at this stage. It can be induced by incubating excised young embryos in abscisic acid. The last two subsets exist throughout embryogenesis, but only one of them appears to function in germination.