The PARENT model: a pathway approach for understanding parents' role after early childhood mild traumatic brain injury.

OBJECTIVE: Mild traumatic brain injury (mTBI or "concussion") is a highly prevalent health condition in children, and those under the age of 6 years have the highest rate of Emergency Department presentation for suspected head injuries. The outcome of mTBI is determined by a range of child (injury, biological, functional) and environmental (socio-economic status, parent, family) factors. The aim of this work is to present evidence supporting the central role of parental and familial factors in pediatric mTBI recovery, and to illustrate ways in which parental factors can especially influence the outcome of early mTBI, defined as injuries sustained by infants, toddlers and preschoolers. METHOD: The manuscript first presents a topical review of empirical studies providing evidence that family functioning and parental factors such as their mental or affective state, parenting style, and the quality of their interactions with their child, are affected by and determine the course of recovery after pediatric mTBI. Then, a pathway approach and conceptual model are proposed to illustrate probable scenarios associated with how parents detect and react to their child's post-concussive symptoms and changes in behavior after early mTBI. CONCLUSION: The "Perception, Attribution, and Response after Early Non-inflicted Traumatic Brain Injury" (PARENT) model suggests that parental roles and factors are especially influential in the context of early brain injuries, and that parents' ability to perceive, attribute and respond to the symptoms experienced by their child in a well-adjusted and adaptive manner critically sets the direction and rhythm of the early mTBI recovery process.

Assessing social cognition: age-related changes in moral reasoning in childhood and adolescence.

OBJECTIVE: There is increasing recognition that socio-cognitive skills, such as moral reasoning (MR), are affected in a wide range of developmental and neuropsychological conditions. However, the lack of appropriate measures available to neuropsychologists poses a challenge for the direct assessment of these skills. This study sought to explore age-related changes in MR using an innovative visual tool and examine the developmental sensitivity of the task. METHOD: To address some of the methodological limitations of traditional measures of MR, a novel, visual task, the Socio-Moral Reasoning Aptitude Level (So-Moral), was used to evaluate MR in 216 healthy participants aged 6-20 years. RESULTS: The findings show a linear increase in MR from childhood to late adolescence with significant group differences between childhood (6-8 years) and preadolescence (9-11 years), and between early adolescence (12-14 years) and middle adolescence (15-17 years). CONCLUSIONS: Interpreted in light of current brain development research, the results highlight age-related changes in MR that offer insight into typical MR development and opportunities for comparisons with clinical populations. The findings also provide evidence of the potential of the So-Moral as a developmentally appropriate measure of MR throughout childhood and adolescence.

Tako-tsubo cardiomyopathy.

A 48-year-old woman presented to her local hospital with chest pain. Her electrocardiogram showed incomplete right bundle branch block, diffuse ST segment elevation and QTc prolongation. Shortly after admission, she became hypotensive and was referred for a coronary angiogram. Her coronary arteries were normal, but left ventriculography showed morphological changes typical of apical ballooning, as found in tako-tsubo cardiomyopathy. An echocardiogram confirmed complete akinesis of the left ventricular apex, with hyperkinesis of basal segments and an ejection fraction of 35% to 40%. Dynamic left ventricular outflow tract obstruction was also noted. After temporary support with intra-aortic balloon counterpulsation, fluids and noradrenaline, she recovered promptly. The present paper reviews the characteristic features of tako-tsubo cardiomyopathy.

Acute pericarditis with transient constriction.

Transient constrictive pericarditis is a rare entity. It is characterized by clinical and echocardiographic features similar to constrictive pericarditis, but is distinguished by its transient nature. This feature is important to recognize for avoiding unnecessary pericardectomy. The case of a patient who presented with acute myopericarditis and typical echocardiographic features of constriction is described. Within weeks, all signs of constriction disappeared spontaneously.

Oral anticoagulant therapy for heart disease: results in actual cardiology practice.

OBJECTIVE: To determine whether the success and complication rates of oral anticoagulation obtained in large, well controlled trials, upon which recommendations are based, are comparable with routine cardiology practice. DESIGN: An observational, prospective cohort study collected data on all patients followed at an anticoagulant clinic over one calendar year. PATIENTS: One thousand and seventy-eight patients anticoagulated for cardiovascular indications, mainly atrial fibrillation, prosthetic valves and ventricular dysfunction, were followed for 804 patient-years of treatment. No patient was lost to follow-up. INTERVENTIONS: Telephone conversations and regular verification of medical files were used to record and classify all bleeding and thromboembolic events according to severity. International normalized ratios (INR) were compared with target ranges. RESULTS: One hundred and twelve bleeding events, ie, 13.9/100 patient-years (% p-y), were recorded, of which 61 required medical attention. Major hemorrhages, defined as those requiring treatment or hospital observation for more than 24 h, occurred in 15 instances (1.9% p-y). Among these, 9 (1.1% p-y) were classified as life threatening, with four being fatal (0,5% p-y). Twenty-two thromboembolic events (2.7% p-y) occurred, of which 10 were major (1.2% p-y), leaving three patients (0.4% p-y) with long term sequelae and causing two deaths (0.25% p-y). INRs were within target range 62.3% of the time, with 2.2% of values recorded above 5 and 0.3% above 10. CONCLUSION: The low failure and complication rates obtained in large, controlled trials are similar to those observed in actual cardiology practice.

Pharmacokinetics and hematological effects of the PEGylated thrombopoietin peptide mimetic GW395058 in rats and monkeys after intravenous or subcutaneous administration.

GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 microg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 microg/kg) serum t1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 microg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (

Characterization of a 3-dehydroquinase gene from Actinobacillus pleuropneumoniae with homology to the eukaryotic genes qa-2 and QUTE.

A gene was cloned from Actinobacillus pleuropneumoniae strain 4074 by complementation of an aroD strain of Escherichia coli. The E. coli gene aroD codes for a 3-dehydroquinase enzyme of type I, active in the aromatic biosynthesis pathway. The A. pleuropneumoniae gene, termed aroQ, displays no base or amino acid sequence homology to aroD of E. coli. It is instead homologous to the QUTE and qa-2 genes, respectively of Aspergillus nidulans and Neurospora crassa. These genes code for 3-dehydroquinase enzymes of type II, involved in the catabolism of quinic acid. The 1.8 kb fragment, which includes aroQ, carries four overlapping or adjacent open reading frames: a dapD gene; aroQ; one without homology to sequences in GenBank; and one with homology to the C-terminal 40% of chIN of E. coli.

Alpha-hemolysin contributes to the pathogenicity of piliated digalactoside-binding Escherichia coli in the kidney: efficacy of an alpha-hemolysin vaccine in preventing renal injury in the BALB/c mouse model of pyelonephritis.

Digalactoside-binding (Gal-Gal) pili and alpha-hemolysin of Escherichia coli have been implicated as important virulence determinants in the pathogenesis of human ascending, nonobstructive pyelonephritis. The pathogenic significance of these determinants was evaluated in vitro and in the BALB/c mouse pyelonephritis model by employing wild-type, avirulent laboratory, and genetically defined cosmids, transformants, and recombinant strains. In vitro data suggest that the cytolytic activity of hemolysin is significantly (P less than 0.05) enhanced among digalactoside-binding strains which agglutinate erythrocytes. The basis of increased hemolysis is related presumably to more efficient delivery of the toxin to target lipid substrate in the host plasma membrane. Intravesicular administration of bacteria that express both digalactoside binding and hemolysin generally resulted in greater mortality and renal parenchymal injury in mice than strains that expressed none or only one of these determinants. Analyses convincingly demonstrate that digalactoside-binding pili are correlated with upper urinary tract colonization and that hemolysin is correlated with septicemia and renal parenchymal damage. These determinants collectively constitute the minimal virulence factors to produce disease in this model. Their efficacy as vaccines for the prevention of pyelonephritis was also assessed. A purified Gal-Gal pilus vaccine prevented (P less than 0.05) subsequent colonization by a challenge wild-type strain that exhibited homologous pili. The hemolysin vaccine did not abrogate subsequent bacterial renal colonization on challenge, but it did protect (P less than 0.05) mice which survived challenge from subsequent renal injury compared with those in the saline control group. The combination of these determinants was also protective. The combination of Gal-Gal pili and hemolysin in a vaccine preparation represents a potentially worthwhile strategy for human immunoprophylaxis against pyelonephritis by interdicting several steps in the pathogenesis of a bacterial mucosal infection.

Cardiobacterium hominis endocarditis.

A 53-year-old man presented with nonspecific symptoms, evidence of aortic valve regurgitation and hepatosplenomegaly. Blood cultures grew Cardiobacterium hominis after 14 days of incubation. Endocarditis is caused by fastidious organisms such as C hominis in less than 5% of cases. To date approximately 40 cases of endocarditis due to this pleomorphic facultative anaerobic Gram-negative bacillus have been reported. C hominis is part of the normal human mouth flora.

Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with N-acetylcysteine.

To better understand the mechanism of nitrate tolerance in patients with congestive heart failure, 13 patients received a 24 h infusion of nitroglycerin (1.5 micrograms/kg body weight per min) with or without N-acetylcysteine (225 mg/kg per 24 h). The infusions were separated by a 24 h nitrate-free interval. By the end of the nitroglycerin infusion, mean arterial pressure had returned to baseline values and there was a significant increase in ventricular filling pressures and systemic vascular resistance compared with values after 1 h of treatment. The simultaneous infusion of N-acetylcysteine had no effect on these changes. Although a strict fluid restriction of 1.5 liters/day was maintained for 1 week before and throughout the study, after 24 h of nitroglycerin infusion there was a significant and similar degree of hemodilution whether nitroglycerin was infused alone (9.1 +/- 4.3%) or with N-acetylcysteine (8.7 +/- 4.1%). This hemodilution corresponded to an increase in intravascular volume of 745 +/- 382 ml, most of which occurred during the 1st h. Plasma renin activity increased and plasma atrial natriuretic peptide decreased during the infusion. The results of this study suggest that nitrate tolerance is multifactorial. In addition to the previously described pharmacologic tolerance to the effect of nitroglycerin on vascular smooth muscle, a capillary fluid shift from the extravascular to intravascular space appears to be involved, especially during the 1st h of the infusion. A third mechanism, reflex neurohumoral activation, also seems to contribute to the genesis of nitroglycerin tolerance.

Sustained beneficial effect of a seventy-two hour intravenous infusion of nitroglycerin in patients with severe chronic congestive heart failure.

To determine whether a 72-hour infusion of nitroglycerin produces hemodynamic improvement in patients with severe congestive heart failure and to assess the contributing role of various possible causes of hemodynamic tolerance to nitroglycerin, 19 patients received an infusion of nitroglycerin 1.5 micrograms/kg/min for 72 hours. In a subgroup of patients (n = 10), there was an increase in stroke work index and a decrease in ventricular filling pressures throughout the infusion and even after it was discontinued. Tolerance to the hemodynamic effects of nitroglycerin was partially reversed 8 hours after the infusion was stopped. Neurohumoral changes occurred but appeared to play only a minor role in the development of nitroglycerin tolerance. However, hematocrit fell 9 +/- 5%, which suggests that an increased intravascular volume contributed to tolerance. In summary: (1) a 72-hour infusion of nitroglycerin improves ventricular function in some patients with severe heart failure; (2) volume shifts from the extravascular to the intravascular compartments may, at least in part, be responsible for nitroglycerin tolerance; and (3) reflex neurohumoral activation may also play a small role in nitrate tolerance.

Captopril does not prevent nitroglycerin tolerance in heart failure.

Tolerance to the continuous intravenous infusion of nitroglycerin is thought to be largely the result of a decrease in vascular responsiveness, possibly due to intra-smooth muscle sulfhydryl group depletion. Another mechanism proposed to contribute to tolerance is nitroglycerin-induced reflex neurohumoral activation resulting in vasoconstriction and sodium and water retention. It has been proposed that the sulfhydryl group-containing angiotensin converting enzyme (ACE) inhibitor captopril may be useful in preventing tolerance to nitroglycerin by repleting sulfhydryl groups and by decreasing reflex neurohumoral activation. However, by decreasing renal perfusion pressure, the combination of captopril and nitrates could also lead to renal dysfunction. The objectives of this study were to determine whether captopril prevented or significantly reduced hemodynamic tolerance to a 72 h infusion of nitroglycerin, and to determine whether the combination of nitroglycerin and captopril caused deterioration of renal function. Nineteen patients with congestive heart failure received nitroglycerin (1.5 micrograms/kg/min) alone (n = 11) or in combination with oral captopril (63 +/- 8 mg/day) (n = 8). In both groups, partial hemodynamic tolerance developed within the first 24 h of nitroglycerin infusion. Nitroglycerin therapy, with or without captopril, did not affect plasma adrenaline, noradrenaline, aldosterone or arginine vasopressin. However, plasma renin activity increased and atrial natriuretic peptide decreased in both groups, these changes being significant after 1 h of infusion but gradually returning towards baseline, in both groups, over the next 71 h. The nitroglycerin infusion did not alter body weight, urine output, creatinine clearance or fractional sodium excretion in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral characterization of intracranial self-stimulation from mesolimbic, mesocortical, nigrostriatal, hypothalamic and extra-hypothalamic sites in the non-inbred CD-1 mouse strain.

A behavioral analysis of intracranial self-stimulation (ICSS) was provided for mesolimbic/mesocortical, nigrostriatal, hypothalamic and extrahypothalamic sites in the CD-1 mouse. Robust responding and rapid acquisition of mesocortical ICSS appeared dorsally along notably fluorescent sites in rostral and caudal planes. ICSS was diminished demonstrably in medial and ventral positions in posterior planes. Mesolimbic ICSS from the medial and ventral nucleus accumbens (Nas), was accompanied by significant elevations in locomotor activity, corresponding to regions of dopamine (DA) and cholecystokinin co-localization. Stimulation-induced seizures appeared from both the Nas as well as the mesocortex. ICSS from the ventral tegmental field (VTA) was evident along its medial, lateral and dorsal borders with longer pulse durations more likely to elicit responding. Seizure activity was absent from the VTA. Striatal ICSS was conspicuously poor in dorsal and medial locations; regions presumably devoid of tegmental innervation. ICSS emerged from both the ventrocaudal and anteromedial striatum; regions linked to innervation by the dorsolateral and ventromedial VTA. The red nucleus, a previously neglected self-stimulation site supported marked responding for ICSS. Regions supporting rubral ICSS were correlated with thalamic innervation sites; notably the ventrolateral thalamic nucleus and the parafascicular nucleus, regions found to support ICSS. The substantia nigra supported high rates of responding for ICSS when electrode placement was restricted to the dorsomedial portion of the pars compacta. Electrode deviations lateral and dorsal to the substantia nigra pars medialis induced a progressive decline in responding. Hypothalamic sites were found to support significant responding for ICSS, although such performance was frequently associated with seizure induction. Taken together these data (1) provide the first behavioral analysis of ICSS in mice responding from previously unexamined DA sites in the mesolimbic (e.g. VTA, Nas) and nigrostriatal systems (e.g. caudate, red nucleus) (2) suggest an anatomical reconsideration of the assumptions underlying the elicitation of ICSS from the frontal cortex (3) suggest that the neural circuitry underlying thalamic, caudate, rubral and frontal cortical ICSS are interrelated and (4) suggest that the Nas and the frontal cortex, like the hypothalamus, in the mouse appear to be particularly sensitive to stimulation-induced seizures.

Development of a shuttle vector and a conjugative transfer system for Actinobacillus pleuropneumoniae.

An original genetic system for Actinobacillus pleuropneumoniae has been developed. A shuttle cloning vector, pYG53, was constructed from the wild-type plasmid pYG10. It permits, in conjunction with electroporation, the introduction of cloned genes into this species. A conjugal transfer system between Escherichia coli and A. pleuropneumoniae involving pYG54, a mobilizable derivative of pYG53, is also described. Conjugation efficiencies of 8.3 x 10(-3) exconjugants per donor can be obtained.

Vasovagal syncope: management with atrioventricular sequential pacing and beta-blockade.

A case of vasovagal syncope in an otherwise healthy 74-year-old woman is described. Attempts to prevent symptoms with ventricular and atrioventricular sequential temporary pacing (documented by continuous monitoring of heart rate and intra-arterial recording of blood pressure during spontaneous episodes) proved inadequate. However, the addition of a beta-blocker to permanent DDD pacing was clinically successful in markedly diminishing symptoms. The mechanisms of action of this treatment modality is discussed.

Transformation of Actinobacillus pleuropneumoniae and analysis of R factors by electroporation.

An efficient method for DNA transfer is essential for the genetic manipulation of any organism. Such a capacity will be required for the genetic analysis of Actinobacillus pleuropneumoniae as a swine pathogen, as well as for its manipulation for vaccination purposes. For this reason, the use of electroporation as a means of plasmid DNA introduction into this species was examined. The multiple antibiotic-resistant strain 80-8141 of Actinobacillus pleuropneumoniae harbors 3 plasmids: pYG10, pYG15, and pYG12 of 5.0, 2.7, and 2.5 kb, respectively. Electroporation of A pleuropneumoniae strain 4074 with a plasmid extract of strain 80-8141 showed that pYG10 encodes chloramphenicol resistance and that pYG12 encodes ampicillin resistance. Electrical pulse conditions for efficient electroporation of strain 4074 were examined by use of pYG10 DNA isolated from a 4074 transformant. Efficiency, expressed as transformants per microgram of plasmid DNA, increased directly with pulse amplitude. However, high efficiencies were only observed in a narrow window of pulse duration (tau = 12 to 22 ms at 6.25 kV/cm). Longer pulse durations resulted in cell death. Electroporation efficiencies increased with cell density. Yield of transformants increased directly with DNA concentration. Results indicate that electroporation can be used to efficiently transform A pleuropneumoniae and that pYG10 and pYG12 are suitable plasmid vectors for use in the genetic manipulation of this organism.

Identification of a hemolysin from Actinobacillus pleuropneumoniae and characterization of its channel properties in planar phospholipid bilayers.

A proteinaceous hemolysin secreted by strain 4074 of serotype 1 of Actinobacillus pleuropneumoniae was purified by diafiltration and ion exchange chromatographic techniques. The hemolytic activity is associated with a 107-kDa band as assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and confirmed by Western blotting and immunoprecipitation. This hemolysin produces pores in membranes as demonstrated by osmotic protection studies using red blood cells and carbohydrate compounds of various molecular weights. These assays suggest a pore diameter in the order of 2 nm. Phospholipid bilayers composed of 1:1 w/w phosphotidylserine:phosphotidylethanolamine exposed to this toxin display discrete current flow events typical of transmembrane channels and consistent with the interpretation that this toxin acts by forming pores in phospholipid membranes. The linear relationship of current amplitude to holding potential when examined over the -60 to +60 mV range indicates that this pore has a constant mean single channel conductance level of 350-400 pS.

Strain-specific effects of inescapable shock on intracranial self-stimulation from the nucleus accumbens.

Responding for electrical stimulation from the nucleus accumbens was assessed in 3 inbred strains of mice (DBA/2J, C57BL/6J and BALB/cByJ) following exposure to uncontrollable footshock. While the operant response was most readily acquired in the DBA/2J strain, exposure to inescapable shock in this strain induced a marked deterioration of self-stimulation responding, which tended to dissipate over a 168-h period. In contrast to these mice, the stressor did not affect self-stimulation responding in the C57BL/6J strain, and produced a transient enhancement of responding in BALB/cByJ mice. It appears that although uncontrollable aversive events may engender an anhedonic effect, such an outcome is strain-dependent. These data suggest the importance of considering individual and genetic differences in the development of animal models of depression.