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A Pediatric Heart Network trial compared outcomes in infants with single right ventricle anomalies undergoing Norwood procedures randomized to modified Blalock-Taussig shunt (MBTS) or right ventricle–to–pulmonary artery shunt (RVPAS). Doppler patterns in the neo-aorta and RVPAS may characterize physiologic changes after staged palliations that affect outcomes and right ventricular (RV) function.

ABSTRACTBackground and Methods:The authors designed and delivered an innovative Web course on cognitive behavioral therapy (CBT), a specific empirically based treatment, to a diverse group of addiction counselors and supervisors in 54 addiction units across the country, and conducted a randomized controlled trial of its effectiveness with 127 counselors. The primary focus of the trial was to assess “adequate adherence to CBT practice” after training as judged by raters blinded to training condition who listened to audiotapes of actual client sessions. Counselors who passed were judged to satisfy 2 criteria: (a) low pass or greater on at least 1 of 3 “CBT-generic skills” assessing session structure; and (b) low pass or greater on at least 1 of 3 “CBT-specific skills” related to use of functional analysis, cognitive skills practice, or behavioral skills practice. Results:Although the counselors’ use of CBT skills in sessions increased after Web course training, it was not statistically significant and not larger than the gain of control-group counselors trained with a written CBT manual.

Background and Methods:The authors designed and delivered an innovative Web course on cognitive behavioral therapy (CBT), a specific empirically based treatment, to a diverse group of addiction counselors and supervisors in 54 addiction units across the country, and conducted a randomized controlled trial of its effectiveness with 127 counselors. The primary focus of the trial was to assess “adequate adherence to CBT practice” after training as judged by raters blinded to training condition who listened to audiotapes of actual client sessions. Counselors who passed were judged to satisfy 2 criteria: (a) low pass or greater on at least 1 of 3 “CBT-generic skills” assessing session structure; and (b) low pass or greater on at least 1 of 3 “CBT-specific skills” related to use of functional analysis, cognitive skills practice, or behavioral skills practice. Results:Although the counselors’ use of CBT skills in sessions increased after Web course training, it was not statistically significant and not larger than the gain of control-group counselors trained with a written CBT manual.

AimTo assess the feasibility of collecting electronic pain data from thalassaemia patients, based on its acceptability and convenience to the participants and study team.MethodsParticipants in the Thalassemia Clinical Research Network Assessment of Pain Survey Study completed the Brief Pain Inventory (BPI) quarterly by paper or phone interview. Participants in a substudy completed the BPI Short Form daily over three non-consecutive transfusion cycles through an automated telephone system.ResultsThe consent rate for the main study was 93%, with 93% retention. The substudy had 75% retention, with more than 75% of scheduled calls completed. Regular monitoring of enrolment, missed calls, data quality, and the performance of the subcontractor for the automated system was crucial to fulfillment of the study goals.ConclusionsUse of electronic data collection for patient-reported outcomes was convenient for both patients and study personnel but required human interactions beyond the automated system to maximise data quantity and quality.

This article examines the diagnosis and management of type-2 diabetes when exactly the same “patient” is encountered by 192 randomly selected primary care doctors in 3 different health care systems—the United States, United Kingdom, and Germany.

We investigated nitric oxide (NO) as a possible cause of the cardiac dysfunction associated with high, lethal doses of tumor necrosis factor-α (TNF-α) in dogs. Eighty-seven awake, 2-year-old (10-12 kg), purpose-bred beagles were randomized to receive an infusion of saline or Nω-monomethyl-L-arginine (L-NMMA), a nonselective NO synthase (NOS) inhibitor, as a 40 mg kg−1bolus followed by a 40 mg kg−1h−1infusion for 3 to 6 h 3 h before (prophylactic) or 3 h after (therapeutic) challenge with TNF-α (60 μg kg−1) or vehicle. Serial radionuclide-heart scans and thermodilution pulmonary artery catheter hemodynamic measurements were performed. The effects of prophylactic L-NMMA on TNF-α-induced cardiac dysfunction as measured by decreases in mean left ventricular (LV) ejection fraction and downward and rightward shifts of LV function plots (peak systolic pressure versus end systolic volume index and LV stroke work index versus end diastolic volume index) were significantly different comparing early (3-6 h) and delayed (24 h) time points (P= 0.02). Prophylactic L-NMMA therapy did not appear to fully prevent early (3-6 h) TNF-α−induced cardiac dysfunction, but at 24 h, complete protection was seen. Therapeutic L-NMMA did not appear to fully protect the heart from TNF-α-induced early or delayed cardiac dysfunction (P= NS). Similarly, L-NMMA given prophylactically, but not therapeutically, blocked TNF-α-induced increases in exhaled NO flow rates and plasma nitrite and nitrate concentrations (both P= 0.02). These data suggest that TNF-α initiates two phases of cardiac injury: an early (3-6 h) phase that may be partially NO independent and a delayed (24 h) phase that is NO dependent. The delayed, more persistent dysfunction can be completely blocked by high doses of a nonselective NOS inhibitor administered before TNF-α.

Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed inEscherichia coliand incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-α (TNFα), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P< .01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-κB and Sp1. These effects are partially mediated by TNFα autocrine stimulation, as anti-TNFα antibodies significantly decrease chemokine and adhesion molecule responses (P≤ .002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.

Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-α (TNFα), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P < .01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-κB and Sp1. These effects are partially mediated by TNFα autocrine stimulation, as anti-TNFα antibodies significantly decrease chemokine and adhesion molecule responses (P ≤ .002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.

We investigated, in a well-established canine model of human sepsis, the effects of two different techniques of sympathetic blockade during bacterial peritonitis on pain relief, hemodynamics, and survival rate. Twenty-two purpose-bred beagles (12–28 months old, weighing 10–12 kg) were studied. Fourteen animals received an epidural infusion of bupivicaine and morphine, and the other eight received either a celiac plexus block (n 4) or a sham block (n 4). Eighteen of the 22 animals received an intraperitoneal challenge of Escherichia coli(1–10 × 109CFU kg−1body weight). At comparable doses of intraperitoneal-implanted E. coli(2.5–5 × 109CFU kg−1body weight), the addition of sympathetic blockade produced a synergistic decrease in survival times (P0.002) and mean left ventricular ejection fraction (P0.008), and increase in creatinine levels (P0.02). There was also a significant increase in tumor necrosis factor (TNF) levels (P0.004) and decrease in blood endotoxin clearance (P0.006) associated with sympathetic blockade during sepsis. The celiac plexus-blocked animals had no improvement in pain scores, and subjectively looked clinically worse than animals with sepsis without a celiac plexus block. In contrast, the epidural block was effective in blocking the pain and discomfort associated with low lethality doses of intraperitoneal bacteria reflected by no increase in pain scores compared with animals not receiving bacterial challenge. This study shows that during severe bacterial peritonitis, maintenance of sympathetic tone irrespective of pain relief provided is necessary for clearance of bacterial toxins, control of proinflammatory mediator release, hemodynamic stability, and survival.

We investigated whether inhibiting an endothelial adhesion molecule [intracellular adhesion molecule 1 (ICAM-1)] would alter outcome and lung injury in a similar fashion to inhibition of a leukocyte adhesion molecule (integrin CD11b) in a rat model of gram-negative pneumonia. Inhibition of ICAM-1 with monoclonal antibody (MAb) 1A29 (1 mg/kg sc or 0.2 or 2 mg/kg iv, q 12 h × 3) or of CD11b with MAb 1B6 (1 mg/kg sc, q 12 h × 3) were compared against similarly administered placebo proteins in rats challenged with intrabronchial Escherichia coli. After challenge, all animals were treated with antibiotics. ICAM-1 MAb (6 mg/kg, iv, total dose) increased mortality vs. control (P= 0.03). CD11b MAb (3 mg/kg, sc, total dose) did not significantly (P= 0.16) increase mortality rates, but this was not in a range of probability to exclude a harmful effect. All other doses of MAb had no significant effect on survival rates. ICAM-1 and CD11b MAbs had significantly different effects on the time course of lung injury, circulating white cells and lymphocytes, and lung lavage white cells and neutrophils (P= 0.04–0.003). CD11b MAb decreased, whereas ICAM-1 MAb increased these measures compared with control from 6 to 12 h after E. coli. However, from 144 to 168 h afterE. coliboth MAbs increased these measures compared with control rats but to a greater level with CD11b MAb. Thus both ICAM-1 and CD11b appear to be necessary for survival during E. colipneumonia. Although these adhesion molecules may participate differently in early lung injury, with CD11b increasing and ICAM-1 decreasing inflammation and injury, both are important for the resolution of later injury. During gram-negative pneumonia the protective roles of ICAM-1 and CD11b may make their therapeutic inhibition difficult.

The reliability of left ventricular (LV) systolic functional indices calculated from blinded echocardiographic measurements of LV size has not been tested in a large cohort of healthy children. The objective of this study was to estimate interobserver variability in standard measurements of LV size and systolic function in children with normal cardiac anatomy and qualitatively normal function.

Pain is not a symptom generally associated with thalassemia. However, healthcare providers have anecdotally noted increasing patient reports of chronic pain over the last decade creating an impetus for the TCRN to conduct this prospective, observational assessment of pain in patients with thalassemia over the age of 12. Study goals include assessment of pain prevalence, severity and sites and whether these factors are impacted by age, gender or diagnosis.Pain was assessed quarterly using the Brief Pain Inventory (BPI). Two hundred fifty-one thalassemia patients ranging in age from 12 to 71 (average age of 28.75) receiving care at one of 12 thalassemia centers across the US and Canada participated in the study. Fifty-four percent of participants were female. Diagnoses included: Beta Thalassemia (80%), E Beta thalassemia (11%), Hemoglobin H and H Constant Spring (6%) and other thalassemia conditions (3%). Eighty percent of participants were chronically transfused, 6% intermittently transfused and 14% had never been transfused. This report reviews baseline findings.At study entry, 64% of the 251 participants reported experiencing pain over the last four weeks, of whom 21% reported pain on a daily basis. In comparison, 26% of the American public, 20 years and older, reported pain over a one month period according to National Center for Health Statistics data, 2006. Ordinal regression analysis of participant ratings of worst, least, and average pain over the last seven days demonstrated significant (p<0.001) correlation of increased age with increased pain across all categories irrespective of diagnosis, transfusion status or gender. Similarly, ordinal regression analysis revealed that pain increased with participant age and significantly correlated (p<0.001) with a negative impact of pain on patient's affect and activity as measured by the BPI interference scales. Eighty-two percent of those reporting pain indicated lower back as a site of pain. In logistic regression models, lower back (p=0.046), arm (p=0.047) and hip (p=0.009) pain significantly increased with age. The number of bodily pain sites (p=0.033) also increased with age which was determined using linear regression. Among patients reporting pain in the last seven days, 77% reported having pain for one year or longer and 26% reported pain for 5 or more years. Participants reporting pain in the last 7 days identified the following reasons for their pain: thalassemia (60%), low hemoglobin (55%), bone pain (37%) and muscle spasm (30%). Participants indicated multiple methods of managing pain including: blood transfusion (54%), rest (51%) massage (46%) and heat (39%). Medications were the most frequently cited pain intervention (72 % of participants) with the most common mediations taken being NSAIDs (71%), followed by acetaminophen (48%), short acting narcotics (24%) and long acting narcotics (11%). Twenty-five percent of participants reported they received no pain relief from medications or non-pharmaceutical treatments, and only 4% reported they received complete pain relief with treatment. Half the population reported they gained about 50% relief from pain with treatments.These data show that pain is a significant issue for patients with thalassemia and as patient's age pain increases. Pain assessment should be conducted on a regular basis for all patients with thalassemia since neither transfusion status nor diagnosis are a reliable indicator of pain status. The study also indicates that chronic pain (pain lasting greater than one year) is an issue for thalassemia patients and underscores the need for further study of pain in this population. Analysis of pain follow up data collected at 3 month intervals post baseline is being conducted to assess whether severity levels vary over time.Coates: Novartis: Research Funding, Speakers Bureau. Neufeld:Novartis, Inc: Research Funding; Ferrokin, Inc: Research Funding.

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