Children after fontan have strength and body composition similar to healthy peers and can successfully participate in daily moderate-to-vigorous physical activity.

The objective of this study was to evaluate the active lifestyle capacity (daily physical activity, strength, flexibility, body composition) of children after the Fontan procedure; hypothesized to be lower than healthy peers. Participants (n = 64, 25 females) were 9.0 ± 1.7 years of age (range 6.0-11.7 years). Fontan completion occurred at 3.3 ± 1.4 years of age (5.7 ± 2.0 years prior). Canadian Health Measures Survey protocols assessed aerobic endurance (paced walking up/down steps), strength (handgrip), flexibility (sit and reach), body composition (body mass index), and daily moderate-to-vigorous physical activity (7-day accelerometry). Difference scores compared participant data to published norms (t tests). Linear regression evaluated age/gender/demographic factor associations. Children after Fontan had strength scores similar (mean difference 1.1 kg) to their peers were less likely to be obese (mean difference of body mass index = 1.1 ± 2.5, p = 0.001) and performed 50 min of moderate-to-vigorous activity (MVPA) per day (12 ± 17 min/day below healthy peers, p < 0.001). Estimated peak endurance (61 % of expected) and flexibility (64 % of expected) were lower than peers (p < 0.001). Almost all (60/63) participants demonstrated the capacity to perform at least 20 min of MVPA per day. Difference from norms was smaller among children younger at Fontan completion (4 ± 2 min/year) and taking antithrombotic medication (7 ± 18 and 22 ± 17 min/day for taking/not taking, respectively). Children after Fontan demonstrate the capacity for the daily physical activity associated with optimal health. They have similar strength and good body composition. We recommend that children after Fontan be counselled that they can successfully participate in healthy, active lifestyles and physically active peer play.

Termite fishing laterality in the Fongoli savanna chimpanzees (Pan troglodytes verus): further evidence of a left hand preference.

Whether nonhuman primates show population-level handedness is a topic of much scientific debate. A previous study of handedness for termite fishing reported population-level left handedness in the chimpanzees from Gombe National Park, Tanzania. In the current study, we examined whether similar hand preferences were evident in a savanna-dwelling chimpanzee population with regards to termite fishing. Hand preference data were collected for 27 chimpanzees from February 2007 through July 2008 and November 2011 through January 2012 in southeastern Senegal. Overall, the Fongoli chimpanzees demonstrate a trend toward population-level handedness, though the results did not reach conventional levels of statistical significance likely due to the limited sample size. Fongoli chimpanzees showed the same pattern of left hand preference as reported at Gombe and the two populations did not differ significantly. When the data were combined across all studies, wild chimpanzees showed a population-level left hand preference for termite fishing.

Early determinants of atherosclerosis in paediatric systemic lupus erythematosus.

OBJECTIVES: To assess traditional and non-traditional cardiovascular risk factors and to determine the prevalence and correlates of early vascular markers of atherosclerosis in paediatric systemic lupus erythematosus (pSLE). METHODS: Fifty-four adolescents with pSLE had cardiovascular risk factor assessment, disease activity and vascular testing including carotid intima-media thickness (CIMT), flow-mediated dilatation (FMD), arterial stiffness measures, and myocardial perfusion studies. RESULTS: The traditional risk factors of hypertension, elevated triglycerides, apolipoprotein B, haemoglobin A1c and insulin levels and non-traditional risk factors of elevated homocysteine and fibrinogen were present (all p<0.001). Some arterial stiffness measures, central pulse wave velocity and characteristic impedance were elevated (p<0.001), but CIMT, FMD and myocardial perfusion were normal. Cumulative prednisone dose correlated with total cholesterol (r=0.5790, p<0.001) and elevated LDL-C (r=0.4488, p=0.0012). Hydroxychloroquine treatment correlated negatively with total cholesterol (r=-0.4867, p=0.0002), LDL-C (r=-0.4805, p=0.0002) and apolipoprotein B (r=-0.4443, p=0.0011). In multivariate analysis LDL-C correlated with cumulative prednisone dose and negatively with hydroxychloroquine treatment (R2=0.40, p<0.001). CONCLUSIONS: An increased burden of traditional and non-traditional risk factors and early evidence of insulin resistance and increased central arterial stiffness were present in paediatric SLE. Disease-specific and therapy-related factors are likely modifying these cardiovascular risk profiles warranting prospective longitudinal studies.

Radiation Therapy for Plasma Cell Disease of the Brain and Skull: Poor Palliation and Survival After Treatment for Central Nervous System Involvement.

PURPOSE: Myeloma lesions of the head can present with central nervous system (CNS) involvement (leptomeningeal disease or brain metastasis), cranial neuropathy (CN), or impending neurologic involvement (INI). We analyzed response and survival after palliative radiation therapy (RT) to the brain and/or skull for myeloma lesions to determine whether CNS involvement fared worse than other RT indications. METHODS AND MATERIALS: We retrospectively analyzed 54 palliative RT courses administered at our institution from 2008 to 2019. Eleven courses were administered for CNS disease, 28 for CN, and 15 for INI. Demographic, disease, and RT variables were recorded as well as clinical response, radiographic response, and survival. Univariate analyses were performed for differences between groups, effects of clinical and RT treatment factors on response, as well as dose response. Survival was analyzed with the Kaplan-Meier method and compared by the log-rank test. RESULTS: This heavily pretreated cohort received a median of 20 to 24 Gy, most often to the base of skull, orbit(s), calvarium, or whole brain. Any clinical response (partial or complete vs no response or progressive disease) was significantly more likely for patients with CN and INI when collectively compared with patients with CNS disease (P < .001). Dose response was significant for doses ≥15 and 20 Gy for the whole cohort (P = .026 and .005, respectively) and patients with CN/INI (P = .023 and .002, respectively). Additionally, patients with high-risk cytogenetics were less likely to clinically respond (P = .009). Patients with CNS disease had worse survival (P = .005). CONCLUSIONS: Patients with leptomeningeal disease/brain metastasis have poor clinical response and survival after RT and their responses do not demonstrate a dose response. Given these poor outcomes, the potential benefit of RT may be limited for some patients who may be alternatively managed by supportive care or short RT courses. Patients with CN/INI have longer survival and better response rates and may benefit from RT courses ≥15 to 20 Gy.

Current challenges in three-dimensional bioprinting heart tissues for cardiac surgery.

SUMMARY: Previous attempts in cardiac bioengineering have failed to provide tissues for cardiac regeneration. Recent advances in 3-dimensional bioprinting technology using prevascularized myocardial microtissues as 'bioink' have provided a promising way forward. This review guides the reader to understand why myocardial tissue engineering is difficult to achieve and how revascularization and contractile function could be restored in 3-dimensional bioprinted heart tissue using patient-derived stem cells.

Incidence of infective endocarditis and its thromboembolic complications in a pediatric population over 30years.

BACKGROUND: Pediatric infective endocarditis (IE) has been associated with high morbidity and mortality, mostly related to thromboembolic complications (TEC). The objective of our study was to describe the experience in children with IE and to review the changes over a thirty-year period, regarding origin of IE, incidence of vegetations, TEC and their respective morbidity and mortality rates. METHODS: A retrospective chart review of children aged 0-18years with IE defined by the Duke Criteria and admitted to The Hospital for Sick Children, was conducted. Data were divided into three periods (P); P1 (1979-1988); P2 (1989-1998); and P3 (1999-2008). RESULTS: The study included 113 patients, median age 7yrs.; females: 46 (41%), congenital heart defects 95 (84%), comparable in all periods. Overall, cardiac vegetations were found in 68/113 patients (60%); large vegetations (≥1cm) in 32 patients (28%). Fourty-five (45/133 [40%]) TEC were documented, 22 patients (20%) developed cerebrovascular events (CVE) and 23 patients (20%) had non-CVE. Patients diagnosed during P3 were older, had more vegetations (p<0.05), and a higher incidence of community acquired-IE (p<0.05). Overall, mortality was 15%, comparable in all periods. Significant risk factors for mortality were vegetations (HR 6.44; 95% CI: 2.07-20.01, p=0.002) and heart failure (HR 28.39; 95% CI: 10.49-76.85, p<0.001). CONCLUSIONS: Over the study period, we report a growing incidence of community acquired pediatric IE in older children accompanied by an increasing rate of TEC. Heart failure and vegetations were associated with an increased mortality. These preliminary data need to be confirmed by prospective data.

E2F1 suppresses skin carcinogenesis via the ARF-p53 pathway.

The E2F1 transcription factor, which is deregulated in most human cancers by mutations in the p16-cyclin D-Rb pathway, has both oncogenic and tumor-suppressive properties. This is dramatically illustrated by the phenotype of an E2F1 transgenic mouse model that spontaneously develops tumors in the skin and other epithelial tissues but is resistant to papilloma formation when subjected to a two-stage carcinogenesis protocol. Here, this E2F1 transgenic model was used to further explore the tumor-suppressive property of E2F1. Transgenic expression of E2F1 was found to inhibit ras-driven skin carcinogenesis at the promotion stage independent of the type of promoting agent used. E2F1 transgenic epidermis displayed increased expression of p19(ARF), p53, and p21(Cip1). Inactivation of either p53 or Arf in E2F1 transgenic mice restored sensitivity to two-stage skin carcinogenesis. While Arf inactivation impaired tumor suppression and p21 induction by E2F1, it did not reduce the level of apoptosis observed in E2F1 transgenic mice. Based on these findings, we propose that E2F1 suppresses ras-driven skin carcinogenesis through a nonapoptotic mechanism involving ARF and p53.

E2F4 and E2F1 have similar proliferative properties but different apoptotic and oncogenic properties in vivo.

Loss of retinoblastoma (Rb) tumor suppressor function, as occurs in many cancers, leads to uncontrolled proliferation, an increased propensity to undergo apoptosis, and tumorigenesis. Rb negatively regulates multiple E2F transcription factors, but the role of the different E2F family members in manifesting the cellular response to Rb inactivation is unclear. To study the effect of deregulated E2F4 activity on cell growth control and tumorigenesis, transgenic mouse lines expressing the E2F4 gene under the control of a keratin 5 (K5) promoter were developed, and their phenotypes were compared to those of previously generated K5 E2F1 transgenic mice. In contrast to what has been observed in vitro, ectopically expressed E2F4 was found to localize to the nucleus and induce proliferation to an extent similar to that induced by E2F1 in transgenic tissue. Unlike E2F1, E2F4 does not induce apoptosis, and this correlates with the differential abilities of these two E2F species to stimulate p19(ARF) expression in vivo. To examine the role of E2F4 in tumor development, the mouse skin two-stage carcinogenesis model was utilized. Unlike E2F1 transgenic mice, E2F4 transgenic mice developed skin tumors with a decreased latency and increased incidence compared to those characteristics in wild-type controls. These findings demonstrate that while the effects of E2F1 and E2F4 on cell proliferation in vivo are similar, their apoptotic and oncogenic properties are quite different.

E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model.

Using a transgenic mouse model expressing the E2F1 gene under the control of a keratin 5 (K5) promoter, we previously demonstrated that increased E2F1 activity can promote tumorigenesis by cooperating with either a v-Ha-ras transgene to induce benign skin papillomas or p53 deficiency to induce spontaneous skin carcinomas. We now report that as K5 E2F1 transgenic mice age, they are predisposed to develop spontaneous tumors in a variety of K5-expressing tissues, including the skin, vagina, forestomach, and odontogenic epithelium. On the other hand, K5 E2F1 transgenic mice are found to be resistant to skin tumor development following a two-stage carcinogenesis protocol. Additional experiments suggest that this tumor-suppressive effect of E2F1 occurs at the promotion stage and may involve the induction of apoptosis. These findings demonstrate that increased E2F1 activity can either promote or inhibit tumorigenesis, dependent upon the experimental context.

Review of toxicity and trends in the use of tiagabine as reported to US poison centers from 2000 to 2012.

BACKGROUND: Tiagabine is a novel antiepileptic that acts by increasing synaptic and extracellular gamma-aminobutyric acid concentrations. Information concerning overdose of tiagabine is limited. After introduction, an increasing number of off-label uses suggested that tiagabine use would increase. However in 2005 and 2008, warnings from the Food and Drug Administration (FDA) were issued on the risk of seizures in non-epileptic and increased suicide ideation. We evaluated the temporal trends associated with these two warnings as well as clinical outcomes from tiagabine overdose. METHOD: A retrospective review of all single substance tiagabine exposures in National Poison Data System (NPDS) from 2000 to 2012. RESULTS: A total of 2147 patients had ingested tiagabine, with a mean of 165 year(-1). This was disproportionally distributed, with a steep rise leading up to 2004 (max 559 year(-1)) and then a significant decline (p < 0.05) between 2005 and 2006. The number of cases reported to NPDS mirrored the sales of tiagabine. Clinical effects were predominantly neurological, with the most commonly reported effects being drowsiness (27%), agitation (19%), confusion (12%), seizures (11%), and tachycardia (10%). In all, 758 patients (35%) showed a major or moderate medical outcome, with no deaths reported. A disproportionate share of the major outcomes was in the suicide attempt group (73%). The majority of patients (75%) were treated in a health-care facility (HCF). CONCLUSIONS: The HCF usage is likely due to high rate of symptomatic patients (59%) and the large proportion of suicide attempt cases. The frequency of tiagabine cases in NPDS mirrored pharmaceutical sales, with steep declines temporally related to the 2005 FDA warning.

Massive lindane overdose with toxicokinetics analysis.

BACKGROUND: Lindane is a possible carcinogen with known teratogenicity and immunologic and neurotoxic properties. Despite reports of seizures, coma, and death associated with its use as well as banning of its environmental use by the Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA) still allows treatment with lindane as a second-line scabicide and pediculicide. We present a case of a massive suicidal ingestion of lindane in which the patient survived the ingestion, though he did expire shortly thereafter from an unrelated cause pre-discharge. METHODS: Pharmacokinetic analysis of serum lindane concentrations was performed with Phoenix® WinNONLIN®. The estimated distribution half-life for lindane was 10.3 h, and the terminal half-life was 162.9 h, much longer than the previously reported terminal half-life of 25-36 h. Because of this long half-life, repeated lindane exposures may lead to accumulation of lindane in the tissues. RESULT: After overdose, toxicity may be delayed and full recovery may be prolonged.

Nonfearful panic disorder in neurology patients validated by lactate challenge.

OBJECTIVE: Nonfearful panic disorder meets the DSM-III-R criteria for panic disorder but is not associated with subjective fear and anxiety. The authors determined its prevalence in a group of neurology patients and assessed its diagnostic validity as a panic disorder subtype by evaluating the response of the patients with nonfearful panic disorder to sodium lactate and antipanic pharmacotherapy. METHOD: The subjects were all neurology patients referred over 1 year to a university hospital's psychiatric consultation service because of negative medical workups for their symptoms (N = 48). Patients who met the DSM-III-R criteria for panic disorder but did not report subjective anxiety or fear during panic episodes were diagnosed as having nonfearful panic disorder. Afterward, each of those patients received a sodium lactate infusion and, 5 hours later, a sodium chloride infusion. They were then treated with antipanic medication and followed for at least 6 months. RESULTS: Of the 48 neurology patients referred for psychiatric evaluation, 11 (23%) met the criteria for panic disorder, and all 11 met the criteria for nonfearful panic disorder. All 11 responded positively to lactate but not to placebo, and they each experienced an at least 75% reduction in symptoms during the 6-month follow-up period. Detailed case reports of three of these patients are presented. CONCLUSIONS: These findings support the construct and predictive diagnostic validity of nonfearful panic disorder as a subtype of panic disorder and suggest that a lack of attention to this group leads to both the underestimation of the prevalence of panic disorder and to the withholding of potentially successful treatments for this group.

Panic disorder in cardiology patients: a review of the Missouri Panic/Cardiology Project.

This paper reviews current evidence from several cardiology populations that suggests that panic disorder is prevalent and underdiagnosed. Cardiology patients with atypical angina, and no heart disease have a high likelihood of having panic disorder, as suggested by studies of two separate cardiology populations. That they resemble psychiatric populations with panic is suggested by their positive response to alprazolam. A panic disorder subtype, called non-fear panic disorder also appeared in about one-third of these cardiology panic patients. These patients have most of the panic symptoms but do not report fear during their episodes.

Intermediate follow-up of right ventricular outflow tract reconstruction with allograft conduits.

BACKGROUND: Allograft conduits are among many varieties of material used for right ventricular outflow tract reconstruction. They invariably need to be replaced due to growth of the patient or conduit failure. METHODS: From June 1984 to June 1996, a total of 76 patients underwent reconstruction of the right ventricular outflow tract with an allograft conduit: 51 aortic and 25 pulmonary. The median age, weight and conduit size at surgery were 37 months (range, 0.2 to 228 months), 12.4 kg (range, 2.9 to 61.4 kg), and 17 mm (range, 8 to 26 mm), respectively. RESULTS: The hospital mortality was 5.3% (4 of 76 patients) and 2 patients died at 9 and 78 months follow-up. The median follow-up was 61 months (range, 2 to 132 months). Reoperation was necessary in 22 patients (28.9%) at a median interval of 50.5 months (range, 3 to 109 months) and the median conduit size was 21 mm (range, 12 to 23 months). There was no mortality. Freedom from reoperation at 64 months was 49.5% for conduits 15 mm and smaller, and 73.3% for conduits 16 mm and larger. Analysis by age shows freedom from reoperation at 64 months of 49.4% and 74.5% for patients younger than and older than 2 years, respectively. At 54 months there was no statistical difference in freedom from reoperation between pulmonary and aortic allografts. CONCLUSION: Right ventricular outflow tract reconstruction with allograft conduits results in a high reoperation rate at 4 years but provides significantly longer freedom from reoperation with conduits larger than 15 mm or in patients over 24 months of age.

Risks of repeat sternotomy in pediatric cardiac operations.

BACKGROUND: Repeat sternotomy has been associated with increased perioperative risks. METHODS: We reviewed 165 patients undergoing 192 repeat sternotomies between January 1985 and January 1997 (group 1) and a control group of 184 patients (group 2). The operations in group 1 were valve procedures in 94 patients, Fontan procedure in 46, ventricular septal defect closure in 10, pulmonary arterioplasty in 17, and others in 25; in group 2 ventricular or atrial septal defect closure in 120 patients, tetralogy of Fallot repair in 26, valve procedures in 16, bidirectional Glenn anastomosis in 7, repair of transposition of the great arteries in 7, pulmonary arterioplasty in 4, and others in 4. RESULTS: The hospital mortality was 2.6% in group 1 and 3.8% in group 2. Cardiac laceration occurred in 10 of 192 patients (5.2%), requiring emergent femorofemoral bypass in 6 patients. Two patients sustained an air embolism that was successfully treated with a hyperbaric chamber. Median total blood loss and requirements were not significantly different between the two groups. The length of stay in the intensive care unit and in the hospital were 4 days (range, 1 to 80 days) and 11 days (range, 1 to 135 days) in group 1, and 2 days (range, 1 to 87 days) and 7 days (range, 1 to 131 days) in group 2 (p < 0.02 and p < 0.002, respectively). The rate of complications was not significantly different in group 1 versus group 2. Overall survival was 97% (group 1) and 95% (group 2) at 120 months' follow-up (not significant). CONCLUSIONS: With careful surgical technique and judicious use of femorofemoral bypass, the risk of repeat sternotomy is minimized.

Total cavopulmonary connections in children with a previous Norwood procedure.

BACKGROUND: Outcomes of the Fontan operation in children initially palliated with the modified Norwood procedure are incompletely defined. METHODS: From August 1993 to January 2000, 45 patients (mean age 2.6 +/- 1.1 years, weight 12.7 +/- 2.8 kg) who were palliated with staged Norwood procedures (hypoplastic left heart syndrome, n = 32; nonhypoplastic left heart syndrome, n = 13) underwent a modified Fontan operation. Preoperative features included moderate/severe atrioventricular valve regurgitation (n = 5, 11%), reduced ventricular function on echocardiography in 11 patients, McGoon index 1.56 +/- 0.38, and pulmonary artery distortion in 18 patients (40%). RESULTS: A lateral tunnel (n = 16) or an extracardiac conduit (n = 29) connection with fenestration in 38 patients (84%) was used. Concomitant procedures included pulmonary artery reconstruction (n = 24, 53%), atrioventricular valve repair (n = 4, 9%) or replacement (n = 1). Before Fontan, 12 patients (27%) had an intervention to address neoaortic obstruction, and 7 patients required balloon dilation/stenting of the left (n = 5) or right pulmonary artery (n = 5). Intraoperatively, left (n = 5) or right pulmonary artery (n = 1) stenting was performed in 5 patients (11%). On follow-up, 8 patients required additional interventional procedures to address left pulmonary artery narrowing (n = 5), or venous (n = 5) or arteriopulmonary collaterals (n = 1). Perioperative mortality was 4.4% (n = 2). There were 2 late deaths at a mean follow-up of 39 +/- 20 months. CONCLUSIONS: In relatively high-risk patients, midterm results of the Fontan operation for children initially palliated with the Norwood procedure were good. Combined interventional-surgical treatment algorithms can lead to improved outcomes.

Clinical implications of depression in rheumatoid arthritis.

The clinical implications of depression in the context of rheumatoid arthritis are described. An overview of the diagnostic criteria for depression is provided, with specific focus on major depression and the associated subtypes. The neurobiological literature on major depression is briefly reviewed and the implications of the depression literature for the care of persons with rheumatoid arthritis are discussed.

Mitral valve prolapse, panic disorder, and chest pain.

Mitral valve prolapse is a common cardiac disorder that can readily be diagnosed by characteristic auscultatory and echocardiographic criteria. Although many diseases have been associated with mitral valve prolapse, most affected individuals have the primary form of the disorder. Mitral valve prolapse is an inherited condition commonly associated with myxomatous degeneration of the mitral valve and its support structures. Complications of mitral valve prolapse, including cardiac arrhythmias, sudden death, infective endocarditis, severe mitral regurgitation (with or without chordae tendineae rupture), and cerebral ischemic events, occur infrequently considering the wide prevalence of the disorder. Panic disorder is a specific type of anxiety disorder characterized by at least three panic attacks within a 3-week period or one panic attack followed by fear of subsequent panic attacks for at least 1 month. It too is a common condition with a prevalence and age and gender distribution similar to that of mitral valve prolapse. Panic disorder and mitral valve prolapse share many nonspecific symptoms, including chest pain or discomfort, palpitations, dyspnea, effort intolerance, and pre-syncope. Chest pain is the symptom in both conditions that most commonly brings the patient to medical attention. The clinical description of chest pain in patients with mitral valve prolapse is highly variable, possibly reflecting multiple etiologies. Chest pain in panic disorder is usually characterized as atypical angina pectoris and as such bears resemblance to the chest pain commonly described by patients with mitral valve prolapse. Multiple investigative attempts to elucidate the mechanism of chest pain in both conditions have failed to identify a unifying cause. Review of the literature leaves little doubt that mitral valve prolapse and panic disorder frequently co-occur. Given the similarities in their symptomatology, a high rate of co-occurrence is, in fact, entirely predictable. There is, however, no convincing evidence of a cause-effect relationship between the two disorders, nor has a single pathophysiologic or biochemical mechanism been identified that unites these two common conditions. Until specific biologic markers for these disorders are identified, it may be impossible to do so. The lack of a proven cause-and-effect relationship between mitral valve prolapse and panic disorder and the absence of a unifying mechanism do not diminish the clinical significance of the high rate of co-occurrence between the two conditions. Primary care physicians and cardiologists frequently encounter patients with mitral valve prolapse and nonspecific symptoms with no discernible objective cause who fail to respond to beta-blockade. Panic disorder should be considered as a possible explanation for symptoms in such patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Validating studies for panic disorder in patients with angiographically normal coronary arteries.

This article describes validating studies for diagnosing panic disorder in some patients with angiographically normal coronary arteries (NCA) and chest pain. Psychiatric interviews of 94 such patients showed that 34% met the diagnostic criteria for panic disorder. Further studies showed that NCA patients with panic disorder were more disabled at 3.5-year follow-up, had more relatives with panic disorder, were more likely to suffer from major depression, and were more likely to respond to 35% CO2 challenge with panic symptoms. Because panic disorder is highly disabling but responds well to psychological and pharmacologic treatments, screening NCA patients in the cardiology population for this disorder is recommended.