Chronic vagus nerve stimulation is associated with multi-year improvement in intrinsic heart rate recovery and left ventricular ejection fraction in ANTHEM-HF.

PURPOSE: Disturbed autonomic function is implicated in high mortality rates in heart failure patients. High-intensity vagus nerve stimulation therapy was shown to improve intrinsic heart rate recovery and left ventricular ejection fraction over a period of 1 year. Whether these beneficial effects are sustained across multiple years and are related to improved baroreceptor response was unknown. METHODS: All patients (n = 21) enrolled in the ANTHEM-HF clinical trial (NCT01823887, registered 4/3/2013) with 24 h ambulatory electrocardiograms at all time points and 54 normal subjects (PhysioNet database) were included. Intrinsic heart rate recovery, based on ~ 2000 spontaneous daily activity-induced heart rate acceleration/deceleration events per patient, was analyzed at screening and after 12, 24, and 36 months of chronic vagus nerve stimulation therapy (10 or 5 Hz, 250 µs pulse width, 18% duty cycle, maximum tolerable current amplitude). RESULTS: In response to chronic high-intensity vagus nerve stimulation (≥ 2.0 mA), intrinsic heart rate recovery (all time points, p < 0.0001), heart rate turbulence slope, an indicator of baroreceptor reflex gain (all, p ≤ 0.02), and left ventricular ejection fraction (all, p ≤ 0.04) were improved over screening at 12, 24, and 36 months. Intrinsic heart rate recovery and heart rate turbulence slope were inversely correlated at both screening (r = 0.67, p < 0.002) and 36 months (r = 0.78, p < 0.005). CONCLUSION: This non-randomized study provides evidence of an association between improvement in intrinsic heart rate recovery and left ventricular ejection fraction during high-intensity vagus nerve stimulation for a period of ≥ 3 years. Correlated favorable effects on heart rate turbulence slope implicate enhanced baroreceptor function in response to chronic, continuously cyclic vagus nerve stimulation as a physiologic mechanism.

The Influence of the Solar Coronal Radiation on Coronal Plasma Structures, I: Determination of the Incident Coronal Radiation.

Coronal structures receive radiation not only from the solar disc, but also from the corona. This height-dependent incident radiation plays a crucial role in the excitation and the ionisation of the illuminated plasma. The aim of this article is to present a method for computing the detailed incident radiation coming from the solar corona, which is perceived at a point located at an arbitrary height. The coronal radiation is calculated by integrating the radiation received at a point in the corona over all of the corona visible from this point. The emission from the corona at all wavelengths of interest is computed using atomic data provided by CHIANTI. We obtain the spectrum illuminating points located at varying heights in the corona at wavelengths between 100 and 912 Å when photons can ionise H or He atoms and ions in their ground states. As expected, individual spectral lines will contribute most at the height within the corona where the local temperature is closest to their formation temperature. As there are many spectral lines produced by many ions, the coronal intensity cannot be assumed to vary in the same way at all wavelengths and so must be calculated for each separate height that is to be considered. This code can be used to compute the spectrum from the corona illuminating a point at any given height above the solar surface. This brings a necessary improvement to models where an accurate determination of the excitation and ionisation states of coronal plasma structures is crucial.

Novel method to assess intrinsic heart rate recovery in ambulatory ECG recordings tracks cardioprotective effects of chronic autonomic regulation therapy in patients enrolled in the ANTHEM-HF study.

BACKGROUND: Postexercise heart rate recovery (HRR) is a powerful and independent predictor of mortality. Autonomic regulation therapy (ART) with chronic vagus nerve stimulation (VNS) has been shown to improve ventricular function in patients with chronic heart failure. However, the effect of ART on HRR in patients with heart failure remains unknown. METHODS: A new measure involving quantification of intrinsic HRR was developed for 24-hr ambulatory ECG (AECG) recordings based on spontaneous heart rate changes observed during daily activity in patients with symptomatic heart failure and reduced ejection fraction. Intrinsic HRR values were compared in 21 patients enrolled in the ANTHEM-HF study (NCT01823887) before and after 12 months of chronic ART (10 Hz, 250 µs pulse width, 18% duty cycle, maximum tolerable current amplitude after 10 weeks of titration) and to values from normal subjects (PhysioNet database, n = 54). RESULTS: With chronic ART, average intrinsic HRR was improved as indicated by a shortening of the rate-recovery time constant by 8.9% (from 12.3 ± 0.1 at baseline to 11.2 ± 0.1 s, p < .0001) among patients receiving high-intensity stimuli (≥2 mA). In addition, mean heart rate decreased by 8.5 bpm (from 75.9 ± 2.6 to 67.4 ± 2.9 bpm, p = .005) and left ventricular ejection fraction (LVEF) increased by 4.7% (from 32.6 ± 2.0% to 37.3 ± 1.9%, p < .005). CONCLUSION: Using a new technique adapted for 24-hr AECG recordings, intrinsic HRR was found to be impaired in patients with symptomatic HF compared to normal subjects. Chronic ART significantly improved intrinsic HRR, indicating an improvement in autonomic function.

Clues to unraveling the coral species problem: distinguishing species from geographic variation in Porites across the Pacific with molecular markers and microskeletal traits.

Morphological variation in the geographically widespread coral Porites lobata can make it difficult to distinguish from other massive congeneric species. This morphological variation could be attributed to geographic variability, phenotypic plasticity, or a combination of such factors. We examined genetic and microscopic morphological variability in P. lobata samples from the Galápagos, Easter Island, Tahiti, Fiji, Rarotonga, and Australia. Panamanian P. evermanni specimens were used as a previously established distinct outgroup against which to test genetic and morphological methods of discrimination. We employed a molecular analysis of variance (AMOVA) based on ribosomal internal transcribed spacer region (ITS) sequence, principal component analysis (PCA) of skeletal landmarks, and Mantel tests to compare genetic and morphological variation. Both genetic and morphometric methods clearly distinguished P. lobata and P. evermanni, while significant genetic and morphological variance was attributed to differences among geographic regions for P. lobata. Mantel tests indicate a correlation between genetic and morphological variation for P. lobata across the Pacific. Here we highlight landmark morphometric measures that correlate well with genetic differences, showing promise for resolving species of Porites, one of the most ubiquitous yet challenging to identify architects of coral reefs.

Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study).

BACKGROUND: In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse. METHODS: In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enrolled in the prospective European INES trials. RESULTS: Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) (P<0.0001). Progression-free survival was poorer in patients whose tumours harboured SCA, in the whole population and in trials INES99.1 and INES99.2, in the absence of clinical symptoms (log-rank test, P=0.0001, P=0.04 and P=0.0003, respectively). In multivariate analysis, a SCA genomic profile was the strongest predictor of poorer progression-free survival. CONCLUSION: In infants with stage 4s MYCN-non-amplified NB, a SCA genomic profile identifies patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas in infants with localised unresectable NB, a genomic profile characterised by the absence of SCA identifies patients in whom treatment reduction might be possible. These findings will be implemented in a future international trial.

Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study.

Clinical studies showed that advanced stage, high LDH, poor response to reduction therapy and combined bone marrow and central nervous system disease are significantly associated with a decreased event-free survival (EFS) in pediatric mature B-cell non-Hodgkin's lymphoma (B-NHL) treated on FAB/LMB96. Although rearranged MYC/8q24 (R8q24) is characteristic of Burkitt lymphoma (BL), little information is available on other cytogenetic abnormalities and their prognostic importance. We performed an international review of 238 abnormal karyotypes in childhood mature B-NHL treated on FAB/LMB96: 76% BL, 8% Burkitt-like lymphoma, 13% diffuse large B-cell lymphoma (DLBCL). The main BL R8q24-associated chromosomal aberrations were +1q (29%), +7q and del(13q) (14% each). The DLBCL appeared heterogeneous and more complex. Incidence of R8q24 (34%) was higher than reported in adult DLBCL. The prognostic value of cytogenetic abnormalities on EFS was studied by Cox model controlling for the known risk factors: R8q24, +7q and del(13q) were independently associated with a significant inferior EFS (hazard ratio: 6.1 (P=0.030), 2.5 (P=0.015) and 4.0 (P=0.0003), respectively). The adverse prognosis of R8q24 was observed only in DLBCL, whereas del(13q) and +7q had a similar effect in DLBCL and BL. These results emphasize the significant biological heterogeneity and the development of cytogenetic risk-adapted therapy in childhood mature B-NHL.

Acute neurotoxicity in children with advanced stage B-non-Hodgkin's lymphoma and B-acute lymphoblastic leukaemia treated with the United Kingdom children cancer study group 9002/9003 protocols.

We reviewed the pattern of acute neurotoxicity in children with B-non-Hodgkin's lymphoma (B-NHL) and B-acute lymphoblastic leukaemia (ALL) treated with the UKCCSG 9002/9003 protocols. Among 175 patients, 21 (12%) developed acute neurotoxicity: 9002 protocol (n=11/112) and 9003 (n=10/63). There were 20 boys and the median age was 10 years. Patients with neurological symptoms due to other causes were excluded. Acute neurological symptoms developed following induction chemotherapy in 7 patients, or after a more intensive course of chemotherapy containing high-dose methotrexate (n=14). Nine patients required their chemotherapy to be altered because of the acute neurotoxicity. One patient died of cerebral haemorrhage but none of the remaining six deaths was attributed to acute neurotoxicity. We conclude that acute neurotoxicity is common in children treated with the 9002/9003 protocols and tends to be transient. Intrathecal and systemic chemotherapy including high-dose methotrexate is probably the most common predisposing factor. Modification of subsequent chemotherapy is not invariably necessary.

Use of basiliximab in pediatric liver transplantation for Langerhans cell histiocytosis.

This report describes a 16-month-old girl with multi-system Langerhans cell histiocytosis (LCH), who developed end-stage liver disease despite intensive chemotherapy. She underwent a liver transplant at 28 months of age while receiving maintenance chemotherapy for bony lesions. In view of previous reports of a high incidence of acute cellular rejection and post-transplant lymphoproliferative disease (PTLD) in children transplanted for LCH, basiliximab was added to the post-transplant immunosuppression regime of tacrolimus and prednisolone. Sixteen months post-transplant, she has had no episodes of acute rejection or PTLD and her LCH has remained in remission. Current literature regarding liver transplantation (LTx) for LCH and the use of basiliximab in pediatric LTx is reviewed.

Kikuchi-Fujimoto disease: a rare but important cause of lymphadenopathy.

UNLABELLED: Cervical lymphadenopathy is a common problem in children. Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis) is a rare condition that causes persistent lymphadenopathy and has a characteristic histological appearance. Kikuchi-Fujimoto disease is well recognized in Japan, where it was first described, but descriptions in the paediatric literature are sparse. Paediatricians may therefore be unaware of this rare but important condition. The case is described of a 14-y-old girl suffering from fatigue, weight loss, night sweats and lymphadenopathy. The predominance of systemic symptoms prompted an extensive investigation. The diagnosis of Kikuchi-Fujimoto disease was made after direct histological examination of a lymph node biopsy. The case illustrates the clinical features of this little-known condition and highlights the potential confusion with other diagnoses. The pathological features are discussed and the literature reviewed. CONCLUSION: Kikuchi-Fujimoto disease should be considered in cases of persistent lymphadenopathy. An early biopsy can be instrumental in preventing unnecessary investigations and potentially harmful treatments.

Colorectal carcinoma in children and adolescents--a report of seven cases.

Between 1981 and 1997 seven children and adolescents (5 boys and 2 girls) were treated for colorectal carcinomas in two paediatric centres. The case notes of the patients were studied to determine the presentation, clinical findings, prognosis and the differences of colorectal carcinomas in the young patients compared to adults. Carcinoma of the colon and rectum is uncommon in this age group and has a poor prognosis. The age range was 9 - 15 years, mean age 11.8 years. All segments of the large bowel were represented as sites of the primary tumour. Vague abdominal pain, vomiting and weight loss were the commonest presenting symptoms. The duration of symptoms varied from one month to twelve months (median: four months). Contrast enema was the most useful diagnostic investigation. Five patients had Dukes' stage C and two had Dukes' stage D tumour. Mucin-secreting adenocarcinoma was the commonest histological diagnosis. Five patients had complete resection, two had palliative procedures. Post-operative chemotherapy was given to six patients and two had post-operative radiotherapy.

The influence of neighborhood disadvantage, collective socialization, and parenting on African American children's affiliation with deviant peers.

This study focused on hypotheses about the contributions of neighborhood disadvantage, collective socialization, and parenting to African American children's affiliation with deviant peers. A total of 867 families living in Georgia and Iowa, each with a 10- to 12-year-old child, participated. Unique contributions to deviant peer affiliation were examined using a hierarchical linear model. Community disadvantage derived from census data had a significant positive effect on deviant peer affiliations. Nurturant/involved parenting and collective socialization processes were inversely associated, and harsh/inconsistent parenting was positively associated, with deviant peer affiliations. The effects of nurturant/involved parenting and collective socialization were most pronounced for children residing in the most disadvantaged neighborhoods.

Small round cell tumor with biphenotypic differentiation and variant of t(21;22)(q22;q12).

A 14-year-old boy presented with a soft tissue swelling on the outer aspect of his left upper arm. Examination of the tumor by light microscopy showed a small round cell tumor with a rare focus of myogenic differentiation. Myogenic differentiation was confirmed on ultrastructural examination by immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). Conventional G-banding and fluorescent in situ hybridization (FISH) demonstrated a complex variant of t(21;22)(q22;q12). By RT-PCR, the EWS-ERG fusion transcript was defined as type 9e. This tumor was unusual in that it showed characteristics of myogenic and neural differentiation, and contained a rearrangement of the EWS gene consistent with a diagnosis of Ewing's sarcoma. This supports the hypothesis that a class of biphenotypic childhood sarcomas, with features of myogenic and neural differentiation, exists that may be related to the Ewing's sarcoma family of tumors.

Outcome of relapsed or refractory childhood B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols.

Twenty-six children with B-cell acute lymphoblastic leukaemia (B-ALL) or Murphy Stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) progressed or relapsed after first-line therapy with a short, intensive multiagent chemotherapy regimen [United Kingdom Childhood Cancer Study Group (UKCCSG) 9003] (n = 62) or a slightly less intensive regimen (UKCCSG 9002) (n = 112). Eight patients (4.6%) never achieved complete remission (CR) and 18 (10.3%) relapsed. Second-line therapy resulted in remission for eight patients (30%). All patients initially treated with the 9003 protocol died. Three patients (11.5%) in the 9002 group, including one who never achieved CR in the primary site, are alive after second-line therapy. This study confirms that the prognosis of relapsed or refractory B-ALL/B-NHL is poor and exceptionally so if relapse occurred less than 6 months from diagnosis. High-dose therapy with stem cell rescue was used in only seven patients; its role needs to be studied further.

Congenital alveolar rhabdomyosarcoma: clinical and molecular distinction from alveolar rhabdomyosarcoma in older children.

BACKGROUND: Congenital alveolar rhabdomyosarcoma (RMS) is extremely rare and invariably fatal with current therapy. Its clinical presentation is unusual and is distinct from RMS in older children, with > 50% of patients presenting with multiple cutaneous metastases. To the authors' knowledge, the biology of this condition has not been studied to date. METHODS: The clinical and pathologic findings of four cases of congenital RMS are presented along with those of other cases found in the literature. Molecular analysis was undertaken to detect the characteristic chromosomal translocations of alveolar RMS in three cases with suitable material. RESULTS: To the authors' knowledge, there are no recorded survivors of congenital alveolar RMS. Clinical and histopathologic findings in four patients with congenital alveolar RMS are detailed along with treatment responses. It now is recognized that tumor specific translocations can be detected in the majority of cases of alveolar RMS using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. However, detailed molecular analysis using RT-PCR was unable to detect the presence of either the classic t(2;13) or variant t(1;13) translocation in three cases analyzed at the molecular level. CONCLUSIONS: To the authors' knowledge the optimal treatment for this rare tumor is not known. The longest survivor in the current series underwent myeloablative therapy with peripheral stem cell support, suggesting that more intensive treatment may be of value in this rare condition. None of the three tumors analyzed by RT-PCR harbored characteristic RMS translocations. The molecular biology of this highly malignant and aggressive congenital tumor appears to be different from alveolar RMS in older children and warrants further investigation.

Self-esteem, self-serving cognitions, and health risk behavior.

The current article reviews prospective and experimental research on the relation between self-esteem and perceptions of vulnerability. These studies demonstrate that individuals with high self-esteem who engage in risk behavior often utilize a variety of self-serving cognitive strategies that protect them from fully acknowledging their vulnerability to the potential negative consequences of their behavior; e.g., they minimize their estimates of personal risk and overestimate the prevalence of the risk behavior among their peers. The article also provides data on an additional self-serving cognitive strategy employed by adolescents with high self-esteem--alteration of perceptions of others' reactions to their own risk behavior. Finally, the article reviews the emerging literature on the relation between these cognitive strategies and maladaptive health behavior, and proposes that whether these strategies are maladaptive depends on the nature of the threat and the availability of opportunities to engage in compensatory self-enhancement.

Protection and vulnerability processes relevant for early onset of substance use: a test among African American children.

This research tested predictions from a self-regulation model of factors relevant for early onset of tobacco and alcohol use with a community sample of 889 African American children (mean age = 10.5 years). Criterion variables were peer substance use, willingness to use substances, and resistance efficacy (intention to refuse substance offers). Structural modeling indicated effects of temperament dimensions were mediated through self-control and risk-taking constructs, which were related to school involvement, life events, and perceived vulnerability to harmful effects of substances. Peer use was predicted by life events, poor self-control, and parent-child conflict; willingness was predicted by life events, risk taking, and (inversely) parental support; and resistance efficacy was predicted by perceived vulnerability and (inversely) poor self-control. Findings are discussed with reference to theoretical models of early protection and vulnerability processes.

Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol.

From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n = 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n = 39); IIIB with abdominal multiorgan involvement (n = 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n = 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12-92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2-92.1 %) and 83.7% (95% CI 76.3-89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy.

Mature B-cell lymphoma/leukemia in children and adolescents: intergroup pathologist consensus with the revised European-American Lymphoma Classification.

BACKGROUND: The Revised European-American Lymphoma (R.E.A.L.) Classification criteria were evaluated in the international protocol FAB LMB 96 Treatment of Mature B-cell Lymphoma/Leukemia: A SFOP LMB 96/CCG-5961/UKCCSG NHL 9600 Cooperative Study. This includes B-lineage lymphomas: Burkitt's lymphoma (including ALL-L3); high-grade B-cell lymphoma, Burkitt-like; diffuse large B-cell lymphoma (excluding anaplastic large cell Ki-1 lymphoma). PATIENTS AND METHODS: Cases were independently reviewed by eight hematopathologists from the three cooperative national groups (two SFOP, two CCG, four UKCCSG), without prior discussion of classification criteria or guidelines for case rejection. Consensus diagnosis was determined by each national cooperative group, and final consensus diagnosis established when at least two national consensus diagnoses were in agreement, or following group agreement at a multiheaded microscope. RESULTS: Two hundred eight cases were reviewed, with final consensus diagnosis established in two hundred three. The percent agreement of each group's national consensus diagnosis with final consensus diagnosis was 86%, 86% and 71%. The percent agreement of the group's national consensus diagnosis with final consensus diagnosis for Burkitt's and diffuse large B-cell lymphoma were 88% and 80%, respectively, but only 42% for Burkitt-like lymphoma. CONCLUSIONS: International panel review of mature B-cell lymphoma/leukemia in children and adolescents highlighted difficulties in subclassification, particularly with Burkitt-like, which is a 'provisional entity' in the R.E.A.L. Classification. The absence of previous discussion of classification and guidelines for case rejection may in part explain the discrepancy between pathologists. These results underline that morphology may need to be complemented by other studies, such as molecular genetic and cytogenetics, to discriminate between the mature B-cell lymphomas.