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Background Due to increasing success with repair or palliation in childhood, there is a rapidly growing population of adult patients with complex congenital heart disease who may require transplantation. There remains little data on outcomes of cardiac transplantation in this group. Methods 38 orthotopic cardiac transplants were performed in 37 patients (18 men) ≥18 years of age with congenital heart disease (CHD) from 1988 to 2009 in our institution. Outcomes were reviewed using medical records and transplant databases. Results 15 patients (41%) had univentricular and 22 (59%) biventricular physiology. The biggest group was transposition of the great arteries following atrial switch in eight patients (22%). Six (16%) had no previous surgical intervention. Mean age at transplant was 33.5 years (range 19.1–59.9 years). 11 patients (30%) required additional surgical procedures at transplant. 16 (43%) died, 12 early and 4 late deaths (1.8, 2.4, 2.7 and 7 years). Survival was 70% at 30 days, 68% at 1 year, 58% at 5 years and 53% at 10 and 15 years. Outcome improved in later eras with reduction in 30-day mortality from 50% to 18% and increase in 5-year survival from 50% to 69%. Two patients developed post-transplant lymphoproliferative disease. None required long-term renal replacement therapy. One patient was re-transplanted for cardiac allograft vasculopathy. Conclusions While operative mortality following cardiac transplantation for adult congenital heart disease is higher than for other diagnostic groups, long-term survival is good and comparable to patients without CHD. Disappointing early results are improved with increasing experience.

This article provides the lawyer and other uninitiated readers with an introduction to the principles and practice of cardiac surgery. Medicolegal problems relating to consent, professional competence, supervision of trainees and peri-operative care are outlined. Liability issues in three cardiac operations valve surgery, aortic surgery and coronary artery bypass grafts are discussed.

We sought to investigate the accuracy of dobutamine stress echocardiography to predict the degree and timing of recovery in resting function and contractile reserve (CR) after revascularization of the hibernating myocardium.In all, 24 patients with ischemic cardiomyopathy (ejection fraction40%) underwent dobutamine stress echocardiography 1 week before and 6 weeks, 3 months, and 6 months after coronary artery bypass grafting.Recovery rates at 6 weeks, 3 months, and 6 months postoperation were 21%, 33%, and 45% (P.01) for resting function and 55%, 65%, and 74% (P.01) for CR. Positive and negative predictive values for recovery of resting function and CR at 6 months postrevascularization were 66% vs 97% (P.001) and 78% vs 48% (P.001), respectively. Positive and negative predictive values were both high for recovery of CR at 6 weeks postrevascularization (89% and 78%).Dobutamine stress echocardiography can predict early recovery in CR postrevascularization with an excellent accuracy but may underestimate the degree of late recovery in CR.

Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) and choroid plexus carcinoma (CPC) are rare, highly malignant tumors that predominantly arise in infants and young children. Overlapping clinical, histologic, ultrastructural, or immunophenotypic features may obscure the diagnosis in some cases. AT/RT is characterized by deletions and/or mutations of the INI1 tumor-suppressor gene on chromosome band 22q11.2. We have recently developed an INI1 immunohistochemical staining assay. Negative staining of tumor cells resulting from inactivation of the INI1 gene is a consistent feature of AT/RT. Mutations of INI1 in some CPCs have been reported. The purpose of the present study was to determine if immunohistochemical staining with an INI1 antibody would provide a sensitive means of distinguishing between CPC and AT/RT. We examined 28 tumors with a submitted diagnosis of CPC. Twenty-one CPCs showed retained expression of INI1 and seven tumors showed loss of INI1 expression. Cytogenetic, FISH, and/or INI1 mutation results were also available for 13 tumors. In three of the seven cases, monosomy 22 was the only cytogenetic abnormality, suggestive of AT/RT. However, monosomy 22 was also identified in 3 tumors with complex karyotypes that retained INI1 expression. The 7 tumors that were immunonegative for INI1 had features that were consistent with AT/RT. Immunostaining for INI1 protein is retained in the majority of CPC and is lost in AT/RT. This expression pattern seems to better define the 2 groups of tumors than does light or electron microscopy, routine immunohistochemistry, or cytogenetic analysis alone.

Objective: To explore the association between APOE*4 and pathologically confirmed cases of the Lewy body (LB) variant of Alzheimer disease (AD). Methods: With use of α-synuclein (AS) immunohistochemistry, LBs were detected in 74 of 131 (56.5%) of the AD + LB cases; the remaining 57 cases (43.5%) did not have LBs. Results: There were no differences in gender or age between Caucasian subjects with AD + LB or AD alone or control subjects. The APOE*4 allele frequency was highest in the AD + LB group (47.3%; 95% CI = 37.8 to 57.0%), intermediate in the AD-alone group (35.1%; 95% CI = 25.3 to 46.3%), and lowest in the control group (14.2%; 95% CI = 10.5 to 18.9%). With use of logistic regression analysis, the odds of having AD + LB vs AD alone were 2.1-fold (95% CI = 1.0 to 4.5, p = 0.055) greater in persons with an APOE*4 allele than in those without an APOE*4 allele. Conclusion: The APOE*4 allele is associated with the presence of concomitant Lewy bodies in Alzheimer disease.

Objective: To compare the outcome of life insurance and mortgage applications of adults with congenital heart disease (CHD) with controls and at different severities of CHD. Methods: Two hundred and ninety-nine adult CHD patients underwent a questionnaire-based interview by a trained nurse. They were asked to give an identical questionnaire to a friend to act as a control. One hundred and seventy-seven controls replied. CHD patients were classified into three categories based on severity. Comparisons were made between matched controls and between different severities of CHD. Results: Similar proportions of the CHD group (59%) had applied for life insurance as matched controls (56%). Compared to controls, significantly more of the adults with CHD who had applied for life insurance have been refused (34 vs 4%, P < 0.0001) or asked to pay extra (37 vs 6%, P = 0.0002). Mortgage application rate was also similar in both groups with more of the CHD patients refused than matched controls (20 vs 3%, P = 0.004). These differences in both life insurance and mortgage remain significant when the cases and controls are matched by employment status and NYHA functional class. There was no significant difference in life insurance and mortgage application outcome between the groups of mild, significant and complex CHD. Conclusions: Adults with CHD are significantly more likely to have difficulty obtaining life insurance or a mortgage than controls. Refusal rates appear to be independent of the severity of CHD. This suggests that the label of CHD may have a negative impact despite the lesion being minor and that the outcome of an individual application is difficult to predict based on the severity of the CHD. The increasing numbers of adults with CHD suggest that this problem is likely to increase and needs to be addressed as it can have a major impact on the patient's quality of life.

Incompatibility of the major blood groups A, B, and O has been an absolute contraindication for heart transplantation. However, because of immunologic immaturity, infants may have relative protection from hyperacute rejection and thus could undergo transplantation with ABO-mismatched organs.Since January 2000, the authors have adopted a policy of considering infants for ABO-incompatible heart transplantation. Serum isohemagglutinin titers were measured before, during, and after transplantation. Two infants (3 and 2 months old) and a 21-month-old child underwent ABO-incompatible heart transplantation. During cardiopulmonary bypass, plasma exchange was performed. No other antibody-removal procedures were performed. A routine immunosuppressive regimen was used, and rejection was monitored by endomyocardial biopsies. An additional two patients (31 and 18 months old) were worked up but were unsuitable for ABO-incompatible transplantation because of high isohemagglutinin titers. They were successfully bridged to transplantation and received heart transplants from ABO-compatible donors.All three infants with ABO-incompatible heart transplants are fit and well, 40 months, 30 months, and 12 months postoperatively. All three had serum antibodies to antigens of the donor's blood group before transplantation. No hyperacute rejection occurred. No morbidity attributable to the ABO incompatibility has been observed.ABO-mismatched heart transplantation may be undertaken safely and without any short-term adverse consequences in infants and young children in whom isohemagglutinin production is not yet established.

tion of 5-HT6 receptor mRNA expression by in situ hybridization we applied theQuantiGeneViewRNAplatform fromAffymetrix.We usedMultiplex analysis to study co-expression of a range of neuronal genes. Frozen sections throughout the brains from male Sprague Dawley rats were hybridized for 5HT6 receptors. Following total mapping, 5-HT6 receptor mRNAvisualization was combined with probes for a range of neurotransmitters or interneuron markers. The sectins were analyzed by bright field and fluorescent microscopy. Results: Detection of target genes was both sensitive and specific. 5-HT6 receptor mRNA was expressed exclusively in neurons. The highest expression levelwas detected inmedium spiny neurons in caudate putamen and in nucleus accumbens, and in the olfactory tubercle. The striatal neurons also expressed GAD67, calbindin and D1/D2 receptors. 5-HT6 mRNA was moderately expressed in hippocampus and throughout cortical regions. These neurons co-expressed the glutamatergic marker vGluT1. Furthermore, weak to moderate expression of cholecystokinin and calbindin mRNAwas detecetd in 5-HT6-receptor-positive cortical and hippocampal neurons. The majority of GAD67positive GABAergic interneurons (in cortex, hippocampus, striatum) did not express 5-HT6 receptor mRNA. However, a weak to moderate signal for 5HT6 receptors was present in a subset of calbindinand calretinin-positive GABAergic interneurons. 5-HT6 receptors did not co-localizewith parvalbumin in forebrain structures. 5-HT6 receptor mRNAwas not expressed in serotonergic, dopaminergic or cholinergic neurons, nor was the receptor co-expressed with somatostatin, VIP or NPY. Conclusions: 5-HT6 receptor mRNA is strongly expressed in GABAergic medium spiny neurons and moderately expressed in glutamatergic neurons. A subset of calretininand calbindin-positive GABAergic interneurons express 5-HT6 receptor mRNA. The present data provide new insights to interpret the mechanism of 5-HT6 receptor signalling.

BACKGROUND: WHO grade II low-grade gliomas (LGGs) with high risk factors for recurrence are mostly lethal despite current treatments, and novel approaches are needed. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in human leukocyte antigen (HLA)-A2+ adults with high-risk LGGs in the following three cohorts: 1) newly diagnosed patients without prior radiation therapy (RT); 2) newly diagnosed patients with prior RT, and 3) recurrent patients. METHODS: GAAs were interleukin-13 receptor (IL-13R)α2, EphA2, Wilms Tumor (WT)1, and Survivin, and synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for 8 courses with intramuscular injections of Toll-like receptor 3 agonist Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose (poly-ICLC), followed by q12-week booster vaccines. Primary endpoints were safety and CD8+ T-cell responses against vaccine-targeted GAAs. RESULTS: Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity has been encountered except for one case with Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 fever (Cohort 1). Enzyme-linked Immuno-SPOT (ELISPOT) assays demonstrated robust and sustained interferon (IFN)-γ responses against at least 3 of the 4 GAA epitopes in 10 and 4 cases of Cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFN-γ ELISPOT responses than Cohort 3 patients, suggesting newly diagnosed patients have superior vaccine-responsiveness to recurrent patients. IFN-γ ELISPOT response levels in this study is significantly higher than those observed in our previous phase I/II study in high-grade glioma patients (Okada et al. JCO 2011). Furthermore, IFN-γ ELISPOT response levels were significantly higher than those for IL-5, indicating effective type-1 skewing by the current regimen. Median progression-free survival (PFS) periods are 21 months (Cohort 1; since diagnosis; range 10-42) and 12 months (Cohort 3; since the 1st vaccine; range 3-26). The only patient with large astrocytoma in Cohort 2 has been progression-free for over 58 months since diagnosis. There was a positive trend between IFN-γ ELISPOT responses and progression-free survival (PFS) in Cohort 3 patients (P = 0.08 by The Cox proportional hazards model). CONCLUSIONS: The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade II LGG patients. These results suggest these patients may be suitable populations for vaccine therapy and warrant further evaluations of this approach. SECONDARY CATEGORY: Clinical Neuro-Oncology.

Objective: 1) To examine the clinical differences between AD and AD with Lewy bodies (AD+LB); and 2) to determine the accuracy of Consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) at different levels of dementia severity. Methods: The authors examined the clinical characteristics of 185 patients with pathologically diagnosed AD alone and 60 with AD+LB. The relationship between clinical symptoms and AD+LB was determined by multivariate analyses, controlled by age, duration of symptoms, presence of cerebrovascular disease, and dementia severity. Results: Mild dementia syndrome: No specific clinical symptom was associated with the presence of AD+LB. The sensitivity of the diagnosis of DLB was 62% and specificity was 54%. Moderate dementia syndrome: Extrapyramidal signs (EPS), especially cogwheel rigidity, and major depression were associated with AD+LB. The sensitivity for DLB was 82% and specificity was 31%. Severe dementia syndrome: Cogwheel rigidity and diurnal hypersomnia were associated with AD+LB. The sensitivity for DLB was 93% and specificity was 16%. Conclusions: The presence of EPS is not useful in differentiating AD+LB from AD in patients with mild dementia. However, as the disease progressed, they emerge as defining features, especially cogwheel rigidity. The accuracy of AD+LB diagnosis varies according the severity of the dementia syndrome. The low sensitivity and specificity in AD+LB patients with mild dementia suggest that in early stages AD+LB patients do not present the clinical characteristics of DLB. By contrast, the high sensitivity and low specificity for the diagnosis of DLB in moderate/severe dementia stages suggests that AD patients can also have characteristic symptoms of DLB. These results indicate that the antemortem diagnosis of AD+LB is difficult in all dementia stages, and better clinical and biologic differentiations of these entities are needed.

Fifty one years have passed since grossand Crafoord independently reported successful repair of aortic coarctation. One could be forgiven for assuming that all the surgical controversies have now been settled. This is far from the case, as the numerous publications (frequently with opposing view points) related to timing, technique and complications bear testament. Perhaps the passage of the golden anniversary of this operation should stimulate a degree of reflection among surgeons and cardiologists.

There are no data comparing patient attitudes to sternotomy and thoracotomy scars following surgery for congenital heart disease (CHD).Two hundred and one patients with a scar from CHD surgery (105 sternotomy, 36 thoracotomy, and 60 both scars) had a structured interview to explore attitudes to their scar.Comparable proportions of each group reported that they did not like or hated their scar (23/105 [22 %] sternotomy, 9/36 [25 %] thoracotomy, 17/60 [28 %] both scars). Significantly more patients stated that they where embarrassed by and/or their choice of clothing was affected by a thoracotomy scar (20/36, 56 %) than those with a sternotomy scar (36/105, 34 %), p = 0.04. This was also seen when comparing sternotomy alone with both scars (36/105 [34 %] vs. 34/60 [57 %], p = 0.008).Adults who have undergone surgery for CHD are more likely to have a negative attitude to a thoracotomy than a sternotomy scar. Before a change in surgical approach is considered based on patient preferences, the acceptability and psychological impact of the different scars following surgery needs formal study.

Summary. It is well established that both cyclosporin and nifedipine are associated with gingival overgrowth. However, there is little information on the prevalence of this undesirable effect in paediatric patients. The present study investigated gingival overgrowth in 19 cardiac transplant patients aged 2 years 8 months to 16 years 3 months (1.5–8.5 years post-transplant) and related such changes to variables of daily cyclosporin dosage, trough blood cyclosporin concentration and daily nifedipine dosage. Ten patients showed clinically significant gingival overgrowth and nine relatively minor overgrowth; there was no significant difference between the two groups with respect to age, length of time post-transplant, cyclosporin dosage, whole blood concentration of cyclosporin or intake of nifedipine. The expression of gingival changes therefore did not relate to any drug variable in this group of subjects. Resume. Hypertrophic gingivale chez les enfants transplantes cardiaques: etude de 19 patients âges de 2 a 16 ans Il est connu que la cyclosporine et la nifedipine sont associes a l'hypertrophie gingivale. Mais peu d'informations sont disponibles sur la prevalence de cet effet indesirable chez les patients pediatriques. L'etude a porte sur l'hypertrophie gingivale chez 19 patients transplantes cardiaques âges de 2 ans 8 mois a 16 ans 3 mois (1 an et demi a 8 ans et demi apres transplant) et a enregistre les variations de cyclosporine et de nifepidine dans le sang par des analyses sanguines quotidiennes. Dix patient avaient une hypertrophic gingivale clinquement significative et neuf une hypertrophic relativement mineure; il n'y avait pas de difference significative entre les deux groupes par rapport a l'âge et a l'anciennete du transplant, la dose de cyclosporine, la concentration en cyclosporine sanguin et la prise de nifepidine. L'hypertrophie gingivale n'etait donc en rapport avec aucune des variables medica-menteuses dans ce groupe de patients. Zusammenfassung. Uebermassiges gingvales Wachstum bei padiatrischen Patienten mit Herztransplantation, eine Studie von 19 Patienten zwischen 2 und 16 Jahren Es ist bekannt, dass die Medikamente Cyclosporin und Nifedipine ein ubermassiges Wachstum der Gingiva verursachen aber es ist wenig bekannt uber die Hautigkeit dieser unerwunschten. Nebenwirkung bei padiatrischen Patienten. Diese Studie untersuchte diese Nebenwirkung bei 19 Patienten im Alter von 2 Jahre 8 Monate bis 16 Jahre 3 Monate (1 1/2 bis 8 1/2 Jahre nach der Transplantation). Man bezog diese Aenderungen zu den verschiedenen Cyclosporin-Tagesdosen, der Blutkonzentration von Cyclosporin und den Tagesdosen von Nifedipine. Bei 10 Patienten fand main ein 1 klinisches, signifikantes, ubermassiges. Gingivawachstum und bei den restlichen 9 Patienten nur ein geringes Wachstum. Man fand keinen signifikanten Unterschied zwischen den beiden Gruppen bezuglich des Alters, der Zeitspanne seit der Transplantation, der Cyclosporin-Dosierung, der Blutkonzentration oder der Nifedipine-Einnahme. Dementsprechend wurde keine Beziehung gefunden zwischen den Gingivaveranderung zu irgendeiner medikamentusen Variabilitat bei den Probanten dieser Gruppe. Resumen. Hiperplasia gingival en ninos con transplantes cardiacos: estudion en 19 ninos de 2 a 16 anos Parece claro que la ciclosporina y nifedipina se asocia a crecimiento o hiperplasia gingival exagerada. Hay poca informacion sobre la prevalencia de este efecto indeseable en pacientes pediatricos. El presente estudio investigo hipertrofia gingival en 19 pacientes pediatricos con transplante cardiaco con edades de 2 anos 8 meses a 16 anos y 3 meses y relata los cambios segun la dosis diaria de ciclosporina. 10 pacientes mostraron sobrecrecimiento gingival clinico y 9 sobrecrecimiento relativamanete menor. No hubo diferencias significativas entre los grupos con respecto a la edad, tiempo post-transplante, dosis de ciclosporina, concentracion de ciclosporina en sangre o de nifedipina. Los cambios gingivales no tuvieron correlacion con nicnguan de las variables estudiadas en este grupo de sujetos.

To test the hypothesis that newly synthesized cholesteryl esters are required for hepatic lipoprotein assembly and secretion, isolated livers of African green monkeys were perfused with medium containing an ACAT inhibitor. Three ACAT inhibitors with different structural and chemical properties were used: CI-976 (Parke-Davis), CP-113818 (Pfizer), or PD-138142-15 (Parke-Davis). Each compound produced variable effects on secretion of lipids and apolipoproteins. A significant decrease in the secretion rates of cholesteryl ester and apoB was common to all three inhibitors, indicating that fewer lipoprotein particles were secreted during ACAT inhibition. Triacylglycerol secretion was decreased in the presence of CP-113818 and PD-138142-15 but no decrease in triacylglycerol secretion was observed with CI-976. Particles secreted in the presence of CI-976 were enriched in triacylglycerol relative to apoB. Effects on secretion of other apolipoproteins (apoA-I, apoA-II, and apoE) were variable. When all data were combined, the percent inhibition of cholesteryl ester secretion and apoB secretion in the presence of ACAT inhibitors was positively correlated (r = 0.84), whereas a similar relationship was not observed between triacylglycerol and apoB. While the results demonstrate some lack of specificity for these ACAT inhibitors, the complimentary results using the three different ACAT inhibitors suggest that secretion of cholesteryl ester and apoB are coordinately regulated. The data suggest that newly synthesized cholesteryl esters may participate in and promote the assembly and secretion of hepatic apoB-containing lipoproteins. The availability of triacylglycerol during lipoprotein assembly, while also important, would appear to serve a role separate from that of cholesteryl ester.

To determine whether testing for isolated 1p or 19q losses, or as a codeletion, has any significance in the workup of glioblastomas (GBMs).Upfront 1p/19q testing by fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) was done in 491 gliomas that were histologically diagnosed as GBMs. Outcomes were determined and measured against 1p/19q results.Twenty-eight showed apparent 1p/19q codeletion by either FISH and/or PCR-based LOH, but only 1/26 showed codeletion by both tests. Over 90% of tumours with apparent codeletion by either FISH or LOH also had 10q LOH and/or EGFR amplification, features inversely related to true whole-arm 1p/19q codeletion. Furthermore, only 1/28 tumours demonstrated an R132H IDH1 mutation. Neither 1p/19q codeletion by FISH nor LOH had an impact on GBM survival. Isolated losses of 1p or 19q also had no impact on survival.These data suggest that (i) 1p/19q testing is not useful on gliomas that are histologically GBMs; (ii) codeletion testing should be reserved only for cases with compatible morphology; and (iii) EGFR, 10q, and IDH1 testing can help act as safeguards against a false-positive 1p/19q result.

Anomalous origin of the left coronary artery from the pulmonary artery requires surgical correction. A surgical technique is presented. Two infants underwent re-implantation of their anomalous left coronary arteries by creating a tunnel using autogenous aortic and pulmonary arterial walls. The advantage of this technique is that the new left coronary artery lies in the horizontal plane and in an anatomically correct axis running in the groove behind the pulmonary artery. It also provides a tension free endothelialized autogenous arterial walls with normal growth anticipated.

We have mutagenized the human apoA-I gene and have generated cell lines which express normal and mutant apoA-I forms. Point mutations were introduced which changed Gln-1, Gln-2 to Arg,Arg, Pro99 to His, and Pro121 to His. In addition, the following amino acid deletions (delta) were generated: delta 113-124, delta 148-186, delta 212-233, and delta 213-243. The apoA-I form isolated from the culture medium of C127 cells was analyzed for its ability to activate lecithin-cholesterol acyltransferase (LCAT) and to bind to phospholipid vesicles and high density lipoprotein (HDL). Compared with the wild type (WT) apoA-I, the relative activation of LCAT achieved by the point mutations Gln-1, Gln-2----Arg,Arg, Pro99----His, and Pro121----His were 106 +/- 7, 92 +/- 6, and 77 +/- 9%, respectively. Kinetic analysis of one mutant apoA-I form showed similar Vmax but a 15-fold increase in the Km of the mutant apoA-I form. Furthermore, the activation achieved by the internal deletion mutants delta 113-124, delta 148-186, delta 212-233, and delta 213-243 was 47 +/- 3, 0.5 +/- 0.4, 28 +/- 4 and 13 +/- 5%, respectively. Mutants deficient in their ability to activate LCAT displayed alterations in liposome and HDL binding, compared with WT as determined by density gradient ultracentrifugation analysis of the culture medium. Thus, the peak recovery (approximately 50%) of apoA-I bound to HDL was at density 1.14 g/ml for the WT apoA-I, at 1.18 g/ml for the mutants delta 113-124 and delta 148-186, and at d greater than 1.21 g/ml for the delta 212-233 and delta 213-243. Electron microscopy of the proteoliposome LCAT substrate generated by WT and mutant apoA-I forms showed that the carboxyl-terminal deletion mutants which displayed aberrant binding to HDL also displayed reduced ability to convert the spherical lecithin-cholesterol vesicles into discs compared with WT. The findings suggest that (a) the importance of the carboxyl terminus of apoA-I for LCAT activation is related to its ability to bind to lipid and/or to form discoidal substrate for LCAT, and (b) the interaction of several domains of apoA-I are required for the activation of LCAT.

The Ross procedure for aortic valve replacement was introduced at two paediatric cardiac centres (Freeman Hospital, Newcastle, and Royal Liverpool Children's Hospital) where surgeons had no previous experience of this technique. A structured programme of training and cooperation between the two centres enabled surgeons to minimise the learning curve for this procedure. We share our experience and suggest options for surgeons who wish to undertake new procedures in the current era of surgical practice and clinical governance. Issues of informed consent and risk stratification remain. #### Summary points Surgeons have always recognised the concept of a learning curve when undertaking a new procedure Recent events mean that there is a lack of professional and public tolerance for suboptimal results due to a learning curve Learning a new technique, even for an established consultant, requires some sort of learning curve Introducing a new procedure in a structured way that incorporates formal training courses, cadaveric resection, and assistance from expert practitioners can reduce the learning curve The recent General Medical Council (GMC) inquiry into the Bristol Paediatric Cardiac Surgical Unit highlighted many concerns common to all surgical specialties. At the end of the judgment, the president of the GMC listed 13 issues that the professions should address, and the senate of surgery recently published its response.1 The concept of a learning curve, which has long been recognised by surgeons, was of particular consequence. However, the senate responded that “there should be no learning curve as far as patient safety is concerned.”1 To learn to perform a new procedure without having a learning curve is a dilemma that we, as established consultants in paediatric cardiac surgery, faced when we wanted to introduce the Ross procedure into our surgical practice. We discussed strategies which we hoped would reduce the steepness of our learning curve, and …

Over a 2-year period (1987-1988), 31 children (3% of 960 operations) were found to have a paralysed diaphragm following cardiac surgery. The median age was 5 months with 65% less than 1 year of age. In the 31 patients, 38 paralysed diaphragms were identified. The phrenic nerve injury was on the right in 8 cases, the left in 16, bilateral in 7 and 40% were related to modified Blalock Taussig shunts. The time to extubation was analysed for each patient in two separate groups: Group A: (greater than 1 year): 11 children of whom 5 were extubated without difficulty, 4 had non-respiratory reasons for prolonged ventilation and only 2 were plicated--both were extubated within 4 days. Group B: (less than 1 year): 20 infants of whom 16 were plicated and 4 were not. Three of the children who were plicated died from cardiac causes. Of the 13 survivors, there were 3 who had other reasons for prolonged ventilation. Thus 10 infants required prolonged ventilation (mean 11 days) because of respiratory difficulties. All underwent plication and were extubated at a mean of 2.4 days postoperatively. The 4 who were not plicated were extubated at a mean of 11 days postoperatively. In infants in whom there is no cardiac cause for failure to wean from ventilation, diaphragmatic paralysis should be suspected and plication performed if not extubated 2 weeks after operation.

Although ABO blood group incompatible cardiac transplantation in neonates and infants reduces waiting list mortality without compromising outcome, the technique has not been adopted by all centers, and to date Toronto remains the only center to have published results from a large case series. We present a review of ABO-incompatible heart transplantation in the United Kingdom (UK) where current recipient selection criteria differ somewhat from those used in the United States (US) and Canada. Between February 2000 and November 2006, 21 ABO-incompatible cardiac transplants were performed in children aged 2-40 months (median 10.0). Immunosuppression followed standard regimens. Pretransplant donor-specific isohemagglutinins of >1:4, (the UNOS cutoff), were present in five patients and reduced by plasma exchange. After transplantation, 19/21 recipients demonstrated persisting deficiency of donor-specific isohemagglutinins. Significant donor-specific isohemagglutinins levels were detected repeatedly in 2/21 recipients who have shown no clinical or biopsy evidence of rejection. All recipients survive without retransplantation and there have been no episodes of humoral rejection. We conclude it is possible for other centers to replicate the excellent results achieved in Toronto and that ABO-incompatible transplantation may be performed successfully in some patients beyond infancy with established isohemagglutinin production providing preoperative antibody removing strategies are used.

Objective: To determine the relationship between major depression and the presence of Lewy bodies (LBs) in patients with Alzheimer disease (AD). Methods: The authors examined the presence of major depression in 267 pathologically diagnosed AD cases with Mini-Mental State Examination (MMSE) scores >9. LBs were identified in 142 (53%) patients using alpha-synuclein immunohistochemistry. Subjects were classified according to the Consensus Guidelines for the Clinical and Pathologic Diagnosis of Dementia with LB: 1 to 2 (n = 21), 3 to 6 (n = 26), and 7 to 10 (n = 69). Twenty-six patients had LB only in the amygdala. All cases with LB scores 7 to 10 (or cortical) had amygdala LBs. The association between LBs and major depression was examined with logistic regression analyses, controlled for age at study entry, education level, MMSE scores, antidepressant use, follow-up time, and the presence of cerebrovascular disease. Results: Major depression was present in 11 (9%) AD alone cases, and in 25 (18%) of the AD + LBs cases; amygdala: 8 (31%), scores 1 to 2: 1 (5%), scores 3 to 6: 3 (11.5%), and scores 7 to 10: 13 (14%). Major depression was associated with LBs, in general (relative risk [RR] = 3.06, 95% CI: 1.25 to 7.46), with amygdala only LBs (RR = 8.56 (95% CI: 1.83 to 40.3), and with LB scores 7 to 10 (RR = 3.83, 95% CI: 1.33 to 11.0). There was an association between all amygdala LBs cases (amygdala only LBs + LB scores 7 to 10) and major depression (RR = 4.77, 95% CI: 1.78 to 12.7), but no association was noted between LBs and depression in the absence of amygdala LBs (RR = 0.96, 95% CI: 0.46 to 1.06). Conclusion: Lewy bodies (LBs) in the amygdala and in cortical areas increase the risk for major depression in Alzheimer disease. What is common in these two groups is the presence of LBs in the amygdala. That is, all of the cases with cortical LBs also had LBs in the amygdala, making this region the critical area for the development of depression.

Fig. 1. Transverse midesophageal plane at 458, demonstrating the short axis of the aortic valve in diastole. The ruptured aneurysm of the right coronary sinus protrudes into the right atrium just above the tricuspid valve producing the characteristic ‘windsock’ appearance described in textbooks. Colour-flow Successful surgical repair of a ruptured sinus of Valsalva aneurysm was performed in a 30-year-old man, presenting with acute onset dyspnoea. Transoesophageal echocardiography demonstrated the characteristic ‘windsock’ appearance of the aneurysm described in textbooks and the continuous flow between the aorta and the right atrium corresponding to a continuous murmur. During surgery an 8 mm opening was identified in the right coronary sinus leading into the right atrium, the aneurysm tissue in the right atrium was excised and the base oversewn, whilst a patch of pericardium was used to close the defect from the aortic end (Figs. 1 and 2). Doppler demonstrates continuous blood flow through the ruptured aneurysm between the aorta and the right atrium, corresponding to the continuous murmur. RA (right atrium), LA (left atrium), RV (right ventricle), TV (tricuspid valve), PV (pulmonary valve), PA (pulmonary artery), LCC (left coronary cusp), NCC (non-coronary cusp), RCC (right coronary cusp). Appendix. Supplementary material

To compare the outcome of life insurance and mortgage applications of adults with congenital heart disease (CHD) with controls and at different severities of CHD.Two hundred and ninety-nine adult CHD patients underwent a questionnaire-based interview by a trained nurse. They were asked to give an identical questionnaire to a friend to act as a control. One hundred and seventy-seven controls replied. CHD patients were classified into three categories based on severity. Comparisons were made between matched controls and between different severities of CHD.Similar proportions of the CHD group (59%) had applied for life insurance as matched controls (56%). Compared to controls, significantly more of the adults with CHD who had applied for life insurance have been refused (34 vs 4%, P0.0001) or asked to pay extra (37 vs 6%, P = 0.0002). Mortgage application rate was also similar in both groups with more of the CHD patients refused than matched controls (20 vs 3%, P = 0.0004). These differences in both life insurance and mortgage remain significant when the cases and controls are matched by employment status and NYHA functional class. There was no significant difference in life insurance and mortgage application outcome between the groups of mild, significant and complex CHD.Adults with CHD are significantly more likely to have difficulty obtaining life insurance or a mortgage than controls. Refusal rates appear to be independent of the severity of CHD. This suggests that the label of CHD may have a negative impact despite the lesion being minor and that the outcome of an individual application is difficult to predict based on the severity of the CHD. The increasing numbers of adults with CHD suggest that this problem is likely to increase and needs to be addressed as it can have a major impact on the patient's quality of life.

Alzheimer's disease (AD) is one of the most common causes of dementia, but requires neuropathological verification for a definitive diagnosis because there are a number of other neurodegenerative diseases that may present with dementia. Some of these disorders have considerable overlap both clinically and pathologically with AD, while others have distinct clinical and pathological profiles. Vascular dementia and dementia with Lewy bodies (DLB) have the greatest overlap with AD and considerable controversy still surrounds the exact contribution of the non AD pathology to the dementia syndrome. The frontotemporal dementias are loosely united by clinical presentation, but are pathologically heterogeneous and include Pick's disease, dementia lacking distinctive histopathology, motor neuron disease inclusion dementia and corticobasal degeneration (CBD). CBD can be difficult to distinguish from progressive supranuclear palsy, especially when the latter lacks the distinctive gaze palsy. Finally, Creutzfeldt Jakob disease (CJD) may be difficult to distinguish from AD when the symptoms progress at an atypically slow pace. Recently, a new variant of CJD (vCJD) that has been linked to bovine spongiform encephalopathy ('mad cow' disease) has heightened awareness of these prion protein disorders. The neuropathological criteria for the diagnosis of these non AD dementia disorders will be reviewed.

The uncertainty regarding the nosology and significance of Lewy bodies (LB) in dementia is still very present in current research. It is an acknowledged fact that an important number of cases of Alzheimer s disease (AD) also present LB. These can be detected by a synuclein immunohistochemistry in most of the sporadic cases of AD and is most frequently detected in the amygdala.Although the role of LB and the filaments of Lewy in the pathogenesis of dementia has still to be determined, it is clear that alphya-synuclein immunohistochemistry represents an important advance in the evaluation of the neuropathological changes in AD and in associated dementias.

Brain tumors as a group are the most common solid tumors of childhood and currently have the highest mortality rate. A major emphasis has historically been placed on stratifying therapy for these tumors based on histologic and clinical prognostic factors. However, with the increasing application of molecular approaches to refine the categorization of these tumors, it has become apparent that histologically comparable lesions may exhibit diverse patterns of gene expression and genomic alterations, which may correspond with important prognostic distinctions. This paper summarizes these observations and discusses how they are being applied in a preliminary fashion as a foundation for risk-adapted stratification of childhood brain tumor therapy.

Objectives: Paraplegia following coarctation repair occurs in 0.4% of infants. However, for older children, adults and re-operations, the incidence can be as high as 2.6%. Yet there is no consensus on the need for spinal cord protection or the optimal method. This paper reports our experience with left heart bypass (LHB) in adult and re-do coarctation. Methods: Between 1997 and 2000, nine patients underwent elective resection of coarctation (three re-dos, two balloons) with a mean age of 17.9 years (range, 8–44) and weight of 52 kg (range, 17.3– 109). The mean trans-coarctation gradient was 29.6 mmHg (range, 20–45). Patients were placed on LHB using a centrifugal pump with full heparinization through a fourth-space thoracotomy. Patients were cooled to 31–348C for additional spinal cord protection. Repair was carried out with an inter-positional graft (5/9), a Gore-Tex patch (2/9) or end-to-end anastomosis (2/9). The mean cross-clamp and bypass times were 36.4 (range, 19–65) and 40.3 min (range, 22–70), respectively. Results: No patient developed transient or permanent paraplegia. The mean peak creatinine was 80 mmol/l (range, 51–123). Conclusions: LHB is simple, easy and safe to implement, and is the only technique capable of maintaining independent upper and lower body perfusion pressure. Potentially, it provides the best spinal cord protection, and extends the margin of safety and time to execute an accurate repair. q 2001 Elsevier Science B.V. All rights reserved.

Malignant astrocytoma is one of the most deadly primary central nervous system tumors. Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively little analysis has been done in childhood astrocytomas, which are less common and have a more favorable prognosis. Our previous studies of an institutional cohort of children with malignant gliomas suggested the existence of distinct molecular pathways of tumorigenesis in younger versus older children, based on the finding of a high frequency of TP53 mutations in tumors from children3 years of age at diagnosis, compared with those from younger children. In the current study, the association between TP53 mutations and age was examined in greater detail using the multi-institutional group of children enrolled in Children's Cancer Group Study 945, the largest cohort of childhood high-grade gliomas analyzed to date. Seventy-seven tumors with centrally reviewed diagnoses of anaplastic astrocytoma or glioblastoma multiforme had sufficient archival histopathological material for microdissection-based genotyping. Sections were examined histologically, and topographic targets that contained malignant tissue were isolated by microdissection and subjected to PCR-based amplification and sequencing of TP53 exons 5-8. Twenty-six tumors (33.8%) had mutations in those exons. Mutations were observed in 2 of 17 tumors (11.8%) from children3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children, a difference that was statistically significant (P = 0.04), in agreement with our previous results. Whereas malignant gliomas in older children have a frequency of mutations comparable to tumors that arise in young adults, those from children3 years old do not. The association between age and frequency of TP53 mutations among pediatric malignant gliomas indicates the probable existence of two distinct pathways of molecular tumorigenesis in younger versus older children.

Studies have demonstrated alterations in brain membrane phospholipid metabolite levels in Alzheimer's disease (AD). The changes in phospholipid metabolite levels correlate with neuropathological hallmarks of the disease and measures of cognitive decline. This 31P nuclear magnetic resonance (NMR) study of Folch extracts of autopsy material reveals significant reductions in AD brain levels of phosphatidylethanolamine (PtdEtn) and phosphatidylinositol (PtdIns), and elevations in sphingomyelin (SPH) and the plasmalogen derivative of PtdEtn. In the superior temporal gyrus, there were additional reductions in the levels of diphosphatidylglycerol (DPG) and phosphatidic acid (PtdA). The findings are present in 3/3 as well as 3/4 and 4/4 apolipoprotein E (apoE) genotypes. The AD findings do not appear to reflect non-specific neurodegeneration or the presence of gliosis. The present findings could possibly contribute to an abnormal membrane repair in AD brains which ultimately results in synaptic loss and the aggregation of A beta peptide.

Background . In the absence of reliable national data, we have collected results of all operations for congenital heart defects from five departments to assess mortality rates and compare them among surgeons and departments. Methods . Data relating to all operations (2,718) carried out at the five centers during a period from April 1, 1997 through March 31, 1999. Clearly defined criteria were agreed for the classification of patients into various subgroups. Results . The overall hospital mortality was 4.4% (95% confidence intervals 3.7%–5.3%). Mortality for open operations was 12.6% in neonates, 5.1% in infants, and 3.5% in children. Mortality rates were 1.1% for coarctation, 0.4% ventricular septal defect, 4.1% atrioventricular septal defect, 2.9% Fallot, 0.9% switch, and 15.6% truncus arteriosus. Although individual surgeons' mortality rates ranged from 1.8% to 7.5%, none of the 12 surgeons' data were above 95% confidence intervals. For individual surgeons, the change in mortality rates between the 2 years ranged between −3.3% and +3.8%. Conclusions . With 2 years' data available, estimates of mortality rates are more precise as reflected by tighter confidence intervals. There were relatively small data sets for individual hospitals and surgeons, which made statistical evaluation difficult. For setting standards, data from more departments for a longer period will be required. Statistical methods alone cannot be used as a sole arbiter of what is considered acceptable performance.

Peripheral lymph lipoproteins have been characterized in animals, but there is little information about their composition, and none about their ultrastructure, in normal humans. Therefore, we collected afferent leg lymph from 16 healthy males and quantified lipids and apolipoproteins in fractions separated by high performance-size exclusion chromatography. Apolipoprotein B (apoB) was found almost exclusively in low density lipoproteins. The distribution of apoA-I, particularly in lipoprotein A-I (LpA-I) without A-II particles, was shifted toward larger particles relative to plasma. The fractions containing these particles were also enriched in apoA-II, apoE, total cholesterol, and phospholipids and had greater unesterified cholesterol-to-cholesteryl ester ratios than their counterparts in plasma. Fractions containing smaller apoA-I particles were enriched in phospholipid. Most apoA-IV was lipid poor or lipid free. Most apoC-III coeluted with large apoA-I-containing particles. Electron microscopy showed that lymph contained discoidal particles not seen in plasma. These findings support other evidence that high density lipoproteins (HDL) undergo extensive remodeling in human tissue fluid. Total cholesterol concentration in lymph HDL was 30% greater (P0.05) than could be explained by the transendothelial transfer of HDL from plasma, providing direct confirmation that HDL acquire cholesterol in the extravascular compartment. Net transport rates of new HDL cholesterol in the cannulated vessels corresponded to a mean whole body reverse cholesterol transport rate via lymph of 0.89 mmol (344 mg)/day.

Retroviruses were first described as the causative agent in avian sarcomas: Rous sarcoma virus and avian leukosis virus. The past 80 years have seen numerous other retroviruses identified and characterized, while the past 15 years have seen an explosion of research on the most infamous member, human immunodeficiency virus (HIV). Neurological manifestations of retroviral infection such as peripheral neuropathy, encephalopathy, and neuronal degeneration have been reported; however, the pathogenetic mechanisms remain elusive. This review will describe the neuropathology of these viral infections and detail possible events leading to neurodegeneration, focusing on recent publications.