A review of 15-year experience with anomalous origin of the left coronary artery.

BACKGROUND: Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare condition presenting in infancy with acute myocardial ischaemia. AIMS: A retrospective study was undertaken to assess the presenting features and long-term outcome of all cases of ALCAPA presenting to our institution over a 15-year period. METHODS: All the cases were located using the hospital discharge system and charts were reviewed. RESULTS: The mean age at diagnosis was 4.5 months (2 weeks to 16 months). The predominant presenting symptoms were irritability, pallor, and tachypnoea. The predominant electrocardiogram findings were Q waves and ST segment changes in the anterolateral chest leads. One died from the 11 patients in our series. CONCLUSION: The outcome for surgical re-implantation in infants with a diagnosis of ALCAPA is very good however, early diagnosis is crucial to survival. Although once successfully repaired, patients in general were free of symptoms, ventricular dysfunction was usually present, requiring long-term follow-up.

A stop codon in xeroderma pigmentosum group C families in Turkey and Italy: molecular genetic evidence for a common ancestor.

Xeroderma pigmentosum family G from Van, Turkey had two severely affected children: a son with multiple skin cancers who died at age 10 (XP67TMA), and an 8 y old daughter who began developing skin cancer before 3 y of age (XP68TMA). XP67TMA and XP68TMA cells were hypersensitive to killing by ultraviolet and the post-ultraviolet DNA repair level was 12-16% of normal. Host cell reactivation of an ultraviolet-treated reporter plasmid cotransfected with a vector expressing wild-type XPC cDNA assigned XP67TMA to xeroderma pigmentosum complementation group C. The XPC mRNA level was markedly reduced. Sequencing of the 3.5 kb XPC cDNA from XP67TMA showed a C-T mutation in XPC exon 8 at base pair 1840. This mutation converts the CGA codon of arginine at amino acid 579 to a UGA stop codon resulting in marked truncation of the 940 amino acid xeroderma pigmentosum C protein. Restriction fragment length polymorphism analysis of XPC exon 8 DNA in XP67TMA and XP68TMA showed that both affected children had a homozygous mutation and that both parents had heterozygous normal and mutated sequences at the same position consistent with a history of consanguinity in the family. The mutated allele also contained two XPC single nucleotide polymorphisms. The same mutated XPC allele was reported in an Italian family. Studies of 19 microsatellite markers flanking the XPC gene on chromosome 3 suggest that the XPC allele passed between Italy and Turkey approximately 300-500 y ago. This XPC allele containing a nonsense mutation is associated with severe clinical disease with multiple skin cancers and early death.

Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors.

Although renal cell carcinoma has been shown to respond to immunotherapy, renal cell carcinoma-specific rejection antigens and their corresponding CTL epitopes have rarely been described. The use of dendritic cells (DCs) transfected with mRNA isolated from tumor cells may allow specific immunotherapy even in cancers for which potent rejection antigens have not been identified. Here we show that DCs transfected with RNA isolated from renal cancer tissue are remarkably effective in stimulating tumor-specific T-cell response in vitro but do not cross-react with normal tissue antigens including antigens expressed by renal parenchyma. In contrast, the tumor-specific CTLs lysed allogeneic tumor but not allogeneic normal tissue targets, suggesting the presence of shared albeit unidentified antigens among renal carcinomas. CTL responses against telomerase reverse transcriptase (TERT) accounted in part for the reactivities against allogeneic tumors because renal tumor RNA-transfected DCs stimulated polyclonal CTL responses, which encompassed as a subcomponent a response against TERT. Nonetheless, the tumor-specific CTLs were consistently superior to the CTLs stimulated with TERT RNA-transfected DCs in recognizing and lysing tumor targets, suggesting that tumor-specific CTLs represent a polyclonal response providing more effective antitumor activity than T-cell responses directed against a single antigen in the form of TERT. Tumor RNA-transfected DCs were capable of stimulating T-cell reactivities not only against the primary tumor but also against metastatic tumors, although discrete differences in the antigenic repertoire expressed by these tissues were apparent. Thus, total tumor RNA-transfected DCs may represent a broadly applicable vaccine strategy to induce polyclonal and potentially therapeutic T-cell responses in renal cancer patients.

Manitoba aboriginal kindred with original cerebro-oculo- facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene.

Cerebro-oculo-facio-skeletal (COFS) syndrome is a rapidly progressive neurological disorder leading to brain atrophy with calcification, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low-to-normal birth weight; growth failure; brain dysmyelination with calcium deposits; cutaneous photosensitivity; pigmentary retinopathy, cataracts, or both; and sensorineural hearing loss. CS cells are hypersensitive to UV radiation because of impaired nucleotide excision repair of UV radiation-induced damage in actively transcribed DNA. The abnormalities in CS are associated with mutations in the CSA or CSB genes. In this report, we present evidence that two probands related to the Manitoba Aboriginal population group within which COFS syndrome was originally reported have cellular phenotypes indistinguishable from those in CS cells. The identical mutation was detected in the CSB gene from both children with COFS syndrome and in both parents of one of the patients. This mutation was also detected in three other patients with COFS syndrome from the Manitoba Aboriginal population group. These results suggest that CS and COFS syndrome share a common pathogenesis.

Increased ultraviolet sensitivity and chromosomal instability related to P53 function in the xeroderma pigmentosum variant.

The xeroderma pigmentosum (XP) variant (XPV) is a form of XP that has normal excision repair but shows defective DNA replication after UV irradiation. In developing various transformed fibroblast cell lines from these patients, we have found that there are significant phenotypic changes in transformed cells that seem to correlate with inactivation of p53. After transformation with SV40, XPV cell lines are only slightly UV sensitive, like their primary counterparts, but their sensitization with caffeine and the induction of sister chromatid exchanges (SCEs) by UV irradiation are greatly enhanced. After transformation by HPV16 E7, which targets the retinoblastoma cell cycle regulatory gene, there is no change in the UV sensitivity of XPV cells; but, when transformed by HPV16 E6 or E6 and E7 combined, there is a large increase in UV sensitivity and in the induction of SCEs. These changes are not associated with any detectable changes in the reactivation of an externally irradiated luciferase expression vector, the excision of cyclobutane pyrimidine dimers from bulk DNA, or unscheduled DNA synthesis and, therefore, do not involve excision repair. We suggest that if SCEs represent homologous recombination between sister chromatids, then in the absence of p53 function, the DNA chain arrest typical of UV-damaged XPV cells initiates strand exchange during recovery. In untransformed cells with normal p53, the preferred mode of recovery would then be replication bypass. The symptoms of elevated solar carcinogenesis in XPV patients may, therefore, be associated with increased genomic instability in cells of the skin in which p53 is inactivated by UV-induced mutations.

Excellent long-term functional outcome after an operation for anomalous left coronary artery from the pulmonary artery.

OBJECTIVE: The aim of this study was to review the results of operations for anomalous left coronary artery from the pulmonary artery and the late outcome for exercise capacity, left ventricular function, and mitral regurgitation. METHODS: Twenty-one patients underwent operations over an 18-year period (median age, 9 months; range, 6 weeks-26 years) with a median follow-up of 6.5 years (range, 2 months-18 years). In addition to clinical and echocardiographic follow-up, patients at our institution were also investigated with radionuclide scans (n = 10) and treadmill exercise testing (n = 8). RESULTS: There were no operative or late deaths (0%; 95% confidence interval [CI], 0% and 16%). Five patients required support with a left ventricular assist device. Eighteen patients are currently in New York Heart Association class I, and 3 patients are mildly symptomatic. On nuclear gated scan at a mean of 6 years after the operation, the left ventricular ejection fraction was 64% (SD, 3%) at rest and increased to 74% (SD = 3%) on exercise (95% CI for the difference, 6%, 14%; P =.001). Treadmill endurance was normal for age (9.8-14.5 minutes) in those old enough to exercise. On echocardiography (n = 18), the current fractional shortening was 34% (SD, 4%) in the 15 patients with normal or only mildly abnormal ventricular septal motion. Three patients have undergone mitral valve operations. The left ventricular end-diastolic dimension fell from 48 mm (SD, 5.8 mm) before surgery to 35.1 mm (SD, 5.2 mm) at 1 year after the operation, and the fractional shortening increased over the first year from 19.6% (SD, 9.3%) to 32.8% (SD, 5.9%; both P <.001). CONCLUSIONS: Long-term clinical outcome and left ventricular function are good, despite severe left ventricular dysfunction at presentation.

Therapeutic aerosol delivery during mechanical ventilation.

OBJECTIVE: To provide an overview of aerosol drug delivery during mechanical ventilation in the pediatric and adult populations. DATA SOURCES: Published articles and abstracts identified in a MEDLINE search (1984-July 1994) were reviewed. STUDY SELECTION: All articles and abstracts found, including review articles, in vivo and in vitro studies, case reports, and case series pertaining to issues involving aerosol delivery during mechanical ventilation, were reviewed. No predetermined selection criteria were used to exclude studies. DATA EXTRACTION: Percent delivery of the starting dose to either the patients or the various in vitro lung models, as well as each variable possibly affecting delivery for each study, were tabulated for each study reviewed. DATA SYNTHESIS: The delivery of therapeutic aerosols to endotracheally intubated and mechanically ventilated patients presents a unique challenge for healthcare providers. Delivery can be affected by the diameter of the endotracheal tube and ventilator circuitry, type of ventilator, ventilator modes, type of delivery device, and how the delivery device is operated and introduced into the ventilator circuitry. The drug being aerosolized may behave differently from one delivery system to another. The proper operation of each device requires attention to positioning in the ventilator circuit as well as the mode of ventilation. CONCLUSIONS: No apparent advantage exists for metered-dose inhalers with a large-volume adapter over jet nebulizers, as each method of delivery is capable of similar efficiency (5-15%). Sufficient attention to detail, including the use of an efficient nebulizer and/or adapter and proper placement and operating method, is required to provide optimal delivery. For bronchodilator administration, careful monitoring of outcomes will provide the most optimal dosing schedule.

Determinants of aerosolized albuterol delivery to mechanically ventilated infants.

An in-vitro lung model and a volume ventilator were used to evaluate the delivery of aerosolized albuterol through an infant ventilator circuit. We compared the following: continuous nebulization (CNA) and intermittent nebulization (INA); various nebulizer gas flows, 5.0, 6.5,and 8.0 L/min; and duty cycle of 33% and 50%. The efficiency and consistency of aerosol delivery by metered-dose inhaler (MDI) with four different spacer devices and by nebulizer positioned at the manifold and at the same position as the MDI were also evaluated. A volume ventilator (Servo 900B) was used with settings selected to reflect those of a moderately to severely ill 4-kg infant. A 3.5-mm endotracheal tube was used in all experiments. A specific type of nebulizer used (Airlife Misty Neb; Baxter; Valencia, Calif) and several spacers were studied (Aerochamber and Aerovent, Monaghan Medical Corporation in Plattsburgh, NY [corrected]; ACE, Diemolding Healthcare Division in Canastota, NY [corrected]; and an in-line MDI adapter, Instrumentation Industries Inc, Pittsburgh). CNA delivered significantly more aerosol to the lung model (4.8 +/- 0.6% of the starting dose) than INA (3.8 +/- 0.3%; p<0.01). There was a significant stepwise decrease in aerosol delivery with increasing nebulizer flow (4.8 +/- 1.3% at 5.0 L/min; 3.7 +/- 1.1% at 6.5 L/min; and 2.7 +/- 1.1% at 8.0 L/min). Increasing duty cycle did not significantly affeet delivery. Overall the spacers with MDI were more efficient than the nebulizer in either position delivering about twice the percentage of the starting dose than the nebulizers. All modes of delivery, except the Aerochamber, demonstrated a marked degree of variability. Most of the starting dose of albuterol either remained in the nebulizer (30.4 +/- 6.0% at 5.0 L/min and 25.3 +/- 4.1% at 8.0 L/min) or was deposited in the inspiratory tubing (34.7 +/- 0.7% at 5.0 L/min and 43.7+/- 4.9% at 8.0 L/min) in our system. In conclusion, we have confirmed that aerosol delivery depends on the mode of delivery and the operating conditions. Although delivery with an MDI and spacer is more efficient than a nebulizer, both methods may produce high variability depending on the method or spacer used.

Postoperative follow-up of fibromuscular subaortic stenosis.

OBJECTIVES: This study attempted to determine whether early subaortic resection at lower levels of obstruction reduces the rate of recurrence of subaortic stenosis or reduces secondary damage to the aortic valve, or both. BACKGROUND: Fibromuscular subaortic stenosis is a progressive condition, and at present it is unclear whether early operation reduces the recurrence rate along with decreasing the incidence of aortic insufficiency. METHODS: Thirty-seven patients with fibromuscular subaortic stenosis and no other significant cardiac abnormality who underwent open subaortic resection were evaluated. The preoperative, early and late postoperative catheterization or echocardiographic findings as well as the operative reports were reviewed. The median age at operation was 6.4 years (range 1.1 to 17.3). The entire group has been followed up postoperatively for a median of 5.2 years (range 1.1 to 11). Mean systolic gradients across the left ventricular outflow tract were used for the purpose of this study. RESULTS: There was a significant correlation between the preoperative mean systolic gradient and the incidence of preoperative aortic regurgitation and late postoperative aortic valve thickening as well as the incidence and degree of late postoperative aortic regurgitation. Late postoperative gradient and degree of aortic regurgitation correlated significantly with the follow-up interval. Aortic regurgitation was progressive in some patients despite subaortic resection. A preoperative mean gradient > 30 mm Hg provided a reasonable cutoff for the likelihood postoperatively of needing a reoperation, having a postoperative shelf, a thickened aortic valve, moderate aortic regurgitation or a gradient of > 10 mm Hg. CONCLUSIONS: Our results suggest that although early subaortic resection may not reduce the rate of recurrence of fixed subaortic stenosis, it is likely to reduce acquired damage to the aortic valve.

Pediatric transesophageal echocardiography in the evaluation of acute disruption of the mitral valve following blunt thoracic trauma: case report.

Disruption of the mitral valve following blunt thoracic trauma has been only occasionally reported. A case of a pediatric patient with this complication is presented and the value of transesophageal echocardiography in diagnosis and management is documented.