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BACKGROUND & AIMS: Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population-based study of 1066 individuals from Utah and California. METHODS: The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability. RESULTS: Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01). CONCLUSIONS: We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.

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AIM: To assess guidelines for the emergency triage, assessment, and treatment (ETAT) of sick children presenting to hospitals in the developing world. This study pretested the guidelines in Malawi, assessing their performance when used by nurses compared to doctors trained in advanced paediatric life support (APLS). METHODS: Triage was performed simultaneously by a nurse and assessing doctor on 2281 children presenting to the under 5s clinic. Each patient was allocated one of three priorities, according to the ETAT guidelines. Any variation between nurse and assessor was recorded on the assessment forms. RESULTS: Nurses identified 92 children requiring emergency treatment and 661 with signs indicating a need for urgent medical assessment. One hundred and forty two (6.2%) had different priorities allocated by the APLS trained doctor, but these children did not tend to need subsequent admission. Eighty five per cent of admissions were prioritised to an emergency or urgent category. CONCLUSION: Although there are no gold standards for comparison the ETAT guidelines appear to reliably select out the majority of patients requiring admission.

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AIMS: To evaluate the performance of guidelines for emergency triage and treatment (ETAT) of children presenting to hospitals in the developing world. Part of the study was concerned with the delivery of emergency treatment to the sickest group of patients, characterisation of their illness, and outcome. METHODS AND RESULTS: A total of 236 children were admitted during the study period, 27 of whom died. The three main causes of death were malaria or malaria related illness (n = 7), pneumonia (n = 6), and malnutrition (n = 11). Forty seven children were categorised as needing emergency treatment. Thirty one had no treatment, and eight died; 16 received one or more recommended treatments, of whom five died. The main limitations to delivery of immediate care were the lack of staff in the department and lack of rapidly available blood.

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In response to increasing commercial interest and the high market value of qiviut (the downy underwool of the muskox), we have employed standards and measurements used in the wool and cashmere industries to describe qiviut fiber characteristics. Fleece samples (qiviut with guard hair) were shaved from the midshoulder of 299 wild muskox hides of known sex and age (1, 2, 3, and 4+ yr) during the Banks Island, Canada, muskox harvest in November 1997. Samples were analyzed for fiber diameter distribution of raw fiber and qiviut, scoured and qiviut yields, and lengths of guard hair and qiviut fiber. We found a sex x age interaction for average fiber diameter (AFD) in raw fiber (P= 0.002) and qiviut (P < 0.001) only. Adult males had significantly coarser AFD than females (21.5 microm, males vs 20.1 microm, females and 18.2 microm, males vs 17.5 microm, females) for raw fiber and qiviut, respectively. Qiviut AFD from yearlings was 1.7 microm finer than the AFD of adult qiviut. Fiber diameter distribution (SD) decreased with age in the raw sample (P < 0.003) and qiviut (P < 0.001) and qiviut SD was greater (P < 0.001) in males than in females. Qiviut theoretical yield (% mass of fibers < or = 30 microm) increased (P < 0.001) with age, and females had higher theoretical yields than males (P < 0.001). Scoured yield did not vary between sexes in any age class and averaged 93.3%. Qiviut staple length did not differ with either age or sex. In summary, differences between the sexes were small up to the 3rd yr, and these differences were not likely to be of commercial importance. However, considering that AFD is a primary commercial criterion of value, AFD changes from 16.5 microm in yearlings to 18.2 microm in adults and from 17.5 microm in adult females to 18.2 microm in adult males would be expected to result in significant differences in commercial value.

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Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8% versus 36.9%, P: < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P: < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P: < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats.

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A newborn male presented with watery diarrhea, dehydration and metabolic acidosis. Severe secretory diarrhea of variable magnitude persisted when the patient was on parenteral nutrition with no oral intake. Initial light microscopic evaluation of a small intestinal mucosal biopsy showed partial villous atrophy and crypt hypoplasia. Ultrastructural studies of the villous enterocyte revealed internalized inclusions of microvilli, typical of microvillous inclusion disease. Presented are a case report and a discussion of the differential diagnosis of watery diarrhea in the neonate, as well as a short review of microvillous inclusion disease.

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In laboratory studies, ectopic overexpression of the antiapoptotic protein Bcl-2 has been shown to result in resistance to the cytotoxic effects of many chemotherapeutic drugs. Furthermore, posttranslational modification of moderately expressed endogenous Bcl-2 has been correlated with susceptibility to paclitaxel treatment in vitro. To determine whether tumor expression of Bcl-2 protein correlates with response and ultimate outcome in vivo, we quantified Bcl-2 expression by immunohistochemical analysis of archived biopsy specimens from metastatic breast cancer patients treated with single-agent paclitaxel. The statistical association between the degree of Bcl-2 expression, objective tumor response, and clinical outcome was then determined. In patients (n = 39) whose tumors had low (< or = 10% cells positive) Bcl-2 levels by immunohistochemical analysis, the overall response (complete response + partial response) rate was 21% versus an overall response rate of 22% in patients (n = 36) with high (>10% cells positive) Bcl-2 expression (P = 0.92). In patients with low Bcl-2 expression, the median time to progression was 126 days [95% confidence interval (CI), 63-160 days]. This was not significantly different than the 105 days for patients with high tumor Bcl-2 expression (95% CI, 84-214 days). The median survival time from initiation of paclitaxel therapy for patients with low Bcl-2 expression was 663 days (95% CI, 456-1119 days) and was not significantly different than the 450 days (95% CI, 239-1058 days) observed for patients with high Bcl-2 expression. In conclusion, we found that in metastatic breast cancer, there is no significant association between tumor Bcl-2 expression and response to paclitaxel, median time to progression, or survival, suggesting that the main mechanism of paclitaxelinduced cytotoxicity in breast tumors is independent of Bcl-2 expression.

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OBJECTIVES: The purpose of this study was to determine the effect of volume overload hypertrophy in the newborn heart on the cardiac enzymes controlling fatty acid metabolism. BACKGROUND: Shortly after birth, a rise in 5'-adenosine monophosphate-activated protein kinase (AMPK) activity results in the phosphorylation and inhibition of acetyl coenzyme A (CoA) carboxylase (ACC), and a decline in myocardial malonyl CoA levels with increased fatty acid oxidation rates. Whether the early onset of hypertrophy in the newborn heart alters this maturational increase in fatty acid oxidation is unknown. METHODS: Newborn piglets underwent endovascular stenting of the ductus arteriosus on day 1 of life with a 4.5-mm diameter stent, resulting in a left to right shunt, and left ventricular (LV) volume loading. Left ventricular and right ventricular samples from fetal, newborn, three-week control and three-week stented animals were compared. RESULTS: Stenting resulted in echocardiographic evidence of volume overload and myocardial hypertrophy. In control animals, left ventricular ACC activity declined from 274 +/- 30 pmol/mg/min on day 1 to 115 +/- 12 after three weeks (p < 0.05), but did not display this maturation drop in hypertrophied hearts, remaining elevated (270 +/- 50 pmol/mg/min, p < 0.05). At three weeks, malonyl CoA levels remained 2.8-fold higher in hypertrophied hearts than in control hearts. In control hearts, LV AMPK activity increased 178% between day 1 and three weeks, whereas in hypertrophied hearts AMPK activity at three weeks was only 71% of control values, due to a significant decrease in expression of the catalytic subunit of AMPK. CONCLUSIONS: Early onset LV volume overload with hypertrophy results in a delay in the normal maturation of fatty acid oxidation in the newborn heart.

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OBJECTIVE: To assess the utility of transesophageal echocardiography (TEE) in radiofrequency (RF) catheter ablation of left-sided atrioventricular bypass tracts. PATIENTS: RF catheter ablation was assisted with TEE in 13 children and adolescents aged 9.9 to 16.3 years (mean 13.3). Results were compared with 21 procedures done in 19 patients (age 8.8 to 18 years, mean 14.5) without TEE assistance. MAIN RESULTS: RF ablation success rate was similar in both groups (90% to 92%). Successful RF ablation required 6 +/- 8 RF pulses in the TEE group and 10 +/- 7 RF pulses in the non-TEE group (nonsignificant). Fluoroscopy time was 36 +/- 17 mins and 54 +/- 28 mins, respectively (P = 0.03). Characteristic tenting of the fossa ovalis by a transseptal needle was easily visualized with TEE. TEE allowed for precise positioning of the ablation electrode on the mitral valve ring. At the successful site, the ventriculoatrial (VA) time was 42 +/- 10 ms in the TEE group and 52 +/- 16 ms in the non-TEE group (P = 0.05). The atrioventricular (A:V) ratio was 1.1 +/- 1.1 and 1.2 +/- 0.7, respectively (nonsignificant) with a large scatter of individual values. Electrogram amplitudes and VA conduction times that are desirable for RF ablation were also recorded on the mitral valve leaflets and over the coronary sinus. TEE visualized thrombus formation in the right atrium (three patients) and in the left atrium (two patients). CONCLUSIONS: TEE should be strongly considered as supplemental imaging for RF ablation of left-sided bypass tracts performed under general anesthesia in children and adolescents. TEE renders transseptal puncture safe. TEE may decrease fluoroscopic exposure. TEE confirmation of the ablation catheter tip in the angle between the coronary sinus and the mitral valve ring may allow limitation of unnecessary RF lesions and injury to the mitral valve. The demonstration of early intracardiac thrombus formation argues for prompt and full heparinization after transseptal puncture.

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Idiopathic dilation of the right atrium (IDRA) is a rare cardiac anomaly of unknown etiology. Whether it is an acquired or congenital lesion is controversial. A case of IDRA detected in utero and confirmed postnatally is reported. The postnatal course was complicated by the development of atrial flutter successfully treated with sotalol. A review of the literature concerning IDRA is presented.

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Cholinergic agonists stimulate isotonic fluid secretion in the parotid gland. This process is driven by the apical exit of Cl-, which enters the cells partly via Cl-/HCO-3 exchange across the basolateral membrane. Acidification of the cytosol by the extrusion of HCO-3 is prevented by the concomitant activation of the Na+/H+ exchanger (NHE), which is directly activated by cholinergic stimulation. Multiple isoforms of the NHE have been described in mammalian cells, but the particular isoform(s) present in salivary glands and their mechanism of activation have not been defined. Reverse transcriptase-polymerase chain reaction with isoform-specific primers was used to establish that NHE-1 and NHE-2, but not NHE-3 or NHE-4, are expressed in parotid glands. The presence of NHE-1 was confirmed by immunoblotting and immunofluorescence, which additionally demonstrated that this isoform is abundant in the basolateral membrane of acinar cells. The predominant role of NHE-1 in carbachol-induced Na+/H+ exchange was established pharmacologically using HOE694, an inhibitor with differential potency toward the individual isoforms. Because muscarinic agonists induce stimulation of protein kinases in acinar cells, we assessed the role of phosphorylation in the activation of the antiport. Immunoprecipitation experiments revealed that, although NHE-1 was phosphorylated in the resting state, no further phosphorylation occurred upon treatment with carbachol. Similar phosphopeptide patterns were observed in control and carbachol-treated samples. Together, these findings indicate that NHE-1, the predominant isoform of the antiporter in the basolateral membrane of acinar cells, is activated during muscarinic stimulation by a phosphorylation-independent event. Other processes, such as association of Ca2+-calmodulin complexes to the cytosolic domain of the antiporter, may be responsible for the activation of Na+/H+ exchange.

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A new method of creating atrial septal defect, using a 3- or 4-blade cutting balloon catheter combined with conventional static balloon dilation, is discussed. Radially directed surgical cuts made in the atrial septum were enlarged by balloon angioplasty, producing defects measuring 3 to 8 mm, with a mean Qp/Qs of 1.96/L.

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OBJECTIVES: To assess the efficacy of Doppler echocardiography (DE) in the quantification of patent ductus arteriosus (PDA) shunt volume and to correlate PDA shunt volume with clinical outcome in infants with hyaline membrane disease. METHODS: Ninety-eight DE studies were performed in 30 preterm ventilated infants with hyaline membrane disease within the first 24 hours of age and then at 48-hour intervals to a maximum of three studies while ventilated with a final study after extubation. Right and left ventricular outputs (QRV and QLV, respectively) and PDA flow were calculated using cross-sectional area and flow velocity integrals. Left atrial-to-aortic root diameter measurements were also taken. Clinical outcomes were correlated with the shunt fraction (QLV/QRV). RESULTS: QLV/QRV demonstrated a linear relationship with the left atrial-to-aortic root diameter ratio (n = 92; r = .79). In the absence of a PDA (n = 33 studies), QRV versus QLV demonstrated a linear relationship (r = .88). In the presence of a PDA (n = 64 studies) the mean QLV (334 +/- 133 ml/kg per minute) was significantly greater than the mean QRV (237 +/- 84 ml/kg per minute). There was a linear relationship between QLV-QRV (PDA shunt volume) and PDA flow (n = 60; r = .84). In studies with exclusive left-to-right shunting at the PDA (n = 48), the mean QLV-QRV (112 +/- 83 ml/kg per minute) was significantly higher than in those with bidirectional shunting (n = 16; mean QLV-QRV = 50 +/- 27 ml/kg per minute). Two infants with severe intraventricular hemorrhage (IVH grade 3) and two infants with periventricular leukomalacia (PVL) had significantly higher QLV/QRV (2.09 +/- 0.36 and 1.67 +/- 0.02 respectively) than those with no IVH (n = 6; QLV/QRV = 1.31 +/- 0.18) or those with IVH grades 1 and 2 (n = 8; QLV/QRV = 1.48 +/- 0.27). There was no difference in QLV/QRV in infants with or without bronchopulmonary dysplasia and retinopathy of prematurity. Necrotizing enterocolitis did not develop in any of the 30 infants. CONCLUSION: PDA shunt volume can be quantified by DE. Larger studies are needed to correlate clinical outcome with QLV/QRV.

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Permanent junctional reciprocating tachycardia (PJRT) is a rare cause of supraventricular tachycardia in the pediatric population and is resistant to most pharmacological therapy. A case of supraventricular tachycardia that, on the basis of postnatal electrocardiographic and Holter monitor evidence, was diagnosed as PJRT and presented in utero as an atypical tachycardia with severe tachycardia-induced cardiomyopathy confirmed postnatally is presented. It is the only case of which the authors are aware that was controlled in the neonatal period by amiodarone and that resulted in complete resolution of systolic dysfunction. The literature discussing how tachycardia may induce cardiomyopathy and the use of amiodarone in treatment both pre- and postnatally are reviewed.

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Fluid secretion by epithelial cells can be modulated by agents that activate Cl- channels in the apical membrane. To sustain secretion, Cl- influx across the basolateral membrane must also be accelerated. To examine the cellular mechanisms that couple Cl- efflux across the apical membrane to Na(+)-coupled Cl- entry across the basolateral membrane, we employed optical imaging techniques, utilizing single rat salivary acinar cells. Na+ influx was negligible in resting cells but was rapidly increased by carbachol due to activation of a Na(+)-H+ exchanger, a Na(+)-K(+)-2Cl- cotransporter, and, most likely, a nonselective cation channel. Receptor stimulation was not necessary, since elevation of intracellular Ca2+ concentration ([Ca2+]i) by thapsigargin activated the Na+ transporters at equivalent rates. Cell acidification, activation of protein kinase C, cell shrinkage, and other events associated with the rise of [Ca2+]i had little effect on Na+ transport in resting cells. Nevertheless, stimulation of cells in a medium that prevented normal Ca(2+)-induced cell shrinkage prevented activation of all three transport pathways. The block of the activation was not overcome by osmotic shrinkage but was relieved when [Cl-]i was allowed to fall, including conditions in which [Cl-]i fell in the absence of cell shrinkage. Activation of a Na(+)-H+ exchanger, Na(+)-K(+)-2Cl- cotransporter, and nonselective cation channel therefore exhibits a requirement for agonist-induced fall in [Cl-]i. Low [Cl-]i may create a permissive environment for Ca(2+)-dependent activation of multiple Na(+)-transport pathways, providing a mechanism for cross talk that coordinates transport activities of the apical and basolateral membranes in secretory epithelial cells.

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