Clinical analysis of NSCLC patients reveals lack of association between EGFR mutation and TET1 downregulation.

Lung cancer is one of the leading causes of death from cancer worldwide, with a poor prognosis in advanced cases. In the past decade, epidermal growth factor receptor (EGFR) inhibitors have shown significant efficacy towards treatment for EGFR mutant lung cancer. Expanding our knowledge of oncogenic EGFR signaling pathways is therefore of highly importance for the cancer field. Recently it has been proposed that mutant EGFR transcriptionally silences the TET1 (ten-eleven translocation methylcytosine dioxygenase 1) gene in cellular and animal models of lung cancer. Since TET1 is a known DNA demethylase, EGFR-mediated TET1 silencing therefore downregulates demethylation of tumor suppressor genes, which then leads to tumor growth inhibition, potentiating the role of TET1 as a tumor suppressor gene in NSCLC. In our study, we examined the role of EGFR-TET1 silencing in NSCLC patient samples. By independently analyzing the TCGA (The Cancer Genome Atlas) NSCLC data set as well as a cohort of patient samples from our hospital and a data set from publicly deposited databases, we did not observe the aforementioned mutant EGFR silencing of TET1. Conversely, in our cohort, TET1 expression levels were significantly elevated in EGFR mutant samples (P=0.007). Patients with higher TET1 levels showed a trend of better response rates to EGFR inhibitors compared to low TET1 staining levels, although the result was not significant (P=0.08). Furthermore, we did not observe a correlation between TET1 expression levels and patient survival. We conclude that while oncogenic EGFR suppression of TET1 is established in cellular and animal models of lung cancer, its role in patient outcome and prognosis remains inconclusive and warrants further investigation.

Multimodal imaging including spectral-domain optical coherence tomography and confocal near-infrared reflectance for characterization of lacquer cracks in highly myopic eyes.

PURPOSE: To compare multimodal imaging in detecting lacquer cracks in highly myopic eyes, and to correlate these findings with those of spectral-domain optical coherence tomography (SD-OCT). METHODS: An observational case series study. Patients with a refractive error worse than -8 diopters and lacquer cracks were recruited. The rates of detection of the lacquer cracks using multimodal imaging including near-infrared reflectance (NIR) imaging, fundus autofluorescence (FAF) imaging, and fluorescence angiography (FA) were compared. The characteristic findings of multimodal imaging were correlated with those of SD-OCT. RESULTS: NIR imaging was more sensitive (92.9%) in detecting lacquer cracks than either FAF (12.5%) or FA (67.9%). Lacquer cracks showed hyperreflectance on NIR, and they were consistently associated with a continuous retinal pigment epithelium-Bruch's membrane complex, thinner choroid, and acoustic shadows on SD-OCT. CONCLUSIONS: NIR imaging is superior to blue laser light (FAF and FA) imaging in detecting lacquer cracks. SD-OCT in combination with NIR located primary pathological lacquer cracks in the intact retinal pigment epithelium-Bruch's membrane complex as well as thinner choroid. These findings indicate that multimodal cSLO and SD-OCT imaging allow for detecting of lacquer cracks in highly myopic eyes.

Refractive errors after the use of bevacizumab for the treatment of retinopathy of prematurity: 2-year outcomes.

PURPOSE: To evaluate the refractive outcomes in children treated after intravitreal injection of bevacizumab (IVB) for retinopathy of prematurity (ROP). METHODS: A retrospective, bi-centre study of 34 patients (64 eyes) was conducted. The patients were divided into three groups, patients received intravitreal IVB (IVB group), patients received combined IVB and laser treatment (IVB + Laser group), or patients received lens-sparing vitrectomy (IVB + LSV group). Cycloplegic refraction and axial length (AXL) were evaluated at 2 years old. RESULTS: The prevalences of myopia and high myopia were 47.5 and 10.0% in the IVB group, respectively, which were lower than those in the IVB + Laser (82.4 and 29.4%) and IVB + LSV (all 100%) groups (P = 0.001 and P < 0.001). The prevalences of emmetropia in the IVB group, IVB + Laser group, and IVB + LSV group were 50, 5.9, and 0% (P = 0.001). The AXL were similar among all groups. CONCLUSIONS: At the 2-year follow-up, severe ROP patients treated with IVB alone were more likely to remain emmetropic and had lower prevalences of myopia and high myopia. The development of high myopia in severe ROP patients could not be explained by AXL changes but may be associated with abnormalities in the anterior segment.

Cellular origin of fundus autofluorescence in patients and mice with a defective NR2E3 gene.

AIM: To characterise new clinical features in a family with enhanced S-cone syndrome (ESCS) and investigate the pathogenesis of these clinical features in the homozygous Nr2e3(rd7) (rd7) mutant mice. METHODS: Four patients from an affected family were included for genotypic and phenotypic study. Eye tissues from rd7 mice were used to detect a possible relationship between macrophages and autofluorescent material by immunohistochemistry (IHC) staining. RESULTS: Homozygous mutation in R311Q in NR2E3 was detected in this family. Colour photographs revealed that white dots do not correlate to hyperautofluorescent spots seen in autofluorescence imaging of the macula. OCT showed rosette-like lesions similar to those found in rd7 mice histology sections. From IHC analysis, we observed that F4/80 (a pan macrophage marker) and autofluorescence were colocalised to the same cells within the retina rosettes. CONCLUSIONS: The retinal structure of a young ESCS patient with homozygous R311Q mutation in the NR2E3 gene is similar to that seen in the rd7 mice. The macrophages were found to contain autofluorescent materials in the retinal rosettes of rd7 mice. These data are consistent with macrophage infiltration contributing to the hyperautofluorescent spots found in our patients.

Paediatric retinal detachment: comparison of high myopia and extreme myopia.

AIMS: To compare the clinical features and surgical outcomes of paediatric retinal detachment (RD) in high myopia and extreme myopia. METHODS: The clinical charts of 107 children who experienced RD and had a spherical equivalent (SE) of at least 6.00 dioptres (D) were reviewed. The patients were separated into a high myopia group (SE -6.0 to -10.0 D) and extreme myopia group (SE >-10.0 D). RD characteristics and outcomes were compared between these two groups. RESULTS: There were significant differences between the two groups in total RD (p<0.001), the presence of posterior staphyloma (p<0.001) and some types of breaks. More eyes in the extreme myopia group required vitrectomy after the initial RD repair. In the high myopia group, retinal reattachment was achieved in 79 eyes (97.5%) at the end of the intervention, whereas in the extreme myopia group, retinal reattachment was achieved in 22 eyes (73.3%). Multiple logistic regression showed that a higher refractive error was the only negative predictor of surgical outcome (p = 0.026). CONCLUSION: Due to differences in aetiologies, clinical characteristics, required surgical procedure after initial repair, surgical and functional outcomes, paediatric RD with extreme myopia should be addressed differently from paediatric RD with high myopia.

Spontaneous closure of ventricular septal defects in the first year of life.

BACKGROUND AND PURPOSE: The recent increase in the prevalence of ventricular septal defect (VSD) has been ascribed to the improved detection of small defects with echocardiography and the wider use of screening. The aim of this study was to determine the prevalence and timing of spontaneous closure of specific types of VSD in neonates using echocardiographic screening and follow-up. METHODS: Two-dimensional color Doppler echocardiography was performed in 3,472 clinically normal full-term neonates born at Cathay General Hospital to detect isolated VSD. The relative prevalence of muscular versus perimembranous defects and their outcome in the first year of life were evaluated. RESULTS: VSD was found in 74 neonates (34 male, 40 female), resulting in a prevalence of 21.3/1,000 live births. There were 48 muscular, 25 perimembranous, and one subpulmonic defects. Of the 74 patients, 11 were lost to follow-up. Within the observation period of 12 months, spontaneous closure occurred in 40 patients in the muscular group and in six patients in the perimembranous group. The overall rate of spontaneous closure was 73% by the end of the first year. Only five patients with perimembranous defects received digoxin therapy. CONCLUSIONS: The prevalence of VSD in this series of neonates was 21.3/1,000 live births. The most common location of VSD in the neonatal period was in the region of the muscular septum. Muscular defects were more likely to close spontaneously than perimembranous defects. Most muscular defects underwent spontaneous closure during the 12-month follow-up period.

Antioxidants may mitigate the deterioration of coronary arteritis in patients with Kawasaki disease unresponsive to high-dose intravenous gamma-globulin.

During the early stages of Kawasaki disease, a marked increase in oxygen-free-radicals (OFRs), which are produced by activated polymorphonuclear cells, may induce coronary arteritis. Early use of high-dose intravenous gamma-globulin (IVIG) and aspirin effectively blocked this deteriorating course of coronary arteritis; however, late use of IVIG, even using a high-dose schedule, did not achieve the same efficacy. The causes and reactions to the scenario of IVIG refractoriness have rarely been mentioned in the literature. We present an 11-month-old male infant with Kawasaki disease and deteriorating coronary arteritis owing to late use of IVIG who showed dramatic responsiveness to the addition of alpha-tocopherol and ascorbic acid. We also discuss the possible mechanism.

Central venous catheter-induced atrial ectopic tachycardia with reverse alternating Wenckebach periods.

A centrally inserted venous catheter may cause atrial ectopic tachycardia. The association of atrial ectopic tachycardia with spontaneous reverse alternating Wenckebach periodicity has rarely been reported. We describe a 4-year-old boy with tetralogy of Fallot who developed atrial ectopic tachycardia with reverse alternating Wenckebach periods postoperatively after central venous catheter placement. All such episodes emerged from a 3:2 atrioventricular block, followed by runs of 2:1 atrioventricular block with progressive shortening of the conducted PR intervals. Normal sinus rhythm returned after the catheter was withdrawn to the superior vena cava. Reverse alternating Wenckebach periodicity may be a tachycardia-dependent physiologic phenomenon.

Cardiotoxicity in imipramine intoxication: report of one case.

Imipramine is the most commonly prescribed tricyclic antidepressant of acute life threatening self-poisoning. We report a 15-month-old boy of accidental poisoning with imipramine, who developed generalized tonic-clonic convulsions and drug-related cardiac conduction abnormalities with PR prolongation, QRS widening, and QTc lengthening. The patient's imipramine level was 1389 ng/ml. The rapid resolution of intraventricular conduction delay and normalization of the QRS-T complexes after gastric lavage, installation of activated charcoal and alkalinization of the blood strongly implicates imipramine intoxication in the etiology of the cardiotoxicity. The patient made a full recovery without neurological sequelae.

Multi-undulant T-U-wave, sinus bradycardia and long QT syndrome: a possible phenotype of mutant genes controlling the inward potassium rectifiers.

Inward rectifying potassium currents (Ikr and Iks) during phase 3 repolarization of the myocyte from the beginning to the end of repolarization of the myocardial syncytium will inscribe a T-U-wave on the surface electrocardiogram (ECG). Type two congenital long QT syndrome (LQT2) is a phenotype of human ether-a-go-go-related gene (HERG) mutation on the chromosome 7q 35-36. Type one congenital long QT syndrome (LQT1) is a phenotype of KvLQT1 mutation on the chromosome 11p15.5. Both LQT1 and LQT2 relate with inward rectifying potassium currents and is repolarization related, therefore, it is speculate that patients of LQT1 and LQT2 may have an abnormal T-U-wave on their surface ECG. To two probands of congenital LQT, 8 patients of structural heart disease treated by open heart surgery, 13 patients of structural heart disease without open-heart surgery, and 10 patients of normal controls, 24 hour-Holter monitoring was performed from July to December 1996. Their corrected QT interval (QTc) as well as the RR interval of every heart beat was calculated by a computer. The results showed that all 33 patients exhibited beat-by-beat fluctuation of their QTc and RR daily. The RR intervals of these two probands of congenital LQT were somewhile more than 1200 ms during circadian waking time, while 31 cases without LQT showed their RR prolongation only during the circadian sleeping time. A multi-undulant T-U-wave, or a beat-to-beat changing of vectors or amplitudes of their T-U-wave observed in these two probands of congenital LQT, were not observable in those 31 patients without congenital LQT. Therefore, we concluded that multi-undulant T-U-wave, sinus bradycardia and a longer QTc was a phenotype of the mutated genes which control the inward rectifying potassium currents during phase 3 repolarization.

Prognostic value of color Doppler echocardiographic findings in premature newborns with patent ductus arteriosus.

This study intended to evaluate the relationship between the prognosis for premature newborns (PM) with patient ductus arteriosus (PDA) and their Doppler echocardiographic findings. From January 1989 to December 1995, of 369 premature newborns in their first postnatal week, 196 underwent ductal evaluations echocardiographically: 47 of these 196 cases were found to have PDA. Each echocardiogram had complete data for cardiac output, ejection fraction, the left atrial-to-the-aortic ratio (LA/AO), the systolic time interval of the right ventricle (RVSTI), the transvalvular pressure gradient from tricuspid regurgitation (TGTR) and ductal Doppler color flow maps. These 47 premature newborns with PDA were grouped into (A) "asymptomatic" patients whose ductus closed spontaneously within a one-year follow-up (15 subjects), (B) "symptomatic" patients whose ductus were closed by pharmacological or surgical managements (20 subjects), and (C) "complicated" patients whose ductus caused mortality of the host (12 subjects). The remaining 149 premature newborns with a closed ductus (CD) served as controls. The RVSTI in these 47 premature newborns with PDA was found to be significantly higher than those of 149 CD (0.26 +/- 0.12 vs. 0.18 +/- 0.06, p < 0.005), and denoting that PM-PDA had a higher mean pulmonary arterial pressure. The TGTR of these 47 premature newborns with PDA was also higher than these of the 149 CD controls (30.50 +/- 11.85 mmHg vs. 20.54 +/- 6.88 mmHg, p < 0.005), denoting that PM-PDA had a higher pulmonary arterial systolic pressures. Gestational age of group C neonates was younger than group A (29.46 +/- 3.41 weeks vs. 32.80 +/- 2.78 weeks, P < 0.01). The birth weight of Group C neonates was lower than that of Group A (1366.17 +/- 684.28 gm vs. 2061.67 +/- 751.77 gm. p < 0.01), therefore, extreme prematurity and small-for-gestational-age could have increased the mortality of PM-PDA. Doppler color flow maps of group C showed a wider ductal patency, less ductal waist-narrowing, more vehement red-color forward flow and less midstream mosaicism. It was concluded that patient with extreme prematurity, with very-low-birth-weight or wider patent ductus, higher pulmonary hypertension, less midstream mosaicism, or less ductal waist-narrowing would have a poorer prognosis.

Effect of continuous positive airway pressure on cardiac output in neonates.

To determine the cardiac output change in neonates who were under nasal continuous positive airway pressure (CPAP) therapy, eleven newborn neonates, who were admitted to our neonatal intensive care unit with respiratory diseases, were enrolled in the study. Cardiac output was measured by pulsed Doppler echocardiogram at various pressures of 0, 2, 4, 6, 8, and 10 cm H2O and revealed 301 +/- 47, 300 +/- 49, 289 +/- 55, 275 +/- 64, 269 +/- 59 and 242 +/- 50 ml/min/kg, respectively. Cardiac output depressed significantly between 0 cm H2O and 8 cm H2O (P = 0.025), and between 0 cm H2O and 10 cm H2O (P = 0.004). We conclude that cardiac output may be depressed in neonates who are under high levels of nasal CPAP therapy, and suggest that high levels of nasal CPAP therapy must be used with caution, especially when the therapy is applied to the low birth weight neonates.

An echocardiographic study on asymptomatic multiple interatrial septal defects in newborns.

In a prospective study on the integrity of the interatrial septum in the neonates, multiple interatrial septal defects or openings with shunting were discovered in nine neonates by means of the color flow mapping technique used in their first week of life among 130 Chinese neonates. Eight of the nine neonates had two openings each, and the remaining one had four openings. Thus a total of 20 openings were found in the 9 neonates. Openings located between the tip of the flap valve and the superior limbus of the foramen ovale were classified as "location A openings" (valve-like openings). Those located at the flap valve itself were classified as "location B openings" (fenestrations). Each of the 9 neonates had one opening at location A, eight of them had another opening at location B; one had three openings at location B. Six of the nine neonates were followed up at age of one month, three months and six months by means of color-flow mapping, with a total of six openings at location A and eight openings at location B. Four out of the six openings of location A and seven out of the eight openings at location B closed spontaneously before the age of six months. In conclusion, seven percent (9/130) of these Chinese neonates have multiple interatrial openings. The openings tend to close spontaneously, regardless of their locations.

Breath hydrogen test for assessment of lactose malabsorption following rotavirus gastroenteritis.

Ninety infants and young children with acute gastroenteritis were investigated for lactose malabsorption. Each of them was given an oral lactose load of 2g per kg of body weight after which breath hydrogen excretion was measured, and each was observed for clinical symptoms of lactose intolerance. Only 2 patients, given 2g per kg of lactose, had clinical lactose intolerance. Forty-nine of the 90 patients studied were found to have the rotavirus antigen in their stools. Forty-five of them were found to have an abnormal lactose breath hydrogen test (LBHT). Twenty-three patients with abnormal LBHT were restarted on a diluted lactose-containing formula for oral feeding. They required longer hospitalization (mean 6.7 days, range 3-14 days) and were free of diarrhea in 14 days (mean 7.5 days). Twenty-two patients found to have an abnormal LBHT were given a nonlactose-containing formula (Isomil, Nursoy, Alsoy, ProSobee, or Bebelac FL) when restarted on oral feeding. All patients require less than 5 days of hospitalization and free of diarrhea in 5 days (mean 3.4 days). The difference was statistically significant (p less than 0.05).

Reevaluation of streptococcal infection in the pathogenesis of Kawasaki disease.

Twenty-five sera from forty-nine children with Kawasaki disease (KD) in the convalescent stage, and 191 sera from controls did not disclose a higher anti-streptolysin O titer; 23 bacterial cultures from the throat swab of KD patients during the acute stage did not show a higher rate of streptococcal isolation. It was therefore concluded that there was no relation between the genesis of KD and direct immediate streptococcal infection.

Cerebral blood flow velocity in newborn infants with asphyxia.

A pulsed-Doppler real-time technique was used to assess the anterior cerebral artery (ACA) flow velocity in 30 asphyxiated infants during the first 5 days after birth. Thirty healthy term infants were also studied as controls. Peak systolic flow velocity (PSFV), end diastolic flow velocity (EDFV), mean flow velocity (MFV), and pulsatility index (PI) were measured. Mean PI values of the ACA of the asphyxiated and control groups were 0.63 +/- 0.05 vs 0.71 +/- 0.04 (p less than 0.001) on the first day; 0.64 +/- 0.03 vs 0.70 +/- 0.05 (p less than 0.001) on the third day and 0.69 +/- 0.04 vs 0.70 +/- 0.04 (p greater than 0.05) on the fifth day of life. The asphyxiated group also had significantly higher EDFV and MFV than those of control group until the 5th day of life. The low PI values of asphyxiated infants were mainly due to an increase in EDFV. These results suggest that the cerebrovascular resistance of asphyxiated infants, as reflected by the PI, is low during the first 3 days of life, indicating an increase in cerebral blood flow. With this technique, we can repeatedly and safely evaluate the cerebral hemodynamic changes in asphyxiated newborn infants.

Echocardiographic changes following balloon valvuloplasty in valvular pulmonic and aortic stenosis.

Nineteen patients with pulmonary valvular stenosis and two with aortic valvular stenosis, aged 20 days to 12 years, were studied before and after balloon dilatation valvuloplasty (BDV) by M-mode, 2-D, pulsed wave (PW) and continuous wave (CW) Doppler, and color flow mapping echocardiography. In those with pulmonary stenosis, a dome-shaped valve was found in 16(84%) of 19 cases before BDV, and the valve remained dome shaped only in 4(27%) of 15 after procedure (P less than 0.001). Restricted valve motion which was noted in 18(95%) of 19 before BDV, persisted only in 2(13%) of 15 after procedure (P less than 0.001). Thickening of the pulmonic valve and poststenotic dilatation of the main pulmonary artery stayed almost unchanged. The pressure gradient across the pulmonic valve measured by cardiac catheterization and CW Doppler agreed well (r = 0.862). Echocardiographic evidence of pulmonary regurgitation was detected in 1(25%) of 4 patients before, and 7(50%) of 14 after BDV. In two patients with aortic stenosis, the echocaardiograms showed the valve was thickened and dome-shaped. Following BDV, echocardiographic evidence of mild aortic regurgitation was observed only in one patient who had had such a regurgitationn before BDV. The diameter of the valve annulus measured on 2-D echo and angiocardiograms correlated well (r = 0.912), and it stayed unchanged following BDV. It is concluded that 2-D and Doppler echocardiographic examinations proved to be useful in the measurement of valve annulus, delineation of stenotic semilunar valves and monitoring of the efficacy of BDV.