Genetic profile of naïve untreated primary cutaneous melanomas with a negative sentinel lymph node.

Sentinel lymph node (SLN) biopsy is typically offered to patients with primary cutaneous melanomas (PCMs) of ≥ 1 mm depth, but not all SLNs are positive using this cutoff. To ascertain whether positivity is genetically regulated, genetic analysis was performed using an augmented enrichment-based next-generation DNA and RNA sequencing assay in SLN-negative (Group 1, n = 8, mean depth 1.3 mm) and SLN-positive PCMs (controls, Group 2, n = 4, mean depth 1.4 mm). In Group 1, the mean number of mutations was 21 (range 3-48) with the most frequent mutations occurring in NF1 (75%) followed by TP53 (63%), CDKN2A and BRAF (38%), and NRAS (25%), while in Group 2, the ean number of mutations was 9.5 (range 5-18) with mutations in NRAS and BRAF being the most frequent (50%) followed by those in ATM, CDKN2A, CDKN2B, and NOTCH1 (25%). Increased frequency of NF1-inactivating mutations in Group 1 provides provocative early data that the presence of NF1 mutations might confer a less aggressive phenotype.

Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development.

The effects of DNA repair and transcription gene abnormalities in human pre-natal life have never been studied. Trichothiodystrophy (TTD) is a rare (affected frequency of 10(-6)) recessive disorder caused by mutations in genes involved in nucleotide excision repair (NER) pathway and in transcription. Based on our novel clinical observations, we conducted a genetic epidemiologic study to investigate gestational outcomes associated with TTD. We compared pregnancies resulting in TTD-affected offspring (n = 24) with respect to abnormalities during their antenatal and neonatal periods to pregnancies resulting in their unaffected siblings (n = 18), accounting for correlation, and to population reference values. Significantly higher incidence of several severe gestational complications was noted in TTD-affected pregnancies. Small for gestational age (SGA) <10th percentile [Relative risk (RR ) = 9.3, 95% CI = 1.4-60.5, p = 0.02], SGA <3rd percentile (RR = 7.2, 95% CI = 1.1-48.1, p = 0.04), and neonatal intensive care unit (NICU) hospitalization (RR = 6.4, 95% CI = 1.4-29.5, p = 0.02) occurred more frequently among TTD-affected neonates compared with their unaffected siblings. Compared with reference values from general obstetrical population, pregnancies that resulted in TTD-affected infants were significantly more likely to be complicated by hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (RR = 35.7, 95% CI = 7.6-92.5, p = 0.0002), elevated mid-trimester maternal serum human chorionic gonadotropin (hCG) levels (RR = 14.3, 95% CI = 7.0-16.6, p < 0.0001), SGA <3rd percentile (RR = 13.9, 95% CI = 7.4-21.1, p < 0.0001), pre-term delivery (<32 weeks) (RR = 12.0, 95% CI = 4.9-21.6, p < 0.0001), pre-eclampsia (RR = 4.0, 95% CI = 1.6-7.4, p = 0.006), and decreased fetal movement (RR = 3.3, 95% CI = 1.6-5.2, p = 0.0018). Abnormal placental development is an underlying mechanism that may explain the constellation of observed complications in our study. Thus, we hypothesize that TTD DNA repair and transcription genes play an important role in normal human placental development.

Hyperthermal neutral beam sources for material processing.

Hyperthermal neutral beams have a great potential for material processes, especially for etching and thin film deposition for semiconductor and display fabrication as well as deposition for various thin film applications. Plasma-induced damage during plasma etching is a serious problem for manufacturing deep submicron semiconductor devices and is expected to be a problem for future nanoscale devices. Thermal and plasma-induced damage is also problematic for thin film depositions such as transparent conductive oxide films on organic light emitting diodes or flexible displays due to high temperature processes in plasma environments. These problems can be overcome by damage-free and low-temperature processes with hyperthermal neutral beams. We will present the status of the hyperthermal neutral beam development and the applications, especially, in semiconductor and display fabrication and introduce potential applications of thin film growing for optoelectronic devices such as light emitting diodes.

Development of antiangiogenin peptide using a phage-displayed peptide library.

Angiogenesis is essential for tumor growth and metastasis. Here, we have developed a peptide antagonist of human angiogenin, which is a potent and tumor-associated angiogenic factor. ANI-E peptide was derived from the phage clone, which binds to angiogenin via the disulfide-constrained octapeptide epitope that is displayed on its surface, and is displaced by actin. Disulfide-constrained ANI-E peptide inhibits the interaction of angiogenin with actin, which is regarded as the angiogenin-binding protein on the surface of endothelial cells, without any visible effect on the ribonucleolytic activity of angiogenin. The peptide also inhibits the neovascularization that is induced by angiogenin in the chick chorioallantoic membrane assay. The antiangiogenic activity of the peptide is specific for angiogenin because the peptide does not have any apparent effect on embryonic angiogenesis or the preexisting blood vessels. The disulfide bond and the glutamic acid inside the disulfide ring of ANI-E peptide are indispensable for its antiangiogenin activity. Furthermore, ANI-E peptide blocks the angiogenesis that is induced by the angiogenin-secreting PC3 human prostate adenocarcinoma cells, without any direct effect on the proliferation, as well as the adhesion of PC3 cells to angiogenin. Therefore, the inhibition of the tumor-induced angiogenesis by ANI-E peptide is most likely caused by the neutralization of the extracellular angiogenin that is secreted by PC3 cells. On the basis of our results, ANI-E peptide may be effective for the treatment of various human tumors that secrete angiogenin. Our results also strongly support the hypothesis that the interaction of angiogenin with the cell surface actin-like protein is essential for the biological action of angiogenin, and angiogenin has an essential role in tumor-induced angiogenesis.

Bathroom greywater recycling using polyelectrolyte-complex bilayer membrane: Advanced study of membrane structure and treatment efficiency.

Polyelectrolyte-complex bilayer membrane (PCBM) was fabricated using biodegradable chitosan and alginate polymers for subsequent application in the treatment of bathroom greywater. In this study, the properties of PCBMs were studied and it was found that the formation of polyelectrolyte network reduced the molecular weight cut-off (MWCO) from 242kDa in chitosan membrane to 2.71kDa in PCBM. The decrease in MWCO of PCBM results in better greywater treatment efficiency, subsequently demonstrated in a greywater filtration study where treated greywater effluent met the household reclaimed water standard of <2 NTU turbidity and <30ppm total suspended solids (TSS). In addition, a further 20% improvement in chemical oxygen demand (COD) removal was achieved as compared to a single layer chitosan membrane. Results from this study show that the biodegradable PCBM is a potential membrane material in producing clean treated greywater for non-potable applications.

The orally active urotensin receptor antagonist, KR36676, attenuates cellular and cardiac hypertrophy.

BACKGROUND AND PURPOSE: Blockade of the actions of urotensin-II (U-II) mediated by the urotensin (UT) receptor should improve cardiac function and prevent cardiac remodelling in cardiovascular disease. Here, we have evaluated the pharmacological properties of the recently identified UT receptor antagonist, 2-(6,7-dichloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-methyl-N-(2-(pyrrolidin-1-yl)-1-(4-(thiophen-3-yl)phenyl) ethyl)acetamide (KR36676). EXPERIMENTAL APPROACH: Pharmacological properties of KR36676 were studied in a range of in vitro assays (receptor binding, calcium mobilization, stress fibre formation, cellular hypertrophy) and in vivo animal models such as cardiac hypertrophy induced by transverse aortic constriction (TAC) or myocardial infarction (MI). KEY RESULTS: KR36676 displayed high binding affinity for the UT receptor (Ki : 0.7 nM), similar to that of U-II (0.4 nM), and was a potent antagonist at that receptor (IC50 : 4.0 nM). U-II-induced stress fibre formation and cellular hypertrophy were significantly inhibited with low concentrations of KR36676 (≥0.01 µM). Oral administration of KR36676 (30 mg·kg(-1) ) in a TAC model in mice attenuated cardiac hypertrophy and myocardial fibrosis. Moreover, KR36676 restored cardiac function and myocyte size in rats with MI-induced cardiac hypertrophy. CONCLUSIONS AND IMPLICATIONS: A highly potent UT receptor antagonist exerted anti-hypertrophic effects not only in infarcted rat hearts but also in pressure-overloaded mouse hearts. KR36676 could be a valuable pharmacological tool in elucidating the complicated physiological role of U-II and UT receptors in cardiac hypertrophy.

Chromosome assignment of aberrant NotI restriction DNA fragments in primary hepatocellular carcinoma.

DNA aberrations in human hepatocellular carcinoma (HCC) were studied by two-dimensional DNA electrophoresis analysis. Five intensified and 60 dwindling spots were detected recurrently in the two-dimensional profile which showed about 3000 restriction DNA fragments as distinctive spots. We assigned these aberrant spots to chromosomes, using the chromosome-assigned two-dimensional profile. Four of the five intensified, and 53 of the 60 dwindling spots were given chromosome assignments. Intensified spots were assigned to chromosomes 5, 6, 9 through 12, 16 and 18. Among the dwindling spots, the highest incidence of aberrations was found on chromosome 16, followed by 9 through 12 and chromosome 2. No aberrations were detected in chromosomes 7, 21, 22 or Y.

Pulmonary hyperinflation in ventricular septal defect.

Pulmonary hyperinflation (PH) has frequently been seen in patients with ventricular septal defect (VSD). Mean age of patients at the time of cardiac catherization and operation was less in Group II (PHI) than in Group I (normal pulmonary inflation). There is a statistically significant difference in the ratio of mean pulmonary to mean systemic blood flow and the ratio of mean peak pulmonary to mean peak systemic systolic pressures, with the higher values recorded for Group II. There is no statistically significant difference in the pulmonary vascular resistance in the two groups. Thirty-five of the 44 patients with PHI developed normal inflation within a month after surgical correction of VSD. Possible mechanisms of PHI in VSD are discussed. PHI is prolong and perpetuate respiratory distress and can lead to progressive lung disease. PHI is therefore another indication for early surgical correction of VSD.

Clinical implications of postoperative unilateral phrenic nerve paralysis.

Unilateral phrenic nerve paralysis (PNP) folowed 32 (1.7 percent) of 1,891 consecutive cardiac surgical procedures during an 8 year peroid. Diagnosis was based on radiographic criteria with comparison of preoperative and postoperative chest radiographs and was confirmed in all 21 evaluated by fluoroscopy. Six had persistent radiographic abnormality more than 12 months postoperatively. PNP occurred most frequently in association with Blalock-Taussig shunts. These operations represented 22 percent of this series, and PNP complicated 7 percent of all Blalock-Taussig shunts. PNP was less well tolerated in the 14 infants than in the 18 older children. Eleven infants had serious difficulties during weaning from mechanical ventilatory support. Five infants required tracheostomy, one underwent diaphragmatic plication, and three died. Infants had a mean duration of mechanical ventilation of 24 days and required prolonged intensive care and long-term hospitalization. In comparison, older children had a more benign postoperative course. Diaphragmatic plication should be considered in infants with paradoxical motion of the hemidiaphragm who remain dependent on mechanical ventilatory support for more than 2 weeks postoperatively.

Sintering of TCP-TiO2 biocomposites: influence of secondary phases.

TCP-TiO2 ceramic biocomposites with various alpha-to-beta TCP ratios can be prepared by quenching the alpha phase. The presence of dopants (Ca, P, or Na) leads to the precipitation of secondary phases, which decreases the densification of titania. In the system TCP-TiO2, there is a eutectic with a composition of 63 wt% TCP-37 wt% TiO2 at a temperature of 1380 degrees C.

Origin of the high affinity and selectivity of novel receptors for NH4+ over K+: charged hydrogen bonds vs cation-pi interaction.

[structure: see text]Given the recent report of a novel pyrazole receptor exhibiting a high selectivity for NH4+ over K+, it would be interesting to investigate the origin of this selectivity and affinity so that better receptors could be designed. On the basis of extensive theoretical studies, we conclude that the origin arises from a subtle interplay of charged H-bonds and cation-pi interactions. The approach employed herein would be very useful in the rational design of novel functional molecular systems.

Unilateral inguinal hernias in children: What about the opposite side?

The decision for or against bilateral exploration in unilateral hernias in infants is necessitated by the high incidence of obscure anatomic hernias on the opposite side. On the basis of studies done in 400 pediatric patients (mostly under 2 years of age), we believe that unilateral repair of a known hernia without ascertaining the presence of a contralateral hernia is unjustified. Because of an appreciable risk to the gonads and/or vas deferens, we do not believe routine bilateral herniorrhaphies in all infants are indicated. The attempts at an intraoperative, transperitoneal insertion of a Bakes dilator into a contralateral sac were unreliable in our hands. Herniography is a reliable, safe way to reduce the incidence of unnecessary contralateral exploration. It should be liberally used where the necessary radiologic expertise is available.

Abnormal pulmonary aeration in infants and children.

There are many intrinsic and extrinsic, and congenital or acquired lesions that cause aeration disturbances in infants and children. The radiographic diagnosis of these entities and the pathophysiologic mechanisms by which they produce overinflation or underinflation are discussed. Longstanding airway compression may have serious effects on the developing lung and its vascular supply.

Radiographic manifestations of anomalies of the lung.

Congenital nonvascular anomalies of the lung can be subdivided into those affecting the bronchial tree and those affecting parenchymal abnormalities. Embryologic development of the lung is briefly reviewed to facilitate an understanding of developmental pulmonary anomalies. Clinical, radiographic, and therapeutic aspects of these anomalies are discussed.

Disturbances of bone growth and development.

"What is growth anyway? Can one talk about positive growth in childhood, neutral growth in maturity, and negative growth in old age?" Our goal is to help promote normal positive growth in infants and children. To achieve this, we must be cognizant of the morphologic changes of both normal and abnormal bone formation as they are reflected in the radiographic image of the skeleton. The knowledge of the various causes and the pathophysiologic mechanisms of the disturbances of bone growth and development allows us to recognize the early radiographic manifestations. Endocrine and metabolic disorders affect the whole skeleton, but the early changes are best seen in the distal ends of the femurs, where growth rate is most rapid. In skeletal infections and in some vascular injuries two-or three-phase bone scintigraphy supercedes radiography early in the course of the disease. MRI has proved to be very helpful in the early detection of avascular bone necrosis, osteomyelitis, and tumor. Some benign bone tumors and many bone dysplasias have distinct and diagnostic radiographic findings that may preclude further studies. In constitutional diseases of bone, including chromosomal aberrations, skeletal surveys of the patient and all family members together with biochemical and cytogenetic studies are essential for both diagnosis and genetic counseling. Our role is to perform the least invasive and most informative diagnostic imaging modalities that corroborate the biochemical and histologic findings to establish the definitive diagnosis. Unrecognized, misdiagnosed, or improperly treated disturbance of bone growth can result in permanent deformity usually associated with disability.

Telltale signs of congenital heart disease.

There are several key plain film findings that raise suspicion for and aid in the differentiation of congenital heart defects. These 'telltale' signs and their significance and the additional necessary imaging studies of cardiac lesions are discussed with particular emphasis on the role of magnetic resonance imaging.

Radiographic manifestations of congenital anomalies of the skull.

Congenital anomalies of the pediatric skull are caused by a diverse group of disorders. For the purposes of this discussion, these entities can be classified according to the radiographic appearance of the skull, which may be similar in a variety of different diseases. Enlarged parietal foramina, sinus pericranii, aplasia cutis congenita, anterior fontanelle dermoid, cephaloceles, and craniolacunia are all examples of loceles, and craniolacunia are all examples of calvarial defects. Although there are numerous causes for wormian bones (Table 1), OI, cleidocranial dysplasia, congenital hypothyroidism, and hypophosphatasia are disorders that are commonly associated with defective ossification and the appearance of wormian bones. Osteopetrosis is an important example of rare bony dysplasias that cause sclerosis and hyperostosis of the skull. A partial list of other disorders causing similar radiographic findings is found in Table 2. Craniosynostosis results in an abnormality of skull shape. The suture(s) involved may be predicted by the deformed calvarial configuration. Knowledge of the growth and development of the skull and an understanding of the varied causes of congenital skull anomalies can enable the radiologist to provide the diagnosis or an informed differential diagnosis when confronted with a specific radiographic finding.

Radiographic manifestations of anomalies of the gastrointestinal tract.

Congenital anomalies of the gastrointestinal tract can pose serious threats to the health of newborn infants and children. Perhaps nowhere has pediatric surgery had as dramatic an impact as in the care and treatment of these conditions. The pediatric radiologist works closely with the surgeon in evaluating these anomalies in young children. Plain radiographic films and contrast studies have been and remain the first step in studying these anomalies. Newer imaging modalities, however, also have made contributions to the continuing importance of the role of the radiologist in the diagnosis and care of children with these anomalies.

Radiographic manifestations of anomalies of the limbs.

Limb anomalies and their commonly associated organ malformations are increasingly recognized in fetal life because of the use of high resolution real-time sonography. In most instances plain radiography establishes the diagnosis of limb anomalies shortly after birth. In some neonates the diagnosis is tentative until full skeletal maturity is attained. When evaluation of the soft tissues and unmineralized cartilage or ossification center is a prerequisite to early definitive therapy, computed tomography and magnetic resonance imaging are the procedures of choice.

Radiologic evaluation of the diaphragm.

Recent technical advancements allow us to better evaluate the diaphragm and juxtadiaphragmatic lesions. Plain radiographs demonstrate morphology of the diaphragm in most cases. Function of the diaphragm can easily be evaluated by ultrasonography and fluoroscopy. Ultrasonography can be performed at bedside and should be used before fluoroscopy in infants and children. Ultrasonography can also demonstrate congenital anomalies of the diaphragm in utero. CT clearly discloses the underlying pathology and the extent of most juxtadiaphragmatic lesions. The newest modality, MRI, is quite promising and may become the procedure of choice for evaluation of diaphragmatic as well as juxtadiaphragmatic lesions in the very near future.