[Towards perfection: the ethical downside of the ideal of beauty]. / Op weg naar perfectie: de ethische keerzijde van het schoonheidsideaal.

Beauty, it seems, is a fascination inherent in human nature. Research shows that an attractive face plays a significant factor in human life, such as in the areas of appreciation and judgment.The growing demand for cosmetic treatments is amplified by social media and influencer marketing. However, there are possible negative effects, such as addiction and dissatisfaction with treatment outcome in people with Body Dysmorphic Disorder. It remains important to recognize that risks are inherent in medical procedures.

Enhancement of bulk second-harmonic generation from silicon nitride films by material composition.

We present a comprehensive tensorial characterization of second-harmonic generation from silicon nitride films with varying compositions. The samples were fabricated using plasma-enhanced chemical vapor deposition, and the material composition was varied by the reactive gas mixture in the process. We found a six-fold enhancement between the lowest and highest second-order susceptibility, with the highest value of approximately 5 pm/V from the most silicon-rich sample. Moreover, the optical losses were found to be sufficiently small (below 6 dB/cm) for applications. The tensorial results show that all samples retain in-plane isotropy independent of the silicon content, highlighting the controllability of the fabrication process.

The value of fine needle aspiration cytology diagnosis in ovarian masses in children and adolescents.

STUDY QUESTION: Is ovarian cytology a reliable predictor for a malignant ovarian mass? SUMMARY ANSWER: Cytology of an ovarian mass in children and adolescents cannot be used to exclude malignancy. WHAT IS KNOWN ALREADY: It is hard to predict malignancy in case of an ovarian mass in a child or adolescent. The most common reason to perform fine needle aspiration cytology (FNAC) is to exclude malignancy. Ovarian cytology has shown varying results in adults, but test performance in a younger population is unknown. STUDY DESIGN, SIZE, DURATION: This was a retrospective diagnostic test accuracy study. We used a nationwide registry, the PALGA database, to select girls aged 18 or younger with matching ovarian cytology and histology reports available between 1990 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Histology diagnoses were classified according to the WHO classification of ovarian pathology. Cytology diagnoses were classified as benign, borderline malignant or malignant. Cases with inconclusive cytology diagnoses were excluded from the analysis of diagnostic accuracy. Diagnostic accuracy was calculated using a 2 × 2 table. MAIN RESULTS AND THE ROLE OF CHANCE: Included were 552 girls under the age of 18 who had a cytology and a histology report of the same ovary available in the PALGA database. In 523 (94.7%) patients the mass was benign; 19 (3.4%) patients had a borderline malignancy and 9 (1.7%) patients had a malignant tumour. The histology diagnosis was unknown in one patient due to torsion of the ovary. Cytological diagnosis was inconclusive in 96 patients (17.4%). Cytology had a sensitivity of 32.0% and a specificity of 99.8%. Post-test probability of malignancy with positive cytology was 88.9%; the post-test probability of a malignancy with negative cytology was 3.8%, compared with a pre-test probability of 5.5%. LIMITATIONS, REASONS FOR CAUTION: This study was retrospective, using data gathered over 24 years. Cytology was retrieved during surgery or at the pathology department in 86.6% of the cases and pathologists were not blinded, which can be a cause for bias. WIDER IMPLICATIONS OF THE FINDINGS: Since the sensitivity is low, FNAC is not a recommended diagnostic tool in children. The post-test probability of a negative test compared with the incidence in our population resulted in a minimal difference not worth an invasive procedure. STUDY FUNDING/COMPETING INTERESTS: No study funding was received and no competing interests are present. TRIAL REGISTRATION NUMBER: NA.

External validation of the paediatric risk of malignancy index.

OBJECTIVE: This study aimed to validate the paediatric risk of malignancy index (PRMI), as previously published. DESIGN: External validation study. SETTING: Academic hospital: Radboud University Medical Center. POPULATION: Female paediatric patients under the age of 18 years diagnosed with, or treated for, an adnexal mass between January 1999 and October 2013. METHODS: Information was collected on diagnosis, presenting symptoms, and signs and imaging characteristics. The PRMI was calculated for each patient. Sensitivity, specificity, and positive and negative predictive values were calculated, and the results were visualised using a receiver operating characteristic curve (ROC curve). MAIN OUTCOME MEASURES: Histological diagnosis, discriminative performance using the area under the curve (AUC) of the ROC curve and sensitivity and specificity. RESULTS: Seventy-eight patients were included, with a median age of 12 years. A malignant mass was found in 17 patients (21.8%). The PRMI with a cut-off value of 7 resulted in a sensitivity of 70.1% (95% CI 44.1-89.6%) and a specificity of 85.3% (95% CI 73.8-93.0%). The area under the ROC curve was 0.868 (95% CI 0.756-0.980). CONCLUSIONS: The PRMI showed less discriminative capacity than originally published, but its performance was still good; however, further prospective validation studies are needed to define whether the model is useful in daily clinical practice.

Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines.

BACKGROUND AND PURPOSE: The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K(+) current (I(Kr)), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a 'first line' test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here. EXPERIMENTAL APPROACH: hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits. KEY RESULTS: 576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC(50), 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 microM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts. CONCLUSION AND IMPLICATIONS: The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an approximately 15-25% incidence of death.

Activation of the Na+/K+ pump current by intra- and extracellular Li ions in single guinea-pig cardiac cells.

Li+ is the only ion that can replace the physiological intra- and extracellular activator cations of the Na+/K+ pump. In order to study this singular property of Li+ in some detail, the activation of the Na+/K+ pump current (Ip) by intra- and extracellular Li+ (Li+; Li[o]+) was measured in isolated guinea-pig ventricular myocytes by means of whole cell recording at 34 degrees C and a holding potential of -20 mV. Ip was identified as current blocked by dihydro-ouabain. Half-maximal Ip activation occurred at 23 mM Li(o)+ (K0.5 value) in cells containing Na+ (50 or 100 mM) and at 73 mM Li(o)+ in myocytes containing Li+ (100 mM). The K0.5 value of Ip activation by Li(o)+ increased with depolarisation, suggesting the transfer of 0.2 of an elementary charge across the electric field of the sacrolemma during Li(o)+-binding. An intracellular Li+ concentration of 36 mM caused half-maximal Ip activation in cells superfused with Na+- and Li+-free media containing 1 mM K+. In Na+-free solutions. the Ip-V curve displayed a positive slope at negative membrane potentials. A negative slope at positive potentials was observed in Li+-containing media. It is concluded that Li+ is less efficacious and potent than the physiological pump activator cations. The shape of the Ip-V curves in Na+-free solutions supports the view that the cardiac Na+/K+ pump contains a channel-like structure and suggests that there are voltage-sensitive steps in the pump cycle, apart from the binding of external cations.

The antagonistic effect of K+o and dihydro-ouabain on the Na+ pump current of single rat and guinea-pig cardiac cells.

1. The antagonistic effect of extracellular potassium ions (K+o) and dihydro-ouabain (DHO) on the Na(+)-K+ pump current (Ip) was studied in isolated ventricular cells. 2. The myocytes were isolated from rats and guinea-pigs, two species with different sensitivity towards cardiac glycosides. Ip measurements were performed at 32-34 degrees C by means of whole-cell recording. The membrane potential was held at -20 mV throughout. 3. The DHO concentration ([DHO]) required for half-maximal Ip inhibition (apparent KD value, KD') amounted to 2.4 x 10(-3) and 1.4 x 10(-5) M for rat and guinea-pig myocytes, respectively, at 5.4 mM K+o. 4. The data suggest one-to-one binding of DHO to the Na(+)-K+ pump and a smaller association rate constant, as well as a larger dissociation rate constant, for binding of DHO in the rat cells. 5. Ip activation by K+o was nearly identical in myocytes of both species and was measured to be half-maximal at approximately 1 mM K+o. Half-maximal Ip activation by K+o remained essentially unchanged, but Ip decreased in media containing [DHO] near the respective KD' at 5.4 mM K+o. 6. The concentration-response curve of Ip inhibition by DHO was shifted to higher [DHO] at higher [K+]o. KD' increased correspondingly. The slope of the curve was unaffected. 7. Ip and KD' displayed a similar dependence on [K+]o. 8. KD' was larger in Na(+)-free than in Na(+)-containing media under conditions in which the activation of Ip by K+o was nearly the same. 9. It is concluded that the antagonism between K+o and DHO, with regard to the activation of Ip, is non-competitive. A possible mechanism of the antagonism is discussed. The mechanism implies binding of K+o and DHO to different conformational states of the Na(+)-K+ pump which are temporarily exposed to the external face of the sarcolemma in the pump cycle. The DHO-bound states do not participate in the generation of Ip.

The effect of cardiac glycosides on the Na+ pump current-voltage relationship of isolated rat and guinea-pig heart cells.

1. Whole-cell recording from isolated rat and guinea-pig ventricular myocytes revealed a change of the cardiac Na+ pump current (Ip)-voltage (V) relationship by cardiac glycosides, specific inhibitors of the Na(+)-K+ pump. 2. Dihydro-ouabain (DHO) diminished Ip in rat ventricular cells at 0 mV in a concentration-dependent manner. 3. The concentration-response curve of Ip inhibition caused by DHO was shifted to higher [DHO] at higher extracellular K+ concentrations ([K+]o) or at more negative membrane potentials. 4. In rat myocytes, DHO immediately flattened the normalized cardiac Ip-V curve and evoked or enhanced a region of negative slope. 5. Ouabain, at concentrations which caused a comparable inhibition of Ip, exerted DHO-like effects on the Ip-V relationship of rat ventricular myocytes. However, the effects developed more slowly. 6. A slowly developing alteration of the Ip-V curve was also observed upon application of DHO to guinea-pig ventricular cells. The range of [DHO] used was about 100-fold lower than that applied to rat ventricular cells, but was equally effective for Ip inhibition. 7. Increasing the K+ concentration of DHO-containing media affected the existing equilibrium of DHO binding to the cardiac Na(+)-K+ pump. A new equilibrium was reached within about 3 s in rat ventricular myocytes, but only within about 50 s in guinea-pig ventricular cells under the experimental conditions chosen. 8. It is concluded that the changes of the cardiac Ip-V curve induced by cardiac glycosides are mediated by voltage-dependent variations of the local [K+]o at the K+ binding sites of the Na(+)-K+ pump in an 'access channel'. The variations were estimated by means of the Boltzmann equation. The estimations agreed with those derived from the measured DHO binding to the Na(+)-K+ pump at various [K+]o. A new equilibrium of glycoside binding to the pump is established at the altered [K+]o. The time necessary to reach the new binding equilibrium varies with the cardioactive steroid, its concentration and the glycoside sensitivity of the cardiac cells.

Visual outcome of low-birth-weight infants (1500-2500 g) at one year of corrected age.

Visual functions (grating acuity, visual field size, optokinetic nystagmus and eye alignment) were tested as part of a longitudinal study in 96 low-birth-weight infants (birth weight 1500-2500 g) at one year of corrected age. Except for optokinetic nystagmus, deficit rates of all visual functions were low, and the obtained values comparable with normal age values in full-term infants. Effects of gestational duration, birth weight and intrauterine growth retardation on visual functions could not be demonstrated. Some perinatal risk factors (mechanical ventilation, oxygen treatment for more than one day, the presence of maternal hypertensive disorders) and a less-optimal neurodevelopmental status at one year had a negligible effect on visual field size. The observed deficits are not likely to cause disability. Low-birth-weight infants appeared not to be at risk for developing visual deficits at one year of corrected age.

Appendicitis caused by carcinoid tumor.

A previously healthy man had a carcinoid tumor that caused obstruction and dilatation of the appendiceal lumen, with subsequent inflammation of the appendix. He had acute pain in the lower right abdomen, loss of appetite, constipation, pyrexia, and an increased erythrocyte sedimentation rate without leukocytosis. Although his clinical signs and symptoms subsided, the persistent pathologic finding of a large dilated appendix at examination with ultrasound warranted surgery, which, with microscopy, established the correct diagnosis.

Visual acuity in low birth weight (1500-2500 g) neonates.

Binocular grating acuity was tested in 138 low birth weight (LBW) neonates (birth weights ranging from 1500 to 2500 g) by means of the prototype version of the Acuity Card Procedure. No surrounding screen was used. Mean visual acuity of 107 neonates successfully assessed at mean corrected ages of -1.9 weeks (+/- 1.9 weeks) amounted to 0.58 cycles/degree (S.D. 0.71 octaves). Success rate was 77.5%. Mean postnatal age was 2.3 weeks (+/- 1.6 weeks). Acuity values of various subgroups ranged between 0.68 cycles/degree (S.D. 1.3 octaves) in low-risk, small for gestational age (SGA) preterms (n = 7), to 0.56 cycles/degree (S.D. 0.7 octaves) in SGA fullterms (n = 34), independent whether at low-or at high-risk. These differences were not significant, although with multiple regression analysis with adjustment for corrected age of testing, mean acuity of low-risk preterms was slightly better than of low-risk fullterms (P = 0.055). No significant change of acuity over corrected age could be demonstrated, except for a slight progress (r = 0.57; P less than 0.05) in the subgroup of 13 low-risk fullterms. The high variability of acuity values in neonates and the slow acuity development at term age hamper assessment of differences between various subgroups of neonates.

Chronic myeloid leukemia may be associated with several bcr-abl transcripts including the acute lymphoid leukemia-type 7 kb transcript.

In the majority of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) patients, the c-abl gene is fused to the bcr gene, resulting in the transcription of an 8.5 kb chimeric bcr-abl mRNA, which is translated into a p210bcr-abl fusion protein. In about 50% of the Ph-positive acute lymphoid leukemias (ALL), the bcr-abl gene fusion is identical to CML, while in 50% an alternative fusion between these two genes occurs, in which the central bcr-sequences are absent. This results in transcription of a 7 kb bcr-abl mRNA, encoding a P190bcr-abl fusion protein. Cloning and sequencing of the chimeric part of bcr-abl cDNAs from two Ph-positive CML patients in chronic phase showed that in one patient, as in the Ph-positive ALL, all central bcr sequences are absent, while in the other patient, part of the bcr central sequences are deleted. Therefore, we speculate that the presence of the 7 kb chimeric ALL type mRNA in one of the patients is not sufficient to drive an acute rather than a chronic leukemic process in this case. The deletions of the central bcr-sequences described here define the minimal sequence requirement of the bcr-abl fusion gene in CML patients so far.

Cytogenetic and molecular analysis in Philadelphia negative CML.

We studied the clinical, hematologic, cytogenetic and molecular biologic features in four patients with Philadelphia (Ph) negative chronic myeloid leukemia (CML). In all four cases the clinical and hematologic characteristics were indistinguishable from Ph positive CML. Cytogenetic analysis showed a normal karyotype in two patients and chromosomal translocations apparently not affecting chromosome 22 in the other two cases. Southern blot analysis using probes of the bcr region, demonstrated a bcr break-point in all four patients. In situ hybridization with bcr, c-abl, and c-sis probes showed unusual hybridization sites for 5'-bcr and c-abl indicating complex chromosomal rearrangements affecting three different chromosomes in the four patients investigated. Using polymerase chain reaction (PCR) followed by hybridization to oligonucleotide probes specific for the bcr-abl fusion region, the expression of a chimeric bcr-abl mRNA was detected. In these patients we demonstrated that (a) CML with a breakpoint in the bcr region without cytogenetically detectable Ph chromosome is characterized by the same genomic recombination of 5'-bcr and c-abl as CML with standard Ph translocation and (b) unusual localization of 5'-bcr and c-abl sequences caused by complex Ph translocation does not interfere with transcription of the bcr-abl fusion gene.

Antibody recognition of the tumor-specific bcr-abl joining region in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by the presence of a 210-kD protein (P210bcr-abl) in the cytoplasm of leukemic cells, generated by the reciprocal translocation between chromosome 9 and chromosome 22. Due to this translocation, the abl oncogene is coupled to the bcr gene, forming a new determinant in this protein encoded by the bcr-abl joining region. In the joining region itself, either the bcr exon 2 is coupled to the abl exon 2 (b2-a2), or the bcr exon 3 is coupled to the abl exon 2 (b3-a2). Thus, these joining regions form by definition new tumor-specific determinants in the respective chimeric P210-bcr-abl molecules. This paper addresses the question as to whether these tumor-specific joining regions are exposed on the P210bcr-abl molecule in such a way that antibodies can be generated to detect these sites. To test this possibility a polyclonal antiserum, termed BP-1, was raised against a synthetic peptide representative for the b2-a2 joining region. The reactivity of BP-1 was analyzed in an ELISA system on various synthetic peptides. Peptide inhibition studies showed the presence of antibodies to different parts of the b2-a2 peptide in the polyvalent antiserum. The reactivity of BP-1 was then tested with native P210bcr-abl molecules in various CML cell lines (K562, LAMA-84, and BV173) using a protein kinase assay. In this context, the bcr-abl junctions were first analyzed at the DNA and RNA level. The present study indicates that BP-1 specifically recognizes the b2-a2 junction in native P210bcr-abl. Furthermore, BP-1 clearly discriminates between b2-a2 P210bcr-abl and b3-a2 P210bcr-abl. We conclude that the tumor-specific b2-a2 joining region is antigenically exposed on the native P210bcr-abl molecule.

Absence of alternative splicing in bcr-abl mRNA in chronic myeloid leukemia cell lines.

The major consequence of the Philadelphia (Ph) translocation in chronic myeloid leukemia (CML) is the formation of a bcr-abl hybrid oncogene encoding a tumor cell-specific protein P210bcr-abl. In contrast to this, in Ph chromosome-positive acute lymphoblastic leukemia (Ph + ALL), a P190bcr-abl can be observed. This P190bcr-abl has been implicated in acute rather than chronic leukemogenesis. Therefore, it can be hypothesized that the transition from chronic to blast phase in CML is accompanied by an alternative splice in the bcr-abl mRNA, which results in a switch of the production of P210bcr-abl into P190bcr-abl. Initial S1 nuclease protection mapping supported this theory. However, this result appears to be based on an artifact in the S1 analysis. By using the polymerase chain reaction we provide evidence for the absence of alternative splicing in bcr-abl mRNA in two CML blast crisis cell lines.

bcr-abl oncogene activation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Tumor-specific alterations in oncogenes are thought to play a central role in the development of cancer. An example is the consistent fusion of the bcr gene to the c-abl oncogene on the Ph chromosome in CML. The Ph chromosome can also be observed in ALL. About 50% of Ph+ ALL cases, in contrast to CML, do not exhibit chromosomal breakpoints in the major cluster region or mcr (Ph+ mcr- ALL). These cases may have a novel bcr-abl fusion gene instead. We tested this hypothesis in eight Ph+ mcr- ALL patients by amplifying the putative hybrid part of the bcr-abl cDNA, using the polymerase chain reaction method. All cases examined showed the same joining of the first exon of the bcr gene to the c-abl oncogene. Thus, the novel bcr-abl fusion in Ph+ mcr- ALL is the result of a molecularly distinct Ph chromosome. This allows the definition of Ph+ leukemias by their respective bcr-abl oncogene activation. Moreover, the cDNA amplification method we use is a clinically useful tool to screen for bcr-abl oncogene activations in leukemia patients.

The suitability of saliva for detection of glucose-6-phosphate dehydrogenase deficiency.

Saliva was investigated for its suitability as a biopsy tissue for the determination of glucose-6-phosphate dehydrogenase deficiency. It appears that there is a significant difference between the activity of the enzyme in patients and controls. However, some controls have very low values making discrimination between patients and controls using a qualitative method impossible. Glucose-6-phosphate dehydrogenase deficiency is a relevant clinical problem in many rural areas in developing countries. Existing methods for determination of the deficiency in blood and hair follicles do not meet the criteria necessary for their large scale introduction in the areas of the world that are concerned by the problem. The present study shows that saliva is not a suitable alternative. Between the three biopsy tissues compared: blood, hair follicles and saliva, hair follicles remain most attractive since their isolation hardly involves the risk of infection. A simplified method for the detection of glucose-6-phosphate dehydrogenase activity in hair follicles that would allow health service workers in the field to determine the carrier status of pregnant women might form the basis for a future kernicterus prevention programme.