Scandcleft randomized trials of primary surgery for unilateral cleft lip and palate: Speech proficiency at 10 years of age.

BACKGROUND & AIM: To assess consonant proficiency and velopharyngeal function in 10-year-old children born with unilateral cleft lip and palate (UCLP) within the Scandcleft project. METHODS & PROCEDURES: Three parallel group, randomized, clinical trials were undertaken as an international multicentre study by nine cleft teams in five countries. Three different surgical protocols for primary palate repair (Arm B-Lip and soft palate closure at 3-4 months, hard palate closure at 36 months, Arm C-Lip closure at 3-4 months, hard and soft palate closure at 12 months, and Arm D-Lip closure at 3-4 months combined with a single-layer closure of the hard palate using a vomer flap, soft palate closure at 12 months) were tested against a common procedure (Arm A-Lip and soft palate closure at 3-4 months followed by hard palate closure at 12 months) in the total cohort of 431 children born with a non-syndromic UCLP. Speech audio and video recordings of 399 children were available and perceptually analysed. Percentage of consonants correct (PCC) from a naming test, an overall rating of velopharyngeal competence (VPC) (VPC-Rate), and a composite measure (VPC-Sum) were reported. OUTCOMES & RESULTS: The mean levels of consonant proficiency (PCC score) in the trial arms were 86-92% and between 58% and 83% of the children had VPC (VPC-Sum). Only 50-73% of the participants had a consonant proficiency level with their peers. Girls performed better throughout. Long delay of the hard palate repair (Arm B) indicated lower PCC and simultaneous hard and soft palate closure higher (Arm C). However, the proportion of participants with primary VPC (not including velopharyngeal surgeries) was highest in Arm B (68%) and lowest in Arm C (47%). CONCLUSIONS & IMPLICATIONS: The speech outcome in terms of PCC and VPC was low across the trials. The different protocols had their pros and cons and there is no obvious evidence to recommend any of the protocols as superior. Aspects other than primary surgical method, such as time after velopharyngeal surgery, surgical experience, hearing level, language difficulties and speech therapy, need to be thoroughly reviewed for a better understanding of what has affected speech outcome at 10 years. WHAT THIS PAPER ADDS: What is already known on the subject Speech outcomes at 10 years of age in children treated for UCLP are sparse and contradictory. Previous studies have examined speech outcomes and the relationship with surgical intervention in 5-year-olds. What this study adds to the existing knowledge Speech outcomes based on standardized assessment in a large group of 10-year-old children born with UCLP and surgically treated according to different protocols are presented. While speech therapy had been provided, a large proportion of the children across treatment protocols still needed further speech therapy. What are the potential or actual clinical implications of this work? Aspects other than surgery and speech function might add to the understanding of what affects speech outcome. Effective speech therapy should be available for children in addition to primary surgical repair of the cleft and secondary surgeries if needed.

IgE and risk of cancer in 37 747 individuals from the general population.

BACKGROUND: Immunoglobulin E (IgE) is produced by plasma cells, often as part of an allergic immune response. It is currently unknown whether plasma IgE levels are associated with risk of cancer in individuals from the general population. We tested the hypothesis that high levels of plasma total IgE are associated with overall risk of cancer and with risk of specific cancers. MATERIALS AND METHODS: Plasma total IgE was measured in 37 747 individuals from the general population, and the participants were followed prospectively for up to 30 years. All statistical tests were two-sided. RESULTS: During a mean follow-up of 7 years, a first cancer was diagnosed in 3454 participants. The multivariable adjusted hazard ratio for a 10-fold higher level of IgE was 1.05 [95% confidence interval (CI) 1.00-1.11; P = 0.04] for any cancer, 0.44 (0.30-0.64; P = 0.00002) for chronic lymphocytic leukemia (CLL), 0.53 (0.33-0.84; P = 0.007) for multiple myeloma, 1.54 (1.04-2.29; P = 0.03) for other non-Hodgkin lymphoma, 1.38 (1.04-1.84; P = 0.03) for cancer of the oral cavity and pharynx, and 1.12 (1.00-1.25; P = 0.05) for lung cancer. The findings for CLL and multiple myeloma were generally robust; however, after correcting for 27 multiple comparisons only the finding for CLL remained significant. CONCLUSION: High levels of plasma total IgE were associated with low risk of CLL and possibly of multiple myeloma, without convincing evidence for high risk of any cancer type.

Discovery of key whole-brain transitions and dynamics during human wakefulness and non-REM sleep.

The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep.

Structure-activity relationships of analogues of thapsigargin modified at O-11 and O-12.

A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant toward beta-disposed substituents, indicating that the alpha-face of the lactone ring is in close contact with the binding site when the inhibitor is bound to the enzyme.

Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis.

A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes.

Novel potent ligands for the central nicotinic acetylcholine receptor: synthesis, receptor binding, and 3D-QSAR analysis.

In the past few years the focus on central acetylcholine receptors has shifted from compounds with affinity for muscarinic acetylcholine receptors (mAChR) to compounds with affinity for nicotinic acetylcholine receptors (nAChR). The therapeutic potential includes treatment of a variety of diseases, e.g., Alzheimer's disease, Parkinson's disease, and Tourette's syndrome. This work describes the synthesis of six novel series of potent ligands with nanomolar affinity for the alpha4beta2 nAChR subtype. Structure-activity relationship (SAR) was evaluated by the calculation of a 3D-QSAR model. 3D-QSAR analysis of the compounds using the GRID/GOLPE methodology resulted in a model of high quality (R(2) = 0.97, Q(2) = 0.81). The coefficient plots reveal that the steric interactions between the target and our compounds are of major importance for the affinity. Bulky substituents in the 6-position of the pyridine ring will reduce the affinity of the compounds, whereas bulky ring systems including a sp(3)-nitrogen will increase the affinity of the compounds.

Inhomogeneous plastic flow investigated by X-ray absorption microtomography of an aluminium alloy containing marker particles.

By combining a synchrotron X-ray source and the microtomography technique, the displacement gradient tensor components can be measured directly throughout the volume of a metal sample containing highly absorbing marker particles to detect material flow. The present article describes application of these techniques to compression of a rectangular Al-W specimen with a central hole. The results show that the externally imposed axial displacement gradient is accommodated mainly in two 45 degrees shear bands passing through the hole. A simple deformation analysis provides insight into shear band formation.

Psychological changes in children after anaesthesia: a comparison between halothane and ketamine.

The psychological reactions to hospitalization, anaesthesia, and operation in a group of 107 children from 1 to 12 years old, anaesthetized with ketamine or halothane after randomization were investigated through questionnaires, which the parents answered 1 month postoperatively. The percentage of replies was 96.3%. Fifty-three children were anaesthetized with ketamine and 50 with halothane. Thirteen children in the ketamine group and nine in the halothane group reacted with negative personality changes; the reactions were of less than 1 month's duration and were most frequent in the youngest children. The parents' preparation of the children had no influence on the results. The number of personality changes caused by the two anaesthetic agents did not differ significantly. Furthermore, the investigation showed the nine children reacted for the better. Thirty-six per cent of the parents felt insufficiently informed of what the hospitalization implied for their child.

Modifications of the alpha,beta-double bond in chalcones only marginally affect the antiprotozoal activities.

Methods for selective alkylation of chalcones in the alpha- or beta-position and for selective reduction of the alpha,beta-double bond have been developed. The antiparasitic potencies of the alpha,beta-double bond modified chalcones only differ marginally from the potencies of the parent chalcones indicating that the propenone residue only functions as a spacer between the two benzene rings, which are the true pharmacophore.

Breast cancer incidence subsequent to surgical reduction of the female breast.

The incidence of breast cancer among 1240 women who were treated surgically for breast hypertrophy in Copenhagen, Denmark between 1943 and 1971 was determined and compared with age- and calendar period-specific rates for the Danish female population. A total of 32 cases of breast cancer had developed by the end of 1990; the expected number was 52.55, yielding a relative risk (RR) of 0.61 [95% confidence interval (CI) 0.42-0.86]. The greatest reduction in risk was observed for women who had 600 g or more of breast tissue removed (RR=0.30; 95% CI 0.10-0.69). This suggests that the number of potential foci is important for cancer development in the female breast. In the group of women who were operated on before the age of 20, four cases of breast cancer developed, compared with 2.23 expected cases, to give an RR of 1.79, suggesting that the aetiology of their breast hypertrophy may be different from that for the rest of the group.

A comparison between reaction time measurement and critical flicker fusion frequency under rising nitrous oxide inhalation in healthy subjects.

Ten subjects volunteered to inhale a test gas containing 0, 10, 20 and 30% nitrous oxide. After equilibration at each nitrous oxide concentration, the reaction time was measured using both the single-hand and the double-hand methods, and then the critical flicker fusion frequency was measured. Using the flicker funsion frequency test, significant changes from the normal range were found at 20 and 30% nitrous oxide in the test gas, whereas no significant changes were found with the fusion flicker frequency test. No significant prolongation was found with either double-hand or single-hand reaction time measurements until 30% nitrous oxide in the test gas was reached. It is concluded that critical flicker fusion frequency measurement is a simpler, more time-saving and more sensitive method for the estimation of the changes which nitrous oxide produces in healthy subjects than reaction time measurement, and that critical flicker fusion frequency measurement will presumably be a useful supplement to clinical examination as an objective method for the estimation of postanaesthetic recovery in patients.

Watching the growth of bulk grains during recrystallization of deformed metals.

We observed the in situ growth of a grain during recrystallization in the bulk of a deformed sample. We used the three-dimensional x-ray diffraction microscope located at the European Synchrotron Radiation Facility in Grenoble, France. The results showed a very heterogeneous growth pattern, contradicting the classical assumption of smooth and spherical growth of new grains during recrystallization. This type of in situ bulk measurement opens up the possibility of obtaining experimental data on scientific topics that before could only be analyzed theoretically on the basis of the statistical characterization of microstructures. For recrystallization, the in situ method includes direct measurements of nucleation and boundary migration through a deformed matrix.

A conical slit for three-dimensional XRD mapping.

Traditionally, depth resolution in diffraction experiments is obtained by inserting pinholes in both the incoming and diffracted beam. For materials science investigations of local strain and texture properties this leads to very slow data-acquisition rates, especially when characterization is performed on the level of the individual grains. To circumvent this problem a conical slit has been manufactured by wire-electrodischarge machining. The conical slit has six 25 microm-thick conically shaped openings matching six of the Debye-Scherrer cones from a face-centred-cubic powder. By combining the slit with a microfocused incoming beam of hard X-rays, an embedded gauge volume is defined. Using a two-dimensional detector, fast and complete information can be obtained regarding the texture and strain properties of the material within this particular gauge volume. The average machining and assemblage errors of the conical slit are found both to be of the order of 5 microm. An algorithm for alignment of the slit is established, and the potential of the technique is illustrated with an example of grain mapping in a 4.5 mm-thick Cu sample.