Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Diagnostic performance of axillary ultrasound and standard breast MRI for differentiation between limited and advanced axillary nodal disease in clinically node-positive breast cancer patients.

Preoperative differentiation between limited (pN1; 1-3 axillary metastases) and advanced (pN2-3; ≥4 axillary metastases) nodal disease can provide relevant information regarding surgical planning and guiding adjuvant radiation therapy. The aim was to evaluate the diagnostic performance of preoperative axillary ultrasound (US) and breast MRI for differentiation between pN1 and pN2-3 in clinically node-positive breast cancer. A total of 49 patients were included with axillary metastasis confirmed by US-guided tissue sampling. All had undergone breast MRI between 2008-2014 and subsequent axillary lymph node dissection. Unenhanced T2-weighted MRI exams were reviewed by two radiologists independently. Each lymph node on the MRI exams was scored using a confidence scale (0-4) and compared with histopathology. Diagnostic performance parameters were calculated for differentiation between pN1 and pN2-3. Interobserver agreement was determined using Cohen's kappa coefficient. At final histopathology, 67.3% (33/49) and 32.7% (16/49) of patients were pN1 and pN2-3, respectively. Breast MRI was comparable to US in terms of accuracy (MRI reader 1 vs US, 71.4% vs 69.4%, p = 0.99; MRI reader 2 vs US, 73.5% vs 69.4%, p = 0.77). In the case of 1-3 suspicious lymph nodes, pN2-3 was observed in 30.4% on US (positive predictive value (PPV) 69.6%) and in 22.2-24.3% on MRI (PPV 75.7-77.8%). In the case of ≥4 suspicious lymph nodes, pN1 was observed in 33.3% on US (negative predictive value (NPV) 66.7%) and in 38.5-41.7% on MRI (NPV 58.3-61.5%). Interobserver agreement was considered good (k = 0.73). In clinically node-positive patients, the diagnostic performance of axillary US and breast MRI is comparable and limited for accurate differentiation between pN1 and pN2-3. Therefore, there seems no added clinical value of preoperative breast MRI regarding nodal staging in patients with positive axillary US.

[Interceptive treatment of maxillary hypoplasia with the use of bone anchors. A review of the literature]. / Interceptieve behandeling van een maxillaire hypoplasie met behulp van botankers. Een literatuuronderzoek.

A Class III malocclusion is mainly caused by a hypoplastic maxilla and therefore the treatment is principally aimed at stimulating the growth of the maxilla. Disadvantages of conventional treatment methods are that treatment effects are mainly dentoalveolar rather than skeletal and that there is often an increase in the height of the lowerface. Moreover, patients are not always cooperative about wearing extra-oral appliances. Because of these disadvantages, a new treatment approach has been developed which makes use of skeletal anchoring. In this new technique, called 'bone anchored maxillary protraction, bone anchors are placed on both sides of the maxilla and the mandibula, onto which Class III elastics are attached. The literature shows that good results have been achieved with this method. Disadvantages of this method are that the placement of the bone anchors requires a surgical procedure and that complications, like the loosening or breaking of the anchors, can occur.

[Orthodontic-surgical treatment puts an end to temporomandibular dysfunction complaints]. / Orthodontisch-chirurgische behandeling maakte einde aan temporomandibulaire disfunctieklachten.

Late in the last decade of the previous century, an orthodontic-surgical treatment was elected for a 31-years-old woman, who had severe malocclusion and temporomandibular complaints. The skeletal pattern (high angled mandibula) and degenerating joints were considered risk factors for relapse and condylar lysis. Nevertheless, the severity of the malocclusion justified the treatment. The goal was a stable occlusion and the creation ofa smooth articulation to eliminate dysfunction and facilitate later temporomandibular joint treatment with splints if necessary. In the 1990s this was considered state of the art treatment. Eliminating the scissors bite of 27 seemed instrumental in the elimination of the symptoms. Surgery brought the face and the occlusion further in harmony. The final occlusion features only one lower incisor.

Effects of casein phosphopeptide amorphous calcium fluoride phosphate paste on white spot lesions and dental plaque after orthodontic treatment: a 3-month follow-up.

The effects of casein phosphopeptide amorphous calcium fluoride phosphate (CPP-ACFP) paste vs. control paste on the remineralization of white spot caries lesions and on plaque composition were tested in a double-blind prospective randomized clinical trial. Fifty-four orthodontic patients, with multiple white spot lesions observed upon the removal of fixed appliances, were followed up for 3 months. Subjects were included and randomly assigned to either CPP-ACFP paste or control paste, for use supplementary to their normal oral hygiene. Caries regression was assessed on quantitative light-induced fluorescence (QLF) images captured directly after debonding and 6 and 12 wk thereafter. The total counts and proportions of aciduric bacteria, Streptococcus mutans, and Lactobacillus spp. were measured in plaque samples obtained just before debonding, and 6 and 12 wk afterwards. A significant decrease in fluorescence loss was found with respect to baseline for both groups and no difference was found between groups. The size of the lesion area did not change significantly over time or between the groups. The percentages of aciduric bacteria and of S. mutans decreased from 47.4 to 38.1% and from 9.6 to 6.6%, respectively. No differences were found between groups. We observed no clinical advantage for use of the CPP-ACFP paste supplementary to normal oral hygiene over the time span of 12 wk.

A new 2-dimensional method for constructing visualized treatment objectives for distraction osteogenesis of the short mandible.

Open bite development during distraction of the mandible is common and partly due to inaccurate planning of the treatment. Conflicting guidelines exist in the literature. A method for Visualized Treatment Objective (VTO) construction is presented as an aid for determining the correct orientation of monodirectional and multidirectional distractors. Distraction on the left and on the right side of the mandible takes place in a parallel manner in order to maintain intercondylar width. It follows that in the absence of marked asymmetry, the amount of mandibular body distraction, the amount of ramus distraction and (should it apply), the amount of closure of the gonial angle, can be derived from a simple 2-dimensional plan. After presurgical orthodontic treatment, a cephalogram is taken and a VTO is constructed, that aims at a good occlusion with the enhanced mandible in centric relation, with little or no change of the original position of the rami.

[Pre- and postsurgical orthodontics]. / Pre- en postchirurgische orthodontie.

Presurgical orthodontic treatment may be hampered by anomalous anatomic relations, function and dento-alveolar compensation. A stabilizing, solid postsurgical occlusion requires presurgical dento-alveolar decompensation. Some sagittal overcorrection simplifies postsurgical orthodontic treatment. In distorelations, a diastema created between maxillary lateral incisors and cuspids may be helpful in this respect. The diastema is providing space for overcorrection and consequently the postsurgical orthodontic treatment can be simplified. In mesiorelations, creating additional space is not required because premature frontal contact is not a disturbing factor. Conversely, in short face patients frontal contact is just useful for gaining facial height.

[Risks of orthodontic treatment]. / Risico's van orthodontische behandeling.

Risks of orthodontic treatment identified in the literature are: enamel damage, root resorption, periodontal damage, temporomandibular disorders, tooth devitalization, treatment failure, and relapse. Enamel damage in the form of irreversible demineralization can take place during treatment with fixed appliances in the absence of adequate oral hygiene. Root resorption occurs, but seldom to the point of clinical relevance. Individual susceptibility and genetics are determining factors. Periodontal damage occurs as gingival recessions. Temporomandibular disorders and tooth devitalization hardly occur. Treatment failure is related to the assessed pre-treatment goals and dependent on the knowledge and skills of the care provider, patient-cooperation, and factors beyond anyone's control. Relapse is a common feature, but does not constitute a treatment risk. The greatest risk is a failure to adequately inform the patient concerning all of the (im)possibilities and their consequences.

[Does orthodontic treatment contribute to oral health?]. / Draagt orthodontische behandeling bij aan de mondgezondheid?

The first part of this article is an edited Dutch summary of the paper "Oral-health-related benefits of orthodontic treatment" by Donald J. Burden in the special issue''Orthodontics: quality of care, quality of life'' in Seminars in Orthodontics (June 2007). Burden carried out a systematic review of the literature on some, historically claimed, beneficial influences of orthodontic treatment, such as reduced susceptibility to dental caries, periodontal disease, temporomandibular dysfunction, and traumatic injury. Based on the results of this review, Burden concludes that the oral health benefits of orthodontic intervention have not been demonstrated. The second part is a critical and balanced commentary on the content of the paper and on Burden's conclusions.

[Dissertations 25 years later. 1. Mesial drift of teeth by occlusal forces]. / Proefschriften 25 jaar na dato 1. Mesiale migratie van gebitselementen door occlusale krachten.

More than 25 years ago the thesis 'Functional occlusion and mesial drift, an experimental study of tooth migration in monkeys' was presented. A literature review was carried out to assess whether the results have withstood the test of time. It was confirmed that occlusion plays an important role in mesial drift, whilst no direct evidence for transseptal fibre contraction as a causal factor has been put forward. Mesial drift is not merely a compensatory mechanism for loss of tooth substance, but may cause crowding, depending on axial inclination and occlusal morphology. This phenomenon has implications for orthodontic and restorative treatments.

The precedence effect for lateralization at low sensation levels.

Using dichotic signals presented by headphone, stimulus onset dominance (the precedence effect) for lateralization at low sensation levels was investigated for five normal hearing subjects. Stimuli were based on 2400-Hz low pass filtered 5-ms noise bursts. We used the paradigm, as described by Aoki and Houtgast (Hear. Res., 59 (1992) 25-30) and Houtgast and Aoki (Hear. Res., 72 (1994) 29-36), in which the stimulus is divided into a leading and a lagging part with opposite lateralization cues (i.e. an interaural time delay of 0.2 ms). The occurrence of onset dominance was investigated by measuring lateral perception of the stimulus, with fixed equal duration of leading and lagging part, while decreasing absolute signal level or adding a filtered white noise with the signal level set at 65 dBA. The dominance of the leading part was quantified by measuring the perceived lateral position of the stimulus as a function of the relative duration of the leading (and thus the lagging) part. This was done at about 45 dB SL without masking noise and also at a signal-to-noise ratio resulting in a sensation level of 10 dB. The occurrence and strength of the precedence effect was found to depend on sensation level, which was decreased either by lowering the signal level or by adding noise. With the present paradigm, besides a decreased lateralization accuracy, a decrease in the precedence effect was found for sensation levels below about 30-40 dB. In daily-life conditions, with a sensation level in noise of typically 10 dB, the onset dominance was still manifest, albeit degraded to some extent.

Lead intoxication in cattle: a case report.

During the autumn of 1989 a feed contamination induced a widespread lead intoxication of cattle in the northern provinces of The Netherlands (Groningen and Friesland). Over 300 farms were involved, affecting about 15,500 animals (mostly dairy cattle). For a period of one to four weeks these animals took up a thousand kg of lead. This resulted in lead levels in milk, livers, and kidneys above the regulatory safety limits. Due to the chelating therapy, which was rapidly applied by the local veterinarians, only about 30 animals died of an acute lead intoxication. A joint action of the governmental and private authorities prevented exposure of consumers to lead-contaminated animal products. Based on observations, measurements and literature data, predictions were made of the lead levels to be expected in animal products and the time needed for depletion of these levels. The appropriate animals were ear-tagged to ensure their identification, and the decline in time of the lead levels in milk and offals was conscientiously monitored. In the second week of 1990 the lead concentrations were decreased to levels well below the regulatory limits, and hence the tags were removed. The present paper reports our observations and conclusions, especially regarding treatment, predictions and outcome of this incident.

Increased metallothionein in the liver and kidney of patients with amyotrophic lateral sclerosis.

To evaluate the putative role of metals and trace elements in the pathogenesis of classic amyotrophic lateral sclerosis, we studied the metallothionein levels in liver and kidney samples obtained at autopsy from 24 patients with amyotrophic lateral sclerosis and 18 controls. To assay metallothioneins and copper, cadmium, and zinc bound to metallothioneins, we used high-performance liquid chromatography directly coupled to flame atomic absorption spectrometry. Total cadmium, zinc, and copper concentrations were determined separately with the use of graphite furnace atomic absorption spectrometry with Zeeman background correction. The median liver metallothionein level was 60.3 mg/kg (range, 9 to 318 mg/kg) in the patients with amyotrophic lateral sclerosis and 12.6 mg/kg (range, 0 to 104.5 mg/kg) in the controls. In the kidney, median metallothionein levels were 126.9 mg/kg (range, 44 to 387 mg/kg) in the patients with amyotrophic lateral sclerosis and 64 mg/kg (range, 13.1 to 187 mg/kg) in the controls. Total zinc, cadmium, and copper concentrations, as measured by atomic absorption spectrometry, were not significantly different in patients vs controls. Our finding of elevated metallothionein levels in organs from patients with amyotrophic lateral sclerosis may indicate an increased exposure to metals.

A compact body mass measuring device for space flight applications.

During spaceflights, it is important to measure an astronaut's body mass ('weight'), both for investigating the influence of the space environment on the human body and for monitoring the physical (health) condition of the astronaut. This paper reports the development of a mass measuring device that is compact, user friendly, and has an absolute measuring accuracy better than 60 gram. The measurement accuracy turns out to be restricted by the way a human body is configured by nature and not by the instrument itself, that has an accuracy much better than required.

[The impacted upper cuspid]. / De geimpacteerde hoektand in de bovenkaak.

Impacted upper cuspids may give rise to problems, such as the formation of cysts and the resorption of adjacent teeth. Early diagnosis (before the age of 12) is important. Proper timing of extraction of the deciduous cuspid may lead to spontaneous correction. When the position of the cuspid is unclear, orthopantomography and a lateral skull film may be helpful. Palatally impacted cuspids should be exposed surgically and moved into position by orthodontic treatment. Labially impacted cuspids are exposed by relocation of an attached gingival flap. The experience of the authors with the treatment of 81 patients are reported.