Nina Timmesfeld

Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies

A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing ~500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.

A meta-analysis of the randomized controlled trials on elective neck dissection versus therapeutic neck dissection in oral cavity cancers with clinically node-negative neck.

There is still no consensus on the optimal treatment of the neck in oral cavity cancer patients with clinical N0 neck. The aim of this study was to assess a possible benefit of elective neck dissection in oral cancers with clinical N0 neck. A comprehensive search and systematic review of electronic databases was carried out for randomized trials comparing elective neck dissection to therapeutic neck dissection (observation) in oral cancer patients with clinical N0 neck. A meta-analysis of the studies which met our defined selection criteria was performed using disease-specific death as the primary outcome, and the relative risk (RR) of disease-specific death was calculated for each of the identified studies. Both fixed-effects (Mantel-Haenszel method) and random-effects models were applied to obtain a combined RR estimate, although between-study heterogeneity was not found to be significant as indicated by an I(2) of 8.5% (p=0.350). Four studies with a total of 283 patients met our inclusion criteria. The results of the meta-analysis showed that elective neck dissection reduced the risk of disease-specific death (fixed-effects model RR=0.57, 95% CI 0.36-0.89, p=0.014; random-effects model RR=0.59, 95% CI 0.37-0.96, p=0.034) compared to observation. This reduction in disease-specific death rate supports the need to perform elective neck dissection in oral cancers with clinical N0 neck.

Day-patient treatment after short inpatient care versus continued inpatient treatment in adolescents with anorexia nervosa (ANDI): a multicentre, randomised, open-label, non-inferiority trial

BACKGROUND In-patient treatment (IP) is the treatment setting of choice for moderately-to-severely ill adolescents with anorexia nervosa, but it is costly, and the risks of relapse and readmissions are high. Day patient treatment (DP) is less expensive and might avoid problems of relapse and readmission by easing the transition from hospital to home. We investigated the safety and efficacy of DP after short inpatient care compared with continued IP. METHODS For this multicentre, randomised, open-label, non-inferiority trial, we enrolled female patients (aged 11-18 years) with anorexia nervosa from six centres in Germany. Patients were eligible if they had a body-mass index (BMI) below the tenth percentile and it was their first admission to hospital for anorexia nervosa. We used a computer-generated randomisation sequence to randomly assign patients to continued IP or DP after 3 weeks of inpatient care (1:1; stratified for age and BMI at admission). The treatment programme and treatment intensity in both study groups were identical. The primary outcome was the increase in BMI between the time of admission and a 12-month follow-up adjusted for age and duration of illness (non-inferiority margin of 0·75 kg/m(2)). Analysis was done by modified intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number Register, number ISRCTN67783402, and the Deutsches Register Klinischer Studien, number DRKS00000101. FINDINGS Between Feb 2, 2007, to April 27, 2010, we screened 660 patients for eligibility, 172 of whom we randomly allocated to treatment: 85 to IP and 87 to DP. DP was non-inferior to IP with respect to the primary outcome, BMI at the 12-month follow-up (mean difference 0·46 kg/m(2) in favour of DP (95% CI, -0·11 to 1·02; pnon-inferiority<0·0001). The number of treatment-related serious adverse events was similar in both study groups (eight in the IP group, seven in the DP group). Three serious adverse events in the IP group and two in the DP group were related to suicidal ideation; one patient in the DP attempted suicide 3 months after she was discharged. INTERPRETATION DP after short inpatient care in adolescent patients with non-chronic anorexia nervosa seems no less effective than IP for weight restoration and maintenance during the first year after admission. Thus, DP might be a safe and less costly alternative to IP. Our results justify the broad implementation of this approach. FUNDING German Ministry for Education and Research.

Comorbid Psychiatric Disorders in Female Adolescents with First-Onset Anorexia Nervosa

OBJECTIVE Patients with anorexia nervosa (AN) exhibit high rates of psychiatric comorbidity. To disentangle the effects of duration of illness on comorbid psychiatric symptoms, we investigated the rates of comorbid psychiatric disorders, suicidality and self-harm behaviour in adolescent patients with a first onset of AN. METHODS In adolescent females (n = 148) with a first onset of AN, body mass index, psychiatric comorbidity (according to DSM-IV), depressive symptoms, suicidality and self-injurious behaviour were assessed. RESULTS Seventy patients (47.3%) met the criteria for at least one comorbid psychiatric disorder. The binge-purging subtype was associated with increased rates of psychiatric comorbidity, suicidality and self-injurious behaviour. The severity of eating disorder-specific psychopathology influenced current psychiatric comorbidity and suicidal ideation. CONCLUSION Prevalence rates of comorbid psychiatric disorders and suicidal ideation are considerably lower among adolescents with AN compared with adults. An early and careful assessment, along with adequate treatment of the eating disorder, might prevent the development of severe psychiatric comorbidities.

A comparison of intraarticular lumbar facet joint steroid injections and lumbar facet joint radiofrequency denervation in the treatment of low back pain: a randomized, controlled, double-blind trial.

BACKGROUND:Lumbar facet joint degeneration is a source of chronic low back pain, with an incidence of 15% to 45% among patients with low back pain. Various therapeutic techniques in the treatment of facet-related pain have been described in the literature, including intraarticular lumbar facet joint steroid injections and radiofrequency denervation. In this study, we compared the effectiveness of intraarticular facet joint steroid injections and radiofrequency denervation. METHODS:Our randomized, double-blind, controlled study included patients who received intraarticular steroid infiltrations in the lumbar facet joints (L3/L4–L5/S1) and patients who underwent radiofrequency denervation of L3/L4–L5/S1 segments. The inclusion criteria were based first on magnetic resonance imaging findings showing hypertrophy of the facet joints L3/L4–L5/S1 and a positive response to an intraarticular test infiltration of the facet joints L3/L4–L5/S1 with local anesthetics. The primary end point was the Roland-Morris Questionnaire. Secondary end points were the visual analog scale and the Oswestry Disability Index. All outcome assessments were performed at baseline and at 6 months. RESULTS:Fifty-six patients were randomized; 24 of 29 patients in the steroid injection group and 26 of 27 patients in the denervation group completed the 6-month follow-up. Pain relief and functional improvement were observed in both groups. There were no significant differences between the 2 groups for the primary end point (95% confidence interval [CI], −3 to 4) and for both secondary end points (95% CI for visual analog scale, −2 to 1; 95% CI for Oswestry Disability Index, −18 to 0). CONCLUSIONS:Intraarticular steroid infiltration or radiofrequency denervation appear to be a managing option for chronic function-limiting low back pain of facet origin with favorable short- and midterm results in terms of pain relief and function improvement, but improvements were similar in both groups.

Advantage of Robotic Needle Placement on a Prostate Model in HDR Brachytherapy

Purpose:To compare the accuracy of the robot-assisted needle positioning with that of the conventional template-guided method with the help of a prostate model in high dose rate (HDR) brachytherapy.Materials and Methods:A prostate model of fresh porcine abdomen and special polyvinylchloride (PVC) sheets was developed. To verify the model, deviations from 311 needle placements of real prostate implants were analyzed. Second, the accuracy of the template-guided positioning versus robot-assisted positioning was measured with 20 needle insertions in the model. For robot-assisted positioning, different velocities (2.7, 5.4, 9.8 mm/s) of needle insertion were investigated.Results:The average needle positioning accuracies of manual template guidance on the model closely resembled those of real patients (approximately 3 mm). The average needle positioning accuracy for the robot-assisted method on the prostate model was 1.8 ± 0.6 mm, at a velocity of 2.7 mm/s and, in comparison to the template-guided method (2.7 ± 0.7 mm), was statistically more precise (p < 0.001). At higher robotic velocities, the measured needle positioning accuracy showed no significant difference from that of the manual insertion procedure.Conclusion:By employing a prostate model, we showed for the first time that robot-assisted needle placement for HDR brachy-therapy is significantly more precise than the conventional method at a velocity of 2.7 mm/s. The robot-assisted needle positioning technique improves the degree of freedom by providing additional oblique insertion channels and could be potentially exploited not only for LDR but also for HDR brachytherapy.Fragestellung:Ziel der Arbeit ist der Vergleich der Genauigkeit der Roboter-assistierten mit der Template-gestützten Nadelpositionierung am Prostatamodell.Material und Methode:Für die Messung wurde ein Prostatamodell aus frischem Schweinebauch und speziellen PVC-Folien entwickelt. Zur Verifikation des Modells wurde die Genauigkeit der interstitiellen Template-gestützten Nadelpositionierung von 311 Nadeln, die im Rahmen einer HDR-Brachytherapie positioniert wurden, anhand von Ultraschallbildern ermittelt. Danach erfolgte die Messung der Genauigkeit von jeweils 20 Roboter-assistierten Nadelpositionierung mit den Geschwindigkeiten 2,7/5,4/9,8 mm/s und 20 Template-gestützten Nadelpositionierung am Prostatamodell.Ergebnisse:Die mittlere Nadelpositionierungsgenauigkeit der manuellen Template-gestützten Nadelapplikation am Modell war mit der Genauigkeit am realen Patienten vergleichbar (≈3mm). Die mittlere Nadelpositionierungsgenauigkeit der Roboter-gestützten Methode am Prostatamodell war mit 1,8 ± 0,6 mm (Geschwindigkeit 2,7 mm/s) signifikant besser als die Template-gestützte manuelle Applikation mit 2.7 ± 0.7 mm. Bei höheren Geschwindigkeiten für die Roboter-gestützte Applikation konnte kein Unterschied in der Positionierungsgenauigkeit im Vergleich zu der manuellen Methode nachgewiesen werden.Schlussfolgerung:Die von uns durchgeführte Studie zeigt erstmals einen signifikanten Vorteil der Roboter-gestützten Nadelapplikation bei einer Geschwindigkeit von 2,7 mm/s gegenüber der konventionellen Methode am Prostatamodell. Die Roboter-gestützte Nadelapplikation ermöglicht auch schräge Einstichkanäle und erhöht dadurch die Freiheitsgrade der Nadelpositionierung, daher ist sie für die LDR- und auch für die HDR-Brachytherapie sinnvoll.

Long-Term Expression of Tissue-Inhibitor of Matrix Metalloproteinase-1 in the Murine Central Nervous System Does Not Alter the Morphological and Behavioral Phenotype but Alleviates the Course of Experimental Allergic Encephalomyelitis

Tissue inhibitors of metalloproteinases (TIMPs) are a family of closely related proteins that inhibit matrix metalloproteinases (MMPs). In the central nervous system (CNS), TIMPs 2, 3, and 4 are constitutively expressed at high levels, whereas TIMP1 can be induced by various stimuli. Here, we studied the effects of constitutive expression of TIMP1 in the CNS in transgenic mice. Transgene expression started prenatally and persisted throughout lifetime at high levels. Since MMP activity has been implicated in CNS development, in proper function of the adult CNS, and in inflammatory disorders, we investigated Timp1-induced CNS alterations. Despite sufficient MMP inhibition, high expressor transgenic mice had a normal phenotype. The absence of compensatory up-regulation of MMP genes in the CNS of Timp1 transgenic mice indicates that development, learning, and memory functions do not require the entire MMP arsenal. To elucidate the effects of strong Timp1 expression in CNS inflammation, we induced experimental allergic encephalomyelitis. We observed a Timp1 dose-dependent mitigation of both experimental allergic encephalomyelitis symptoms and histological lesions in the CNS of transgenic mice. All in all, our data demonstrate that (1) long-term CNS expression of TIMP1 with complete suppression of gelatinolytic activity does not interfere with physiological brain function and (2) TIMP1 might constitute a promising candidate for long-term therapeutic treatment of inflammatory CNS diseases such as multiple sclerosis.

Atlas-based semiautomatic target volume definition (CTV) for head-and-neck tumors.

PURPOSE To develop a new semiautomatic method to improve target delineation in head-and-neck cancer. METHODS AND MATERIALS We implemented an atlas-based software program using fourteen anatomic landmarks as well as the most superior and inferior computerd tomography slices for automatic target delineation, using an advanced laryngeal carcinoma as an example. Registration was made by an affine transformation. Evaluation was performed with manually drawn contours for comparison. Three physicians sampled and further applied a target volume atlas to ten other computer tomography data sets. In addition, a rapid three-dimensional (3D) correction program was developed. RESULTS The mean time to the first semiautomatic target delineation proposal was 2.7 minutes. Manual contouring required 20.2 minutes per target, whereas semiautomatic target volume definition with the rapid 3D correction was completed in only 9.7 minutes. The net calculation time for image registration of the target volume atlas was negligible (approximately 0.6 seconds). Our method depicted a sufficient adaptation of the target volume atlas on the new data sets, with a mean similarity index of 77.2%. The similarity index increased up to 85% after 3D correction performed by the physicians. CONCLUSIONS We have developed a new, feasible method for semiautomatic contouring that saves a significant amount (51.8%) of target delineation time for head-and-neck cancer patients. This approach uses a target volume atlas and a landmark model. The software was evaluated by means of laryngeal cancer but has important implications for various tumor types whereby target volumes remain constant in form and do not move with respiration.

Effect of Storage Temperature on Allograft Bone

Background: The recommendations for storage temperature of allogeneic bone are varying between –20 °C and –70 °C and down to –80 °C. The necessary temperature of storage is not exactly defined by scientific data, and the effect of different storage temperatures onto the biomechanical and the biological behavior is discussed controversially. Methods: The historical development of storage temperature of bone banks is described. A survey on literature concerning the biomechanical and biological properties of allograft bone depending on the procurement and storage temperature is given as well as on national and international regulations on storage conditions of bone banks (European Council, American Association of Tissue Banks (AATB), European Association of Tissue Banks (EATB)). Results: Short-term storage up to 6 months is recommended with –20 °C and –40 °C for a longer period (AATB), and EATB recommends storage at –40 °C and even –80 °C while the regulations of the German German Medical Association (Bundesärztekammer) from 2001 recommend storage at –70 °C. Duration of storage at –20 °C can be maintained at least for 2 years. The potential risk of proteolysis with higher storage temperatures remains, but a definite impairment of bone ingrowth due to a storage at –20 °C was not shown in clinical use, and no adverse biomechanical effects of storage at –20 °C could be proven. Conclusion: Biomechanical studies showed no clinically relevant impairment of biomechanical properties of cancellous bone due to different storage temperatures. Sterilization procedures bear the advantage of inactivating enzymatic activity though reducing the risk of proteolysis. In those cases a storage temperature of –20 °C can be recommended for at least a period of 2 years, and the risk of undesired effects seems to be low for native unprocessed bone.

Test-Retest Reliability of 3D Ultrasound Measurements of the Thoracic Spine

To explore the reliability of the Zebris CMS 20 ultrasound analysis system with pointer application for measuring end‐range flexion, end‐range extension, and neutral kyphosis angle of the thoracic spine.