Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm.

AIMS: In genetic aortopathies (GA) particular attention is paid to aortic root dilatation which has an impact on morbidity and mortality. This study focuses on the effects of therapy with angiotensin-II-receptor-blockers (ARB) or beta-blockers (BB) on aortic root growth and the question which therapy should be initiated at which dosage and at what age. METHODS: Since 1998 we diagnosed 208 patients with GA (170 FBN-1). 81 patients between 5 months and 18 years receiving either ARB or BB therapy were included. We retrospectively analyzed the progression of the dilatation of Sinus Valsalva aortae (SV) using calculated z-scores before and after therapy initiation and compared BB and ARB treatment. RESULTS: Both ARB and BB (p < 0.05) therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB (p < 0.01) independent of age and genetic cause. A detailed comparison of the two drug groups showed a more sustained effect in limiting the progression of the dilatation of the aortic root in patients treated with ARB. Progression of dilatation of the SV was significantly lower in children treated with ARBs compared to BB (delta z-score, p < 0.05). In addition, ARBs were better tolerated and had a significantly lower discontinuation rate (3%) compared to BB (50%) (p < 0.01). Independently of age at initiation all children and adolescents were able to reach the target dose under ARB. CONCLUSION: We demonstrated a significant change in both treatment options, with the effect of ARB being more pronounced while being better tolerated throughout the treatment period.

Children with Autism Spectrum Disorder of All Ages, Levels of Symptom Severity and General Cognitive Ability Display Low Processing Speed Index Scores Warranting Special Educational Assistance.

The processing speed index (PSI) of the Wechsler intelligence scale for children (WISC-IV) has been found to predict a child's level of academic functioning. The consistently reported PSI weakness in children with autism spectrum disorder (ASD) therefore warrants special assistance and attempts at compensation for the disadvantages associated with these children's low PSI. We investigated the association of PSI scores with age, general cognitive ability [as measured by full-scale IQ (FSIQ)], symptom severity and discrepancy between the WISC-IV indices verbal comprehension (VCI) and perceptual reasoning (PRI) in 101 school children with ASD. The PSI weakness in children with ASD was not related to age, FSIQ, VCI-PRI discrepancy or any of the symptom measures. These findings suggest that school children with ASD independent of their age, level of cognitive ability, VCI-PRI profile and most notably independent of their symptom severity should be entitled to special assistance and compensation in educational settings.

Exceptional preservation of mid-Cretaceous marine arthropods and the evolution of novel forms via heterochrony.

Evolutionary origins of novel forms are often obscure because early and transitional fossils tend to be rare, poorly preserved, or lack proper phylogenetic contexts. We describe a new, exceptionally preserved enigmatic crab from the mid-Cretaceous of Colombia and the United States, whose completeness illuminates the early disparity of the group and the origins of novel forms. Its large and unprotected compound eyes, small fusiform body, and leg-like mouthparts suggest larval trait retention into adulthood via heterochronic development (pedomorphosis), while its large oar-like legs represent the earliest known adaptations in crabs for active swimming. Our phylogenetic analyses, including representatives of all major lineages of fossil and extant crabs, challenge conventional views of their evolution by revealing multiple convergent losses of a typical "crab-like" body plan since the Early Cretaceous. These parallel morphological transformations may be associated with repeated invasions of novel environments, including the pelagic/necto-benthic zone in this pedomorphic chimera crab.

Neurocognitive functioning in adults with phenylketonuria: Report of a 10-year follow-up.

BACKGROUND: The long-term prognosis of early treated phenylketonuria (PKU) is still under discussion. Aim of this controlled long-term study was to assess the neurological and neuropsychological outcome in adult patients with early-treated PKU. METHODS: We investigated 35 patients with early-treated classical PKU aged 29 to 51 years (mean age 41 years) and 18 healthy controls matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), attention and information-processing abilities. Magnetic resonance imaging (MRI) of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a five-year and a ten-year follow-up. RESULTS: In the entire interval IQ, information processing and attention of patients and controls remained constant. At both follow-up assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (> 42 years) showed poorer information processing and attention at both assessment times compared to young adult patients (< 42 years) and controls. IQ, information processing and attention showed no correlation to imaging results. IQ, however, was significantly correlated to blood phenylalanine (Phe) levels in patients´ childhood and adolescence, and Phe levels had been higher in the adolescent years of older adult patients. CONCLUSIONS: Cognitive performance in adult patients with early-treated PKU does not seem to deteriorate in a ten-year interval. Neuropsychological assessment in adults with PKU revealed neurocognitive impairment particularly in older adult patients. This seems to refer to an early relaxation of diet that was recommended when the older patients were adolescents. Results indicate a benefit of dietary control during adolescence in PKU.

Children and adolescents with phenylketonuria display fluctuations in their blood phenylalanine levels.

AIM: This study examined the impact of fluctuations in metabolic control on the intelligence quotient (IQ) of children and adolescents with early, continuously treated phenylketonuria (PKU). METHODS: This was a clinic-based study carried out at University Hospital Munster, Germany, from 2015 to 2017. We investigated 49 patients (28 boys) with early treated PKU, who were aged 6-18 years with a mean age of 11.2 ± 4.1 years. All the patients were on a continuous phenylalanine-restricted diet. Of the 49 patients, 29 (18 boys) had classic PKU and 21 patients (11 girls) had mild PKU. The patients' blood phenylalanine levels were assessed every week for 26 weeks and analysed for fluctuations, indicated by the standard deviation of the individual blood phenylalanine levels. We also assessed the concurrent Full Scale IQ (FSIQ) of the patients. RESULTS: In patients with classic PKU, FSIQ was negatively correlated with blood phenylalanine levels, but not with level fluctuations. In patients with mild PKU, FSIQ was not correlated with blood phenylalanine levels, but was negatively correlated with level fluctuations. CONCLUSION: The blood phenylalanine levels of patients with mild PKU showed minor interindividual differences, which may have allowed fluctuations to exert a negative effect on the FSIQ.

Alveolar capillary dysplasia with left heart obstruction - rare but lethal.

Alveolar capillary dysplasia (ACD) is a rare neonatal lung disease characterized anatomically by a defective and hypoplastic development of pulmonary alveoli leading to persistent pulmonary hypertension (PPHN) and finally lethal respiratory failure. It is often associated with congenital left heart obstruction. Given the fatal prognosis an early diagnosis is important. However, due to the fast onset of PPHN in neonates and lack of pathognomonic signs for its cause, safe and fast detection of ACD is challenging. Therefore, following the exclusion of cardiac and common pulmonary causes, lung biopsy becomes essential for diagnosis.We hereby report a case of ACD with atrial septal defect type one and hypoplastic aortic arch with an ante-mortem diagnosis and discuss the current state of medicine in relation to ACD.

[Palliative therapy concepts in intensive care medicine]. / Palliative Therapiekonzepte in der Intensivmedizin.

Involvement of palliative care is so far not common practice for critically ill patients on surgical intensive care units (ICUs) in Germany. The objectives of palliative care concepts are improvement of patient quality of life by relief of disease-related symptoms using an interdisciplinary approach and support of patients and their relatives considering their current physical, psychological, social and spiritual needs. The need for palliative care can be identified via defined screening criteria. Integration of palliative care can either be realized using a consultative model which focusses on involvement of palliative care consultants or an integrative model which embeds palliative care principles into the routine daily practice by the ICU team. Early integration of palliative care in terms of advance care planning (ACP) can lead to an increase in goals of care discussions and quality of life as well as a decrease of mortality and length of stay on the ICU. Moreover, stress reactions of relatives and ICU staff can be reduced and higher satisfaction with therapy can be achieved. The core of goal of care discussions is professional and well-structured communication between patients, relatives and staff. Consideration of palliative care principles by model-based integration into ICU practice can improve complex intensive care courses of disease in a productive but dignified way without neglecting curative attempts.

[Cross-sectional field pain medicine Q14 - the Mainz model : Development of the pain medicine curriculum in the standard study course at the University Medical School of the Johannes Gutenberg University Mainz]. / Querschnittsfach Schmerzmedizin Q14 ­ das Mainzer Modell : Die Entwicklung des Curriculums Schmerzmedizin im Regelstudiengang Humanmedizin an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz.

BACKGROUND AND OBJECTIVES: Following the amendment of the Medical Licensure Act (ÄAppO) in 2012, pain medicine was introduced as a mandatory subject for students during undergraduate medical training. Medical schools were required to define and to implement adequate curricular and formal teaching structures based on interdisciplinary and multiprofessional requirements according to the curriculum for pain medicine of the German Pain Society. These aspects were considered in the new interdisciplinary curriculum for pain medicine, the so-called Mainz model. STUDY DESIGN AND METHODS: A new curriculum based on the Kern cycle was developed and implemented at the Medical Center of the Johannes Gutenberg University in Mainz. Different teaching methods (lectures, interprofessional tutorials and bedside coaching in small groups) were used to impart professional expertise in pain medicine to medical students in an interdisciplinary clinical context. RESULTS: The new curriculum was put into practice and evaluated starting from the winter semester 2014/2015. Before and after the first implementation, medical students were asked about the relevance of pain medicine and their perception of personal competence. CONCLUSION: The interdisciplinary course in pain medicine was successfully introduced into the degree program based on the curriculum of the German Pain Society and the Kern cycle. With educational support, interdepartmental and multiprofessional collaboration the process of implementation of new interdisciplinary courses can be facilitated. In the future, the question how to increase the amount of practical lessons without increasing the load on teaching resources has to be resolved. Blended learning modules, such as a combination of E­learning and practical lessons are currently being studied in smaller cohorts.

[Clinical classification and initial diagnosis of pulmonary hypertension: recommendations of the Cologne Consensus Conference 2016]. / Klinische Klassifikation der pulmonalen Hypertonie und initiale Diagnostik: Empfehlungen der Kölner Konsensus Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed information about the clinical classification and diagnosis of pulmonary hypertension, and furthermore provide novel recommendations for risk stratification and follow-up assessments. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the clinical classification and initial diagnosis of PH. This article summarizes the results and recommendations of this working group.

[Pulmonary hypertension in grown-ups with congenital heart disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Erwachsenen mit angeborenen Herzfehlern: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for different forms of PH, and specifically address PH associated with congenital heart disease (CHD). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to PH in grown-ups with congenital heart disease (GUCH). This article summarizes the results and recommendations of this working group.

[Palliative sedation at a university palliative care unit--a descriptive analysis]. / Palliative Sedierung auf einer universitären Palliativstation.

BACKGROUND: Palliative sedation (pS) is indicated in the presence of end-stage disease with treatment-refractory symptoms not tolerable for the patient. We investigated the practice of pS at a university palliative care unit. METHODS: Before starting pS the following data were documented: indication and decision making, type of sedation, life expectancy evaluated by the physician using the palliative prognostic index. Over the time of pS communication skills, depth of sedation, relief in symptoms, substitution of fluid and nutrition and used medications were collected. RESULTS: During evaluation time 99 patients died. 34 patients received pS (34 %). All patients suffered from cancer. Indications for palliative sedation were: terminal restlessness (56 %), dyspnea (39 %), pain (32 %), psychological distress (15 %), agitated delir (9 %), vomiting (3 %) and bleeding (3 %) (multiple nominations possible). In 31 cases (91 %) nurses were included for decision making. In 33 cases continuous sedation were initiated immediately (median duration 27.5 hours). The most applied medication was midazolam (94 %), sometimes combined with neuroleptics (44 %) and propofol (15 %). 91 % of the patients additionally received opioids. Artificial fluid was substituted in two cases. Palliative sedation started in the median 27.5 hours before death. The final physician assessment revealed complete symptom relief in 12 patients (35 %), very strong symptom relief in 20 patients (59 %) and moderate symptom relief in 2 patients (6 %). CONCLUSIONS: pS was successfully used as last resort for relief of treatment-refractory symptoms in one third of decedents at the investigated palliative care unit.

[Intradermal metal deposits in an industrial worker]. / Intradermale Metalleinsprengungen bei einem Industriearbeiter.

CASE REPORT: We describe a 75-year-old patient with asymptomatic grey pigmentation on the face and fingers. He had worked over two decades in cutting high-voltage cables. The cutting procedures were performed without a face shield or protection gloves. The patient presented with gray punctate lesions beside some homogeneously stained zones. DIAGNOSTICS: Histologically, the deposits presented in the dermal tissue in a horse-shoe, oval, or splinter-like shape. The foreign body material was embedded by a few CD68-positive macrophages. Undyed histological sections were investigated via two-dimensional micro-synchrotron X-ray fluorescence analysis (SRXRF). The deposits were identified as zinc (Zn), copper (Cu), nickel (Ni), and strontium (Sr), which were strongly associated with maximal sulfur (S) concentrations. This association is presumably induced by complex binding between thiol groups and metal ions such as Zn, Ni etc. However, the iron (Fe) distribution patterns were quite different to those of Zn, Cu, or Ni. These heavy metals are major components of the metal wires that the patient worked with in his profession. CONCLUSION: To the best of our knowledge, this is the first case report in the dermatological literature of intradermal metal deposits identified via SRXRF analysis.

[Relevance of preoperative anxiety for postoperative outcome in urological surgery patients: A prospective observational study]. / Bedeutung präoperativer Angst für den postoperativen Verlauf bei urologischen Patienten : Eine prospektive Beobachtungsstudie.

BACKGROUND: Preoperative anxiety is not systematically assessed during premedication appointments, although it may influence the postoperative course and outcome. OBJECTIVES: The aim of this study was to assess preoperative anxiety in a sample of patients before major urological surgery and to characterize the impact on postoperative pain. An additional aim was to analyze the agreement between patients' self-ratings and physicians' anxiety ratings. PATIENTS AND METHODS: In all, 127 male and 27 female patients participated in a prospective observational study. Preoperative anxiety was assessed with two validated instruments - the APAIS (Amsterdam Preoperative Anxiety and Information Scale) and the State Scale of the STOA questionnaire (State-Trait Operation Anxiety) - during the premedication appointment. Physicians provided their subjective ratings on patients' anxiety and need for information using the APAIS. The predictive value of preoperative anxiety for postoperative pain was evaluated. RESULTS: Nearly four out of ten patients were identified as "anxiety cases"; thereof women were more afraid than men were. Preoperative anxiety was not correctly assessed by physicians, who overestimated patients' anxiety. In female patients, preoperative anxiety was predictive of increased postoperative pain scores. CONCLUSION: Preoperative anxiety is a frequent concern and often not correctly assessed by physicians. The use of scoring systems to detect preoperative anxiety is useful in clinical routine and helps to decide on therapeutic interventions.

Development of a new multi-analyte assay for the simultaneous detection of opioids in serum and other body fluids using liquid chromatography-tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometry method using electrospray ionization in positive ionization mode was developed for the simultaneous detection of multiple opioid-type drugs in plasma. The presented assay allows the quantitative determination of alfentanil, buprenorphine, codeine, desomorphine, dextromethorphan, dextrorphan, dihydrocodeine, dihydromorphine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine, pholcodine, piritramide, remifentanil, sufentanil, and tramadol as well as the metabolites 6-monoacetylmorphine, bisnortilidine, morphine-3-glucuronide, morphine-6-glucuronide, naltrexol, norbuprenorphine, norfentanyl, norpethidine, nortilidine, and O-desmethyltramadol. Serum and blood samples were purified by solid-phase extraction. The analytes were separated on a phenyl-hexyl (100mm) column by formic acid/acetonitrile gradient elution using an UPLC 1290 Infinity coupled with a 6490 Triple Quadrupole mass spectrometer. The limits of detection ranged from 0.02 to 0.6ng/mL and the lower limits of quantification ranged from 0.1 to 2.0ng/mL. The calibration curves were linear between Calibration Levels 1-6 for all 35 substances. Recovery rates ranged between 51 and 88% for all compounds except alfentanil, bisnortilidine, pethidine, and morphine-3-glucuronide. The matrix effect ranged from 86% for ethylmorphine to 105% for desomorphine. Using the validation procedure proposed by the German Society of Toxicological and Forensic Chemistry, acceptable precision and accuracy data for almost all analytes were obtained. The method was successfully applied to 206 authentic serum samples provided by the palliative and intensive care units of the University Medical Center and the police authorities. Furthermore, a suspected fatal intoxication is demonstrated by an analysis of the sufentanil in post mortem body fluids and tissues.