Can the fear recognition deficits associated with callous-unemotional traits be identified in early childhood?

Introduction: Callous-unemotional (CU) traits in the presence of conduct problems are associated with increased risk of severe antisocial behavior. Developmentally sensitive methods of assessing CU traits have recently been generated, but their construct validity in relation to neurocognitive underpinnings of CU has not been demonstrated. The current study sought to investigate whether the fear-specific emotion recognition deficits associated with CU traits in older individuals are developmentally expressed in young children as low concern for others and punishment insensitivity. Method: A subsample of 337 preschoolers (mean age 4.8 years, SD = 0.8) who completed neurocognitive tasks was taken from a larger project of preschool psychopathology. Children completed an emotional recognition task in which they were asked to identify the emotional face from the neutral faces in an array. CU traits were assessed using the Low Concern (LC) and Punishment Insensitivity (PI) subscales of the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB), which were specifically designed to differentiate the normative misbehavior of early childhood from atypical patterns. Results: High LC, but not PI, scores were associated with a fear-specific deficit in emotion recognition. Girls were more accurate than boys in identifying emotional expressions but no significant interaction between LC or PI and sex was observed. Conclusions: Fear recognition deficits associated with CU traits in older individuals were observed in preschoolers with developmentally defined patterns of low concern for others. Confirming that the link between CU-related impairments in empathy and distinct neurocognitive deficits is present in very young children suggests that developmentally specified measurement can detect the substrates of these severe behavioral patterns beginning much earlier than prior work. Exploring the development of CU traits and disruptive behavior disorders at very early ages may provide insights critical to early intervention and prevention of severe antisocial behavior.     

The effects of proprioceptive stimulation on cognitive processes in patients after traumatic brain injury.

OBJECTIVE: To investigate the hypothesis that proprioceptive stimulation may be effective in the treatment of brain injury, using neurophysiologic and neuropsychologic measures. DESIGN: Cohort analytic study. SETTING: Patients recovering from traumatic brain injury (TBI) in a neurologic rehabilitation hospital were examined. PARTICIPANTS: Eleven patients with TBI (Glasgow Coma Scale score > 3) and 11 healthy control subjects matched for age and education. INTERVENTIONS: Subjects were examined with the event-related potential (ERP) technique during a computerized choice-reaction-time task, in which they had to discriminate between even and odd digits. There were experimental runs with and without vibratory stimuli applied to the left forearm serving as proprioceptive stimulation. In addition, ERPs were recorded to vibratory stimuli without any additional task. MAIN OUTCOME MEASURES: Outcome measures included latencies and amplitudes of the P300 ERP component and of the late negative component. RESULTS: In the passive vibration condition, both groups showed the same ERP distribution. In the choice-reaction-time task, latencies and amplitudes of the P300 differed between the 2 groups. The patient group showed longer P300 latencies, which were shortened by vibratory stimuli. In contrast, the control subjects were not affected by vibratory stimuli. CONCLUSION: Our findings support the hypothesis that pathologic cognitive processes after TBI can be improved by proprioceptive stimulation. Muscle vibration has positive effects on pathologically slowed cognitive processes but not in healthy subjects.     

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

Tyrosine kinase inhibitors currently confer the greatest survival gain for nonsmall cell lung cancer (NSCLC) patients with actionable genetic alterations. Simultaneously, the increasing number of targets and compounds poses the challenge of reliable, broad and timely molecular assays for the identification of patients likely to benefit from novel treatments. Here, we demonstrate the feasibility and clinical utility of comprehensive, NGS-based genetic profiling for routine workup of advanced NSCLC based on the first 3,000 patients analyzed in our department. Following automated extraction of DNA and RNA from formalin-fixed, paraffin-embedded tissue samples, parallel sequencing of DNA and RNA for detection of mutations and gene fusions, respectively, was performed using PCR-based enrichment with an ion semiconductor sequencing platform. Overall, 807 patients (27%) were eligible for currently approved, EGFR-/BRAF-/ALK- and ROS1-directed therapies, while 218 additional cases (7%) with MET, ERBB2 (HER2) and RET alterations could potentially benefit from experimental targeted compounds. In addition, routine capturing of comutations, e.g. TP53 (55%), KEAP1 (11%) and STK11 (11%), as well as the precise typing of fusion partners and involved exons in case of actionable translocations including ALK and ROS1, are prognostic and predictive tools currently gaining importance for further refinement of therapeutic and surveillance strategies. The reliability, low dropout rates (<5%), minimal tissue requirements, fast turnaround times (6 days on average) and lower costs of the diagnostic approach presented here compared to sequential single-gene testing, highlight its practicability in order to support individualized decisions in routine patient care, enrollment in molecularly stratified clinical trials, as well as translational research.     

Targeting Complement C5a Receptor 1 for the Treatment of Immunosuppression in Sepsis

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Prehypertension in early versus late pregnancy

Introduction: Hypertensive disorders play a significant role in maternal morbidity and mortality. Limited data on prehypertension (preHTN) in pregnancy exist. We examine the risk of adverse outcomes in patients with preHTN in early (<20 weeks) versus late pregnancy (>20 weeks).

Materials and methods: Retrospective cohort study of singleton gestations between August 2013 and June 2014. Patients were divided based on when they had the highest blood pressure in pregnancy, as defined per the Joint National Committee 7 (JNC-7). Groups were compared using χ², Fisher’s exact, Student’s t-test, and Mann–Whitney U test with p?Results: There were 125 control, 95 early preHTN, 136 late preHTN, and 21 chronic hypertension (CHTN). Early preHTN had an increased risk of pregnancy-related hypertension (PRH) (OR 12.26, p?p?p?=?.02) compared with normotensive and decreased risk for PRH (OR 0.26, p?=?.02), and composite adverse outcomes (OR 0.379, p?=?.04) compared with CHTN. Compared with late preHTN, early preHTN had more PRH (OR 2.85, p?p?=?.04).

Conclusions: Early prehypertension increases the risk of adverse obstetrical outcomes. Other than an increased risk of PRH, patients with late prehypertension have outcomes similar to normotensive women.     

Ectopic pregnancies after infertility treatment: modern diagnosis and therapeutic strategy

Ectopic pregnancy (EP) is a major event in a woman's reproductive life. It complicates infertility treatment and must be recognized early to simplify the treatment strategy, which must always be directed towards optimizing subsequent fertility. Epidemiological findings indicate that tubal history and smoking are the principal risk factors of those EP that are considered reproductive (rather than contraceptive) failures. Adding together the attributable risks for EP allows the construction of a risk scale to determine its probability for any given patient. This risk calculation makes it easier to establish a diagnostic strategy that uses abdominal and transvaginal ultrasound and hCG assays. Progesterone assays are useful only for determining the activity of the pregnancy but do not help to identify its site. Conservative treatment is to be preferred unless the EP occurs on a known hydrosalpinx. All the treatment trials and the Cochrane database meta-analysis show that medical treatment with methotrexate, preferably multidose, is equivalent in efficacy to conservative treatment with laparoscopy in the populations studied. Heterotopic pregnancies, which occur most often after assisted reproduction technology (1-3%), should preferably be treated by salpingectomy except in interstitial sites. There is no consensus that IVF is indicated after EP. The patient's age is probably the determining factor: fertility treatment should not be delayed to an age where the results would be altered, especially with the risk of a recurrent EP.     

Toward mechanistic models for genotype–phenotype correlations in phenylketonuria using protein stability calculations

Phenylketonuria (PKU) is a genetic disorder caused by variants in the gene encoding phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine to neurotoxic levels. Here, we analyzed the cellular stability, localization, and interaction with wild‐type PAH of 20 selected PKU‐linked PAH protein missense variants. Several were present at reduced levels in human cells, and the levels increased in the presence of a proteasome inhibitor, indicating that proteins are proteasome targets. We found that all the tested PAH variants retained their ability to associate with wild‐type PAH, and none formed aggregates, suggesting that they are only mildly destabilized in structure. In all cases, PAH variants were stabilized by the cofactor tetrahydrobiopterin (BH₄), a molecule known to alleviate symptoms in certain PKU patients. Biophysical calculations on all possible single‐site missense variants using the full‐length structure of PAH revealed a strong correlation between the predicted protein stability and the observed stability in cells. This observation rationalizes previously observed correlations between predicted loss of protein destabilization and disease severity, a correlation that we also observed using new calculations. We thus propose that many disease‐linked PAH variants are structurally destabilized, which in turn leads to proteasomal degradation and insufficient amounts of cellular PAH protein.