Is Parkinson's disease of early onset a separate disease entity?

Two groups of patients suffering from Parkinson's disease were studied. The first group consisted of 23 patients with an onset age before 40 years; in the second group of 21 patients the onset was after age 50. The clinical findings and the course of the disease were very similar in each group. In spite of a longer disease duration in the patients with early onset of the disease there was no difference in motor impairment; the younger patients did better in mental testing and they were taking less dopaminergic medication. These differences are thought to be due to the age difference rather than to the existence of different disease entities. In the early onset group more familial cases (mostly affecting siblings) were found than in the older ones. The points in favour of there being a hereditary subgroup of early onset Parkinson's disease or of environmental factors causing the disease are reviewed.

Larger visual stimuli are perceived to last longer from time to time: The internal clock is not affected by nontemporal visual stimulus size

Performance on interval timing is often explained by the assumption of an internal clock based on neural counting. According to this account, a neural pacemaker generates pulses, and the number of pulses relating to a physical time interval is recorded by a counter. Thus, the number of accumulated pulses is the internal representation of this interval. Several studies demonstrated that large visual stimuli are perceived to last longer than smaller ones presented for the same duration. The present study was designed to investigate whether nontemporal visual stimulus size directly affects the internal clock. For this purpose, a temporal reproduction task was applied. Sixty participants were randomly assigned to one of two experimental conditions with stimulus size being experimentally varied within either the target or the reproduction interval. A direct effect of nontemporal stimulus size on the pacemaker-counter system should become evident irrespective of whether stimulus size was experimentally varied within the target or the reproduction interval. An effect of nontemporal stimulus size on reproduced duration only occurred when stimulus size was varied during the target interval. This finding clearly argues against the notion that nontemporal visual stimulus size directly affects the internal clock. Furthermore, our findings ruled out a decisional bias as a possible cause of the observed differential effect of stimulus size on reproduced duration. Rather the effect of stimulus size appeared to originate from the memory stage of temporal information processing at which the timing signal from the pacemaker-counter component is encoded in reference memory.

Polymorphisms in MIR27A Associated with Early-Onset Toxicity in Fluoropyrimidine-Based Chemotherapy

PURPOSE The microRNA miR-27a was recently shown to directly regulate dihydropyrimidine dehydrogenase (DPD), the key enzyme in fluoropyrimidine catabolism. A common polymorphism (rs895819A>G) in the miR-27a genomic region (MIR27A) was associated with reduced DPD activity in healthy volunteers, but the clinical relevance of this effect is still unknown. Here, we assessed the association of MIR27A germline variants with early-onset fluoropyrimidine toxicity. EXPERIMENTAL DESIGN MIR27A was sequenced in 514 patients with cancer receiving fluoropyrimidine-based chemotherapy. Associations of MIR27A polymorphisms with early-onset (cycles 1-2) fluoropyrimidine toxicity were assessed in the context of known risk variants in the DPD gene (DPYD) and additional covariates associated with toxicity. RESULTS The association of rs895819A>G with early-onset fluoropyrimidine toxicity was strongly dependent on DPYD risk variant carrier status (Pinteraction = 0.0025). In patients carrying DPYD risk variants, rs895819G was associated with a strongly increased toxicity risk [OR, 7.6; 95% confidence interval (CI), 1.7-34.7; P = 0.0085]. Overall, 71% (12/17) of patients who carried both rs895819G and a DPYD risk variant experienced severe toxicity. In patients without DPYD risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% CI, 0.43-0.9; P = 0.012). CONCLUSIONS These results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of DPYD risk variants. Our data suggest that direct suppression of DPD by miR-27a is primarily relevant in the context of fluoropyrimidine toxicity in patients with reduced DPD activity. However, miR-27a regulation of additional targets may outweigh its effect on DPD in patients without DPYD risk variants.

First evidence for differential and sequential efferent effects of stimulus relevance and goal conduciveness appraisal.

In the context of a memory task, participants were presented with pictures displaying biological and cultural threat stimuli or neutral stimuli (stimulus relevance manipulation) with superimposed symbols signaling monetary gains or losses (goal conduciveness manipulation). Results for heart rate and facial electromyogram show differential efferent effects of the respective appraisal outcomes and provide first evidence for sequential processing, as postulated by Scherer's component process model of emotion. Specifically, as predicted, muscle activity over the brow and cheek regions marking the process of relevance appraisal occurred significantly earlier than facial muscle activity markers of goal conduciveness appraisal. Heart rate, in contrast, was influenced by the stimulus relevance manipulation only.

The Quiet Eye and Information Processing: Facilitation of Stimulus Identification and Response Selection

Background: A prerequisite for high performance in motor tasks is the acquisition of egocentric sensory information that must be translated into motor actions. A phenomenon that supports this process is the Quiet Eye (QE) defined as long final fixation before movement initiation. It is assumed that the QE facilitates information processing, particularly regarding movement parameterization. Aims: The question remains whether this facilitation also holds for the information-processing stage of response selection and – related to perception crucial – stage of stimulus identification. Method: In two experiments with sport science students, performance-enhancing effects of experimentally manipulated QE durations were tested as a function of target position predictability and target visibility, thereby selectively manipulating response selection and stimulus identification demands, respectively. Results: The results support the hypothesis of facilitated information processing through long QE durations since in both experiments performance-enhancing effects of long QE durations were found under increased processing demands only. In Experiment 1, QE duration affected performance only if the target position was not predictable and positional information had to be processed over the QE period. In Experiment 2, in a full vs. no target visibility comparison with saccades to the upcoming target position induced by flicker cues, the functionality of a long QE duration depended on the visual stimulus identification period as soon as the interval falls below a certain threshold. Conclusions: The results corroborate earlier findings that QE efficiency depends on demands put on the visuomotor system, thereby furthering the assumption that the phenomenon supports the processes of sensorimotor integration.

Impact of anti-inflammatory treatment on the onset of uveitis in juvenile idiopathic arthritis: Longitudinal analysis from a nation-wide paediatric rheumatological database

PURPOSE Based on a nation-wide database, this study analysed the influence of methotrexate (MTX), TNF inhibitors and a combination of the two on uveitis occurrence in JIA patients. METHODS Data from the National Paediatric Rheumatological Database in Germany were used in this study. Between 2002 and 2013, data from JIA patients were annually documented at the participating paediatric rheumatological sites. Patients with JIA disease duration of less than 12 months at initial documentation and ≥2 years of follow-up were included in this study. The impact of anti-inflammatory treatment on the occurrence of uveitis was evaluated by discrete-time survival analysis. RESULTS A total of 3,512 JIA patients (mean age 8.3±4.8 years, female 65.7%, ANA-positive 53.2%, mean age at arthritis onset 7.8±4.8 years) fulfilled the inclusion criteria. Mean total follow-up time was 3.6±2.4 years. Uveitis developed in a total of 180 patients (5.1%) within one year after arthritis onset. Uveitis onset after the first year was observed in another 251 patients (7.1%). DMARD treatment in the year before uveitis onset significantly reduced the risk for uveitis: MTX (HR 0.63, p=0.022), TNF inhibitors (HR 0.56, p<0.001) and a combination of the two (HR 0.10, p<0.001). Patients treated with MTX within the first year of JIA had an even a lower uveitis risk (HR 0.29, p<0.001). CONCLUSION The use of DMARDs in JIA patients significantly reduced the risk for uveitis onset. Early MTX use within the first year of disease and the combination of MTX with a TNF inhibitor had the highest protective effect. This article is protected by copyright. All rights reserved.

No Effect of Acupuncture in the Relief of Delayed-Onset Muscle Soreness: Results of a Randomized Controlled Trial

BACKGROUND Delayed-onset muscle soreness (DOMS) is a common symptom in people participating in exercise, sport, or recreational physical activities. Several remedies have been proposed to prevent and alleviate DOMS. DESIGN AND METHODS A five-arm randomized controlled study was conducted to examine the effects of acupuncture on eccentric exercise-induced DOMS of the biceps brachii muscle. Participants were recruited through convenience sampling of students and general public. Participants were randomly allocated to needle, laser, sham needle, sham laser acupuncture, and no intervention. Outcome measures included pressure pain threshold (PPT), pain intensity (visual analog scale), and maximum isometric voluntary force. RESULTS Delayed-onset muscle soreness was induced in 60 participants (22 females, age 23.6 ± 2.8 years, weight 66.1 ± 9.6 kg, and height 171.6 ± 7.9 cm). Neither verum nor sham interventions significantly improved outcomes within 72 hours when compared with no treatment control (P > 0.05). CONCLUSIONS Acupuncture was not effective in the treatment of DOMS. From a mechanistic point of view, these results have implications for further studies: (1) considering the high-threshold mechanosensitive nociceptors of the muscle, the cutoff for PPT (5 kg/cm) chosen to avoid bruising might have led to ceiling effects; (2) the traditional acupuncture regimen, targeting muscle pain, might have been inappropriate as the DOMS mechanisms seem limited to the muscular unit and its innervation. Therefore, a regionally based regimen including an intensified intramuscular needling (dry needling) should be tested in future studies, using a higher cutoff for PPT to avoid ceiling effects.

Predicting the onset of psychosis in patients at clinical high risk: practical guide to probabilistic prognostic reasoning

Prediction of psychosis in patients at clinical high risk (CHR) has become a mainstream focus of clinical and research interest worldwide. When using CHR instruments for clinical purposes, the predicted outcome is but only a probability; and, consequently, any therapeutic action following the assessment is based on probabilistic prognostic reasoning. Yet, probabilistic reasoning makes considerable demands on the clinicians. We provide here a scholarly practical guide summarising the key concepts to support clinicians with probabilistic prognostic reasoning in the CHR state. We review risk or cumulative incidence of psychosis in, person-time rate of psychosis, Kaplan-Meier estimates of psychosis risk, measures of prognostic accuracy, sensitivity and specificity in receiver operator characteristic curves, positive and negative predictive values, Bayes’ theorem, likelihood ratios, potentials and limits of real-life applications of prognostic probabilistic reasoning in the CHR state. Understanding basic measures used for prognostic probabilistic reasoning is a prerequisite for successfully implementing the early detection and prevention of psychosis in clinical practice. Future refinement of these measures for CHR patients may actually influence risk management, especially as regards initiating or withholding treatment.

Incremental value of heart-type fatty acid-binding protein in suspected acute myocardial infarction early after symptom onset.

BACKGROUND The early diagnosis of acute myocardial infarction (AMI) very soon after symptom onset remains a major clinical challenge, even when using high-sensitivity cardiac troponin (hs-cTnT). METHODS AND RESULTS We investigated the incremental value of heart-type fatty acid-binding protein (hFABP) in a pre-specified subgroup analysis of patients presenting with suspected AMI within 1 h of symptom onset to the emergency department (ED) in a multicentre study. HFABP was measured in a blinded fashion. Two independent cardiologists using all available clinical information, including hs-cTnT, adjudicated the final diagnosis. Overall, 1411 patients were enrolled, of whom 105 patients presented within 1 h of symptom onset. Of these, 34 patients (32.4%) had AMI. The diagnostic accuracy as quantified by the area under the receiver-operating characteristics curve (AUC) of hFABP was high (0.84 (95% CI 0.74-0.94)). However, the additional use of hFABP only marginally increased the diagnostic accuracy of hs-cTnT (AUC 0.88 (95% CI 0.81-0.94) for hs-cTnT alone to 0.90 (95% CI 0.83-0.98) for the combination; p=ns). After the exclusion of 18 AMI patients with ST-segment elevation, similar results were obtained. Among the 16 AMI patients without ST-segment elevation, six had normal hs-cTnT at presentation. Of these, hFABP was elevated in two (33.3%) patients. CONCLUSIONS hFABP does not seem to significantly improve the early diagnostic accuracy of hs-cTnT in the important subgroup of patients with suspected AMI presenting to the ED very early after symptom onset.

Land use imperils plant and animal community stability through changes in asynchrony rather than diversity

Human land use may detrimentally affect biodiversity, yet long-term stability of species communities is vital for maintaining ecosystem functioning. Community stability can be achieved by higher species diversity (portfolio effect), higher asynchrony across species (insurance hypothesis) and higher abundance of populations. However, the relative importance of these stabilizing pathways and whether they interact with land use in real-world ecosystems is unknown. We monitored inter-annual fluctuations of 2,671 plant, arthropod, bird and bat species in 300 sites from three regions. Arthropods show 2.0-fold and birds 3.7-fold higher community fluctuations in grasslands than in forests, suggesting a negative impact of forest conversion. Land-use intensity in forests has a negative net impact on stability of bats and in grasslands on birds. Our findings demonstrate that asynchrony across species—much more than species diversity alone—is the main driver of variation in stability across sites and requires more attention in sustainable management.

Variation in Current Management of Term and Late-Preterm Neonates at Risk for Early-Onset Sepsis "An International Survey and Review of Guidelines"

BACKGROUND Uncertainty about the presence of infection results in unnecessary and prolonged empiric antibiotic treatment of newborns at risk for early-onset sepsis (EOS). This study evaluates the impact of this uncertainty on the diversity in management. METHODS A web-based survey with questions addressing management of infection risk-adjusted scenarios was performed in Europe, North America, and Australia. Published national guidelines (n=5) were reviewed and compared to the results of the survey. RESULTS 439 Clinicians (68% were neonatologists) from 16 countries completed the survey. In the low-risk scenario, 29% would start antibiotic therapy and 26% would not, both groups without laboratory investigations; 45% would start if laboratory markers were abnormal. In the high-risk scenario, 99% would start antibiotic therapy. In the low-risk scenario, 89% would discontinue antibiotic therapy before 72 hours. In the high-risk scenario, 35% would discontinue therapy before 72 hours, 56% would continue therapy for five to seven days, and 9% for more than 7 days. Laboratory investigations were used in 31% of scenarios for the decision to start, and in 72% for the decision to discontinue antibiotic treatment. National guidelines differ considerably regarding the decision to start in low-risk and regarding the decision to continue therapy in higher risk situations. CONCLUSIONS There is a broad diversity of clinical practice in management of EOS and a lack of agreement between current guidelines. The results of the survey reflect the diversity of national guidelines. Prospective studies regarding management of neonates at risk of EOS with safety endpoints are needed.

The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity

A missense variant (c.1637C>T, T546M) in ABCC11 encoding the MRP8 (multidrug resistance protein 8), a transporter of 5-fluorodeoxyuridine monophosphate, has been associated with an increased risk of 5-fluorouracil-related severe leukopenia. To validate this association, we investigated the impact of the ABCC11 variants c.1637C>T, c.538G>A and c.395+1087C>T on the risk of early-onset fluoropyrimidine-related toxicity in 514 cancer patients. The ABCC11 variant c.1637C>T was strongly associated with severe leukopenia in patients carrying risk variants in DPYD, encoding the key fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase (odds ratio (OR): 71.0; 95% confidence interval (CI): 2.5-2004.8; Pc.1637C>T*DPYD=0.013). In contrast, in patients without DPYD risk variants, no association with leukopenia (OR: 0.95; 95% CI: 0.34-2.6) or overall fluoropyrimidine-related toxicity (OR: 1.02; 95% CI: 0.5-2.1) was observed. Our study thus suggests that c.1637C>T affects fluoropyrimidine toxicity to leukocytes particularly in patients with high drug exposure, for example, because of reduced fluoropyrimidine catabolism.