The prognosis of functional limb weakness, a 14-year case-control study

Reliable data on the prognosis of functional motor disorder are scarce, as existing studies of the prognosis of functional motor disorder are nearly all retrospective, small and uncontrolled. In this study we used a prospectively recruited, controlled cohort design to assess misdiagnosis, mortality and symptomatic and health outcome in patients with functional limb weakness compared to neurological disease and healthy control subjects. We also carried out an exploratory analysis for baseline factors predicting outcome. One hundred and seven patients with functional limb weakness, 46 neurological and 38 healthy control subjects from our previously studied prospective cohort were traced for follow-up after an average of 14 years. Misdiagnosis was determined in a consensus meeting using information from records, patients and their GPs. Numbers and causes of death were collected via death certificates. Outcome of limb weakness, physical and psychiatric symptoms, disability/quality of life and illness perception were recorded with self-rated questionnaires. Outcome measures were compared within and between groups. Seventy-six patients (71%) with functional limb weakness, 31 (67%) neurological and 23 (61%) healthy controls were included in follow-up. Misdiagnosis was found in one patient in the functional limb weakness group (1%) and in one neurological control (2%). Eleven patients with functional limb weakness, eight neurological control subjects and one healthy control subject had died. Weakness had completely remitted in 20% of patients in the functional limb weakness group and in 18% of the neurological controls (P = 0.785) and improved in a larger proportion of functional limb weakness patients (P = 0.011). Outcomes were comparable between patient groups, and worse than the healthy control group. No baseline factors were independent predictors of outcome, although somatization disorder, general health, pain and total symptoms at baseline were univariably correlated to outcome. This study is the largest and longest follow-up study of functional limb weakness. Misdiagnosis in functional limb weakness is rare after long-term follow-up. The disorder is associated with a higher mortality rate than expected, and symptoms are persistent and disabling. It appears difficult to predict outcome based on common baseline variables. These data should help inform clinicians to provide a more realistic outlook of the outcome and emphasize the importance of active and targeted therapy

Radioguided breast surgery for occult lesion localization – correlation between two methods

<p>Abstract</p> <p>Background</p> <p>The detection of sub-clinical breast lesions has increased with screening mammography. Biopsy techniques can offer precision and agility in its execution, as well as patient comfort. This trial compares radioguided occult lesion localization (ROLL) and wire-guided localization (WL) of breast lesions. We investigate if a procedure at the ambulatorial level (ROLL) could lead to a better aesthetic result and less postoperative pain. In addition, we intend to demonstrate the efficacy of radioguided localization and removal of occult breast lesions using radiopharmaceuticals injected directly into the lesions and correlate radiological and histopathological findings.</p> <p>Methods</p> <p>One hundred and twenty patients were randomized into two groups (59 WL and 61 ROLL). The patients were requested to score the cosmetic appearance of their breast after surgery, and a numerical rating scale was used to measure pain on the first postoperative day. Clearance margins were considered at ≥ 10 mm for invasive cancer, ≥ 5 mm for ductal carcinoma <it>in situ</it>, and ≥ 1 mm for benign disease. Patients were subsequently treated according to the definitive histological result. When appropriate, different statistical tests were used in order to test the significance between the two groups, considering a P value < 0.05 as statistically significant.</p> <p>Results</p> <p>WL and ROLL located all the occult breast lesions successfully. In the ROLL group, the specimen volume was smaller and there were more cases with clear margins (P < 0.05). There were significant differences in mean time of hospital stay between WL and ROLL (21.42 vs. 2.56 hours), but not in operative time (39.4 vs. 29.9 minutes). There were significant differences in the subjective ease of the procedures as rated by the patients (cosmetic outcomes and postoperative pain).</p> <p>Conclusion</p> <p>ROLL is an effective method for the excision of non-palpable breast lesions. It enables more careful planning of the cutaneous incision, leading to better aesthetic results, less postoperative symptoms, and smaller volumes of excised tissue.</p

Regulating craving by anticipating positive and negative outcomes : a multivariate pattern analysis and network connectivity approach

During self-control, we may resist short-term temptations in order to reach a favorable future (e.g., resisting cake to stay healthy). The neural basis of self-control is typically attributed to “cold,” unemotional cognitive control mechanisms which inhibit affect-related regions via the prefrontal cortex (PFC). Here, we investigate the neural underpinnings of regulating cravings by mentally evoking the positive consequences of resisting a temptation (e.g., being healthy) as opposed to evoking the negative consequences of giving in to a temptation (e.g., becoming overweight). It is conceivable that when using these types of strategies, regions associated with emotional processing [e.g., striatum, ventromedial prefrontal cortex (vmPFC)] are involved in addition to control-related prefrontal and parietal regions. Thirty-one participants saw pictures of unhealthy snacks in the fMRI scanner and, depending on the trial, regulated their craving by thinking of the positive consequences of resisting, or the negative consequences of not resisting. In a control condition, they anticipated the pleasure of eating and thus, allowed the craving to occur (now-condition). In line with previous studies, we found activation of a cognitive control network during self-regulation. In the negative future thinking condition, the insula was more active than in the positive condition, while there were no activations that were stronger in the positive (> negative) future thinking condition. However, additionally, multivariate pattern analysis showed that during craving regulation, information about the valence of anticipated emotions was present in the vmPFC, the posterior cingulate cortex (PCC) and the insula. Moreover, a network including vmPFC and PCC showed higher connectivity during the positive (> negative) future thinking condition. Since these regions are often associated with affective processing, these findings suggest that “hot,” affective processes may, at least in certain circumstances, play a role in self-control

Regulating Craving by Anticipating Positive and Negative Outcomes: A Multivariate Pattern Analysis and Network Connectivity Approach

During self-control, we may resist short-term temptations in order to reach a favorable future (e.g., resisting cake to stay healthy). The neural basis of self-control is typically attributed to “cold,” unemotional cognitive control mechanisms which inhibit affect-related regions via the prefrontal cortex (PFC). Here, we investigate the neural underpinnings of regulating cravings by mentally evoking the positive consequences of resisting a temptation (e.g., being healthy) as opposed to evoking the negative consequences of giving in to a temptation (e.g., becoming overweight). It is conceivable that when using these types of strategies, regions associated with emotional processing [e.g., striatum, ventromedial prefrontal cortex (vmPFC)] are involved in addition to control-related prefrontal and parietal regions. Thirty-one participants saw pictures of unhealthy snacks in the fMRI scanner and, depending on the trial, regulated their craving by thinking of the positive consequences of resisting, or the negative consequences of not resisting. In a control condition, they anticipated the pleasure of eating and thus, allowed the craving to occur (now-condition). In line with previous studies, we found activation of a cognitive control network during self-regulation. In the negative future thinking condition, the insula was more active than in the positive condition, while there were no activations that were stronger in the positive (&gt; negative) future thinking condition. However, additionally, multivariate pattern analysis showed that during craving regulation, information about the valence of anticipated emotions was present in the vmPFC, the posterior cingulate cortex (PCC) and the insula. Moreover, a network including vmPFC and PCC showed higher connectivity during the positive (&gt; negative) future thinking condition. Since these regions are often associated with affective processing, these findings suggest that “hot,” affective processes may, at least in certain circumstances, play a role in self-control

Dynamic and static circulating cancer microRNA biomarkers : a validation study

For cancers and other pathologies, early diagnosis remains the most promising path to survival. Profiling of longitudinal cohorts facilitates insights into trajectories of biomarkers. We measured microRNA expression in 240 serum samples from patients with colon, lung, and breast cancer and from cancerfree controls. Each patient provided at least two serum samples, one prior to diagnosis and one following diagnosis. The median time interval between the samples was 11.6 years. Using computational models, we evaluated the circulating profiles of 21 microRNAs. The analysis yielded two sets of biomarkers, static ones that show an absolute difference between certain cancer types and controls and dynamic ones where the level over time provided higher diagnostic information content. In the first group, miR-99a-5p stands out for all three cancer types. In the second group, miR-155-5p allows to predict lung cancers and colon cancers. Classification in samples from cancer and non-cancer patients using gradient boosted trees reached an average accuracy of 79.9%. The results suggest that individual change over time or an absolute value at one time point may predict a disease with high specificity and sensitivity

The ubiquitination landscape of the influenza A virus polymerase.

During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of the IAV polymerase proteins during infection of human alveolar epithelial cells by applying mass spectrometry analysis of immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across the three subunits, PB2, PB1 and PA of the viral polymerase of which 17 distinctively affect mRNA transcription, vRNA replication and the generation of recombinant viruses via non-proteolytic mechanisms. Moreover, further functional and in silico analysis indicate that ubiquitination at K578 in the PB1 thumb domain is mechanistically linked to dynamic structural transitions of the viral polymerase that are required for vRNA replication. Mutations K578A and K578R differentially affect the generation of recombinant viruses by impeding cRNA and vRNA synthesis, NP binding as well as polymerase dimerization. Collectively, our results demonstrate that the ubiquitin-mediated charge neutralization at PB1-K578 disrupts the interaction to an unstructured loop in the PB2 N-terminus that is required to coordinate polymerase dimerization and facilitate vRNA replication. This provides evidence that IAV exploits the cellular ubiquitin system to modulate the activity of the viral polymerase for viral replication

Differences in illness perceptions between patients with non-epileptic seizures and functional limb weakness

Objectives Illness perceptions play an important role in the onset and maintenance of symptoms in functional neurological symptom disorder (conversion disorder). There has, however, been little work examining differences between subtypes of this disorder. We therefore aimed to compare illness perceptions of patients with non-epileptic seizures (NES) and those with functional weakness (FW) with matching neurological disease controls to examine their specificity. Methods The Illness Perception Questionnaire Revised (IPQ-R) was completed by patients with functional limb weakness, non-epileptic seizures and patients with neurological disease causing limb weakness and epilepsy in two separate case control studies. Results Patients with FW (n=107), NES (= 40), Epilepsy (n=34) and neurological disease causing limb weakness (NDLW) (n=46) were included in the analysis. Both FW and NES patients reported a low level of personal control, understanding of their symptoms and a tendency to reject a psychological causation of their symptoms. However NES patients rejected psychological causes less strongly than FW patients (P<.01). Patients with NES were also more likely to consider their treatment to be more effective (P<.01). None of these differences appeared in a similar comparison between patients with epilepsy and patients with NDLW. Conclusion Although patients with NES tended, as a group, to reject psychological factors as relevant to their symptoms, they did so less strongly than patients with functional limb weakness in these cohorts. This has implications for both the way in which these symptoms are grouped together but also the way in which treatment is approached. Keywords Psychogenic non-epileptic seizures; Functional weakness; Conversion disorder; Epilepsy; Illness perception; Neurolog

Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells

Human infection with highly pathogenic avian influenza viruses (HPAIV) is often associated with severe tissue damage due to hyperinduction of interferons and proinflammatory cytokines. The reasons for this excessive cytokine expression are still incompletely understood, which has hampered the development of efficient immunomodulatory treatment options. The host protein TRIM28 associates to the promoter regions of over 13,000 genes and is recognized as a genomic corepressor and negative immune regulator. TRIM28 corepressor activity is regulated by post-translational modifications, specifically phosphorylation of S473, which modulates binding of TRIM28 to the heterochromatin-binding protein HP1. Here, we identified TRIM28 as a key immune regulator leading to increased IFN-β and proinflammatory cytokine levels during infection with HPAIV. Using influenza A virus strains of the subtype H1N1 as well as HPAIV of subtypes H7N7, H7N9, and H5N1, we could demonstrate that strain-specific phosphorylation of TRIM28 S473 is induced by a signaling cascade constituted of PKR, p38 MAPK, and MSK1 in response to RIG-I independent sensing of viral RNA. Furthermore, using chemical inhibitors as well as knockout cell lines, our results suggest that phosphorylation of S473 facilitates a functional switch leading to increased levels of IFN-β, IL-6, and IL-8. In summary, we have identified TRIM28 as a critical factor controlling excessive expression of type I IFNs as well as proinflammatory cytokines during infection with H5N1, H7N7, and H7N9 HPAIV. In addition, our data indicate a novel mechanism of PKR-mediated IFN-β expression, which could lay the ground for novel treatment options aiming at rebalancing dysregulated immune responses during severe HPAIV infection

Referral process to further evaluate poor sleep in breast cancer survivors

Objective: Breast cancer survivors (BCS) are twice as likely to report symptoms of poor sleep as those without cancer. However, sleep disorders are under-assessed and under-treated among BCS. The purpose of this study was to determine the portion of BCS who completed referral visits to a sleep specialist and identify the acceptability, facilitators, and barriers to the screening and referral process. Methods: BCS, who reported having sleep problems, completed questionnaires to screen for symptoms suggestive of sleep disorders. Those with symptoms suggestive of sleep apnea, movement disorders, narcolepsy, insomnia syndrome, or circadian disorders, they were referred to a sleep medicine physician or behavioral sleep medicine psychologist. Two months after the referral, participants were interviewed about their perceptions of the acceptability, barriers, and facilitators to sleep screenings and referrals. Results: Of 34 BCS assessed for eligibility, 29 were eligible and had sleep problems. Only eight of 29 participants (27.6%) completed the sleep referral process. Most thought the screening and referral process was acceptable. However, BCS identified barriers to completing the referral visit, including time, not seeing the need for treatment, insurance/sick leave concerns, and distance/transportation. Conclusion: Adequate evaluation and treatment of sleep disorders in BCS are rare. Creative solutions to address barriers to timely sleep referrals are needed to reduce long-term negative consequences of inadequate sleep