Towards an electroencephalographic measure of awareness based on the reactivity of oscillatory macrostates to hearing a subject's own name.

We proposed that the brain's electrical activity is composed of a sequence of alternating states with repeating topographic spectral distributions on scalp electroencephalogram (EEG), referred to as oscillatory macrostates. The macrostate showing the largest decrease in the probability of occurrence, measured as a percentage (reactivity), during sensory stimulation was labelled as the default EEG macrostate (DEM). This study aimed to assess the influence of awareness on DEM reactivity (DER). We included 11 middle cerebral artery ischaemic stroke patients with impaired awareness having a median Glasgow Coma Scale (GCS) of 6/15 and a group of 11 matched healthy controls. EEG recordings were carried out during auditory 1 min stimulation epochs repeating either the subject's own name (SON) or the SON in reverse (rSON). The DEM was identified across three SON epochs alternating with three rSON epochs. Compared with the patients, the DEM of controls contained more posterior theta activity reflecting source dipoles that could be mapped in the posterior cingulate cortex. The DER was measured from the 1 min quiet baseline preceding each stimulation epoch. The difference in mean DER between the SON and rSON epochs was measured by the salient EEG reactivity (SER) theoretically ranging from -100% to 100%. The SER was 12.4 ± 2.7% (Mean ± standard error of the mean) in controls and only 1.3 ± 1.9% in the patient group (P < 0.01). The patient SER decreased with the Glasgow Coma Scale. Our data suggest that awareness increases DER to SON as measured by SER.

Usefulness of circulating tumor DNA from cerebrospinal fluid in recurrent high-grade glioma.

Molecular documentation at relapse of high-grade glioma is an urgent need for patient care. A prospective pilot study was conducted to assess the rate of mutation detection using targeted deep sequencing on circulating tumor DNA from cerebrospinal fluid (CSF) after chemo-radiotherapy based treatment. Fifteen patients were included: 13 patients with glioblastoma, 1 patient with gliosarcoma and 1 patient with anaplastic astrocytoma. At progression, 10/15 patients (67%) had detectable mutations in the CSF. Among them, 5/10 patients harbored at least one common mutation between initial tumor and ctDNA. CSF protein level and cfDNA concentration were higher, although not significant, in the ctDNA positive group versus ctDNA negative group (1.17g/L vs. 0.79g/L). Molecular documentation obtained from ctDNA in CSF at the time of relapse is informative in around two-thirds of the patients.

Acute Colonic Pseudoobstruction (Ogilvie Syndrome) - A Severe Complication in the Evolution of the Hospitalized or Institutionalized Patients.

Introduction: Ogilvie syndrome, or acute colonic pseudo-obstruction (ACPO), represents a pathological entity, potentially with a severe outcome, due to the acute important dilation of the large bowel, in the absence of a mechanical luminal obstruction. Usually, it occurs in patients admitted in intensive care unit, that associate severe surgical or medical pathologies. The mechanism of the ACPO has not been completely explained, but it is assumed that the motor function of the colon may be affected, as a result of autonomic regulation disturbance. Early diagnosis and treatment help reduce the risk of severe outcome, such as ischemia or perforation. Material and Method: In addition to our experience, a literature search was elaborated in order to evaluate the incidence, the etiology, the clinical presentation and the diagnosis of the ACPO. Results and Conclusions: The present study may be of help in the process of guiding the optimal management of a critically ill patient is at high risk of developing colonic pseudo-obstruction.

Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Prediction of unfavorable outcomes in cryptococcal meningitis: results of the multicenter Infectious Diseases International Research Initiative (ID-IRI) cryptococcal meningitis study.

Cryptococcal meningitis (CM) is mostly seen in immunocompromised patients, particularly human immunodeficiency virus (HIV)-positive patients, but CM may also occur in apparently immunocompetent individuals. Outcome analyses have been performed in such patients but, due to the high prevalence of HIV infection worldwide, CM patients today may be admitted to hospitals with unknown HIV status, particularly in underdeveloped countries. The objective of this multicenter study was to analyze all types of CM cases in an aggregate cohort to disclose unfavorable outcomes. We retrospectively reviewed the hospitalized CM patients from 2000 to 2015 in 26 medical centers from 11 countries. Demographics, clinical, microbiological, radiological, therapeutic data, and outcomes were included. Death, neurological sequelae, or relapse were unfavorable outcomes. Seventy (43.8%) out of 160 study cases were identified as unfavorable and 104 (65%) were HIV infected. On multivariate analysis, the higher Glasgow Coma Scale (GCS) scores (p = 0.021), cerebrospinal fluid (CSF) leukocyte counts > 20 (p = 0.038), and higher CSF glucose levels (p = 0.048) were associated with favorable outcomes. On the other hand, malignancy (p = 0.026) was associated with poor outcomes. Although all CM patients require prompt and rational fungal management, those with significant risks for poor outcomes need to be closely monitored.

Correction to: Prediction of unfavorable outcomes in cryptococcal meningitis: results of the multicenter infectious Diseases International Research Initiative (ID-IRI) cryptococcal meningitis study.

In the original version of this article, Mustafa Sunbul was not included in the list of authors for this article. The name has been added accordingly.

Babinet's principle for mutual intensity.

In classical diffraction theory, Babinet's principle relates the electromagnetic fields produced by complementary sources. This theorem was always formulated for single-point quantities, both intensities or field amplitudes, in conditions where the full spatial coherence is implicitly assumed. However, electromagnetic fields are, in general, partially coherent, and their spatial properties are described in terms of two-point field-field correlation functions. In this case, a generalized Babinet's principle can be derived that applies to the spatial coherence functions. We present both the derivation and the experimental demonstration of this generalized Babinet theorem.

Pituitary metastasis: is there still a place for neurosurgical treatment?

Pituitary metastases are uncommon, ranging from 1 to 5 % of all metastases. Between 10 and 30 % of pituitary lesions are symptomatic responsible for diabetes insipidus, visual field defect or cranial nerve palsy. Primary sites are lung or breast in two-thirds of cases. There is no current reference concerning treatment of such lesions. Overall survival is poor and depends on primary site. Although the role of surgery is currently limited, discussion is warranted in several indications for diagnostic or symptomatic purposes. We report two cases of symptomatic pituitary metastases in a context of breast cancer and review the litterature concerning the role of surgery and other treatment modalities.

Port catheter versus peripherally inserted central catheter for postoperative chemotherapy in early breast cancer: a retrospective analysis of 448 patients.

PURPOSE: We aimed to compare the complication rate between port catheters (PC) and peripherally inserted central catheters (PICC) for the administration of postoperative chemotherapy for breast cancer. METHODS: All patients treated from January 2010 to August 2012 at the Centre Henri Becquerel for early breast cancer requiring postoperative chemotherapy were retrospectively screened. The primary endpoint was the occurrence of a major complication related to the central venous catheter. Major complications were defined as any grade 3 event according to CTCAE 4.0, delay in chemotherapy >7 days, change of the device, life-threatening event, event requiring a hospitalization, or a prolongation of hospitalization. RESULTS: A total of 448 patients were included; 290 had a PC and 158 a PICC. Overall, 31 major complications related to the central venous catheter were observed: 13 for patients with a PC (4.5%) and 18 for patients with a PICC (11.4%). In univariate analysis, having a PICC was the only factor significantly associated with a higher risk of major complications (HR = 2.83, p = 0.0027). We observed a trend for a higher risk of major complications for patients older than 60 years or with BMI >25 (p = 0.06). In multivariate analysis, having a PICC was the only predictive factor of major complications (HR = 2.89, p = 0.004). CONCLUSIONS: In univariate and multivariate analysis, having a PICC instead of a PC was the only predictive factor of device-related major complication. If confirmed prospectively by the NCT02095743 ongoing trial, this result might modify the management of adjuvant chemotherapy administration.

Prominent dysautonomia in a patient with POEMS syndrome.

POEMS syndrome is a rare, multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and/or skin changes. Here we present an unusual case of a patient with POEMS syndrome who exhibited a prominent autonomic neuropathy.

Exploring the glycoproteomics landscape with advanced MS technologies.

The advance of glycoproteomic technologies has offered unique insights into the importance of glycosylation in determining the functional roles of a protein within a cell. Biologically active glycoproteins include the categories of enzymes, hormones, proteins involved in cell proliferation, cell membrane proteins involved in cell-cell recognition, and communication events or secreted proteins, just to name a few. The recent progress in analytical instrumentation, methodologies, and computational approaches has enabled a detailed exploration of glycan structure, connectivity, and heterogeneity, underscoring the staggering complexity of the glycome repertoire in a cell. A variety of approaches involving the use of spectroscopy, MS, separation, microfluidic, and microarray technologies have been used alone or in combination to tackle the glycoproteome challenge, the research results of these efforts being captured in an overwhelming number of annual publications. This work is aimed at reviewing the major developments and accomplishments in the field of glycoproteomics, with focus on the most recent advancements (2012-2014) that involve the use of capillary separations and MS detection.

Statistics of the distribution of the abundance of molecules with various drug loads in maytansinoid antibody-drug conjugates.

The maytansinoid antibody-drug conjugates (ADCs) in clinical development for cancer therapy each contain a derivative of the microtubule-targeting agent, maytansine, covalently attached to the antibody via an engineered linker. A sample of any of these conjugates contains molecules with different numbers of maytansinoid molecules, or "drug" loads, the relative abundance of which can be determined by mass spectrometry. We examined the accuracy of the Poisson distribution and the binomial distribution in predicting the relative abundance of species with different drug loads for three antibody-maytansinoid conjugates with different antibodies and linker-maytansinoid pairings. We used variance, calculated from the experimental mass distribution data, as the parameter to determine the optimal value n of the binomial distribution number of trials. The accuracy of the Poisson distribution in predicting distribution of the species abundance in these conjugates varied among the conjugates. In contrast, the accuracy of the binomial distribution was similar for all three conjugates and comparable to the best accuracy of the Poisson distribution, as supported by a paired t-test.

Absolute Configuration Determination of Azulenyl Diols Isolated From Asymmetric Pinacol Coupling.

A convenient enantioselective approach for the pinacol coupling of 1-acetylazulene involving easily accessible (R)- or (S)-BINOLs as chiral additive is reported. This supposes the preformation of the chiral titanium-BINOL complex in 1:2 ratio and subsequent reduction with zinc when, 2,3-di(azulen-1-yl)butane-2,3-diol can be isolated in around 60% enantiomeric excess. The absolute configuration of the isolated enantiomers was assigned by comparison of the experimental and Boltzmann-weighted calculated VCD and ECD spectra and assigned as (+)-(2S;3S)-di(azulen-1-yl)butane-2,3-diol. Chirality 27:826-834, 2015. © 2015 Wiley Periodicals, Inc.

Lower urinary tract dysfunction in patients with dysautonomia.

OBJECTIVE: With the goal of better defining the types of bladder dysfunction observed in this population, we present the chief urologic complaints, results of urodynamic studies, and treatments of patients with dysautonomia-related urinary symptoms. METHODS: All patients with dysautonomia referred to our neurourology clinic between 2005 and 2015 for management of lower urinary tract dysfunction were retrospectively reviewed. Each patient's chief urologic complaint was recorded and used to initially characterize the bladder storage or voiding symptoms. Patient evaluation included history and physical examination, urinalysis, post void bladder ultrasound, and urodynamic studies. Successful treatment modalities that subjectively or objectively improved symptoms were recorded. RESULTS: Of 815 patients with the diagnosis of dysautonomia, 82 (10 %) were referred for evaluation of lower urinary tract dysfunction. Mean age was 47 years (range 12-83) and 84 % were female. The chief complaint was urinary urgency ± incontinence in 61 % and hesitancy in 23 % of patients. Urodynamic findings demonstrated detrusor overactivity ± incontinence in 50 % of patients, although chief complaint did not reliably predict objective findings. Successful objective and subjective treatments were multimodal and typically non-operative. INTERPRETATION: Lower urinary tract dysfunction may develop in at least 10 % of patients with dysautonomia, predominantly females. Bladder storage or voiding complaints do not reliably predict urodynamic findings. Urodynamically, most patients exhibited detrusor overactivity. The majority of patients were successfully managed with medical or physical therapy.

Novel mutations widen the phenotypic spectrum of slow skeletal/ß-cardiac myosin (MYH7) distal myopathy.

Laing early onset distal myopathy and myosin storage myopathy are caused by mutations of slow skeletal/ß-cardiac myosin heavy chain encoded by the gene MYH7, as is a common form of familial hypertrophic/dilated cardiomyopathy. The mechanisms by which different phenotypes are produced by mutations in MYH7, even in the same region of the gene, are not known. To explore the clinical spectrum and pathobiology, we screened the MYH7 gene in 88 patients from 21 previously unpublished families presenting with distal or generalized skeletal muscle weakness, with or without cardiac involvement. Twelve novel mutations have been identified in thirteen families. In one of these families, the father of the proband was found to be a mosaic for the MYH7 mutation. In eight cases, de novo mutation appeared to have occurred, which was proven in four. The presenting complaint was footdrop, sometimes leading to delayed walking or tripping, in members of 17 families (81%), with other presentations including cardiomyopathy in infancy, generalized floppiness, and scoliosis. Cardiac involvement as well as skeletal muscle weakness was identified in nine of 21 families. Spinal involvement such as scoliosis or rigidity was identified in 12 (57%). This report widens the clinical and pathological phenotypes, and the genetics of MYH7 mutations leading to skeletal muscle diseases.

Autograft Reoperation Following the Ross Procedure: Evolving Strategies and Future Perspectives.

Background: Pulmonary autograft failure remains a cause of reoperation following the Ross procedure. The aim of this study is to describe our evolving approach to autograft reoperations. Methods: Retrospective study of all patients who underwent a pulmonary autograft reoperation following a Ross procedure between June 1997 and July 2022. Results: Two-hundred and thirty-five Ross procedures were performed. Thirty-six patients (15%) plus one referral underwent an autograft reoperation at a median of 7.8 years (IQR 4.6-13.6). The main indication was: neoaortic root dilatation associated with mild/moderate (n = 12) or severe (n = 8) aortic regurgitation; isolated severe aortic regurgitation (n = 6); infective endocarditis (IE) (n = 8); and aortic root pseudoaneurysm with no history of IE (n = 3). The autograft was spared in 29 cases (78%): 9 patients (24%) underwent aortic valve repair or aortic root remodeling, 15 patients (40%) aortic root reimplantation, 5 patients neoaortic root stabilization with a Personalized External Aortic Root Support (PEARS) sleeve. There were no in-hospital deaths. At a median follow up of 37 months (IQR 8-105), all patients were alive, 30 (81%) were asymptomatic. Eight patients (22%) required nine further reoperations. Estimated freedom from further reoperation was 90%, 72%, and 72% at 12-, 36-, and 60-months. Conclusions: Autograft reoperations following the Ross procedure can be safely performed and do not affect overall survival in the early and mid-term. Valve-sparing autograft replacement is technically feasible but remains at risk of further interventions. Alternative strategies, such as the PEARS sleeve, are becoming increasingly available but requires validation in the long term.

Glycoproteomics on the rise: established methods, advanced techniques, sophisticated biological applications.

Glycosylation is the most complex form of protein PTMs. Affected proteins may carry dozens of glycosylation sites with tens to hundreds of glycan residues attached to every site. Glycosylated proteins have many important functions in biology, from cellular to organismal levels, being involved in cell-cell signaling, cell adhesion, immune response, host-pathogen interactions, and development and growth. Glycosylation, however, expands the biological functional diversity of proteins at the expense of a tremendous increase in structural heterogeneity. Aberrant glycosylation of cell surface proteins, as well as their detectable fingerprint in plasma samples, has been associated with cancer, inflammatory and degenerative diseases, and congenital disorders of glycosylation. Therefore, there are on-going efforts directed toward developing new technologies and approaches for glycan sequencing and high-throughput analysis of glycosylated proteins in complex samples with simultaneous characterization of both the protein and glycan moieties. This work is aimed primarily at pinpointing the challenges associated with the large-scale analysis of glycoproteins and the latest developments in glycoproteomic research, with focus on recent advancements (2011-2012) in microcolumn separations and MS detection.

Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin.

Camphor is known to potentiate both heat and cold sensations. Although the sensitization to heat could be explained by the activation of heat-sensitive transient receptor potential (TRP) channels TRPV1 and TRPV3, the camphor-induced sensitization to cooling remains unexplained. In this study, we present evidence for the activation of the cold- and menthol-sensitive channel transient receptor potential melastatin 8 (TRPM8) by camphor. Calcium transients evoked by camphor in HEK293 cells expressing human and rat TRPM8 are inhibited by the TRPM8 antagonists 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide and 2-aminoethyl diphenylborinate. Camphor also sensitized the cold-induced calcium transients and evoked desensitizing outward-rectifying currents in TRPM8-expressing HEK293 cells. In the presence of ruthenium red (a blocker of TRPV1, TRPV3, and TRPA1), the camphor sensitivity of cultured rat dorsal root ganglion neurons was highest in a subpopulation of cold- and icilin-sensitive neurons, strongly suggesting that camphor activates native TRPM8. Camphor has a dual action on TRPM8: it not only activates the channel but also inhibits its response to menthol. The icilin-insensitive chicken TRPM8 was also camphor insensitive. However, camphor was able to activate an icilin-insensitive human TRPM8 mutant channel. The activation and sensitization to cold of mammalian TRPM8 are likely to be responsible for the psychophysical enhancement of innocuous cold and "stinging/burning" cold sensations by camphor.