Light-Induced Tetrazole-Quinone 1,3-Dipolar Cycloadditions.

Quinones were firstly used as dipolarophiles in a photoclick 1,3-cycloaddition with 2,5-diaryltetrazoles, as photoactivatable predipoles, providing a novel and efficient access to three types of pyrazole-fused quinones (indazoledione derivatives). Distinctive features of this protocol include the use of light as the unique reagent and readily available, stable, and easy to handle starting materials and good to excellent yields. Photophysical and electrochemical properties of the quinones and their potential application as photoredox catalysts are also detailed.

Sulfoxide-Induced Homochiral Folding of ortho-Phenylene Ethynylenes (o-OPEs) by Silver(I) Templating: Structure and Chiroptical Properties.

A new family of homochiral silver complexes based on carbophilic interactions with ortho-phenylene ethynylene (o-OPE) scaffolds containing up to two silver atoms are described. These compounds represent a unique class of complexes with chirality at the metal. Chiral induction is based on the inclusion of chiral sulfoxides, which allow efficient transfer of chirality to the helically folded o-OPE, leading to circularly polarized luminescence (CPL)- and vibrational circular dichroism (VCD)-active compounds. In the presence of silver(I) cations, carbophilic interactions dominate, which promote helical structures with a defined helicity. This is one of the very scarce examples of the use of such interactions in the attractive field of abiotic foldamers. The switching event has been extensively studied by using different chiroptical techniques, including circular dichroism, CPL, and VCD, and represents one of the few CPL switches described in the literature.

Musicogenic reflex seizures in epilepsy with glutamic acid decarbocylase antibodies.

BACKGROUND: Musicogenic reflex seizures (MRS) are a rare form of seizures described in patients with temporal lobe epilepsy (TLE), mainly of unknown etiology. Epilepsy with antibodies against glutamic acid decarboxylase (GAD-ab) is a form of autoimmune epilepsy for which no specific semiology has been described. AIM OF THE STUDY: To retrospectively review the incidence of MRS in the general epileptic population and in the series of patients with epilepsy and GAD-ab and to describe its clinical and paraclinical characteristics. METHODS: Patients recorded between January 2010 and January 2016 in the Database of Bellvitge Hospital Epilepsy Unit were reviewed. RESULTS: From a group of 1510 epileptic patients, three reported MRS (0.0019%) (two patients with epilepsy and GAD-ab and one patient with cryptogenic TLE). The incidence of MRS in patients with epilepsy and GAD-ab was 2 of 22 (9%). Both patients had a normal magnetic resonance Imaging (MRI), but FDG-PET showed medial temporal lobe hypometabolism (unilateral or bilateral) in both and also in the insula in one of them. MRS (recorded via video-EEG[electroencephalography] in one patient) arose from the right temporal lobe. CONCLUSIONS: MRS may be a distinctive seizure type in patients with epilepsy and antiGADab. Determination of GAD-ab should be carried out in all cases of MRS, even those with normal structural MRI.

Retrospective study of perampanel efficacy and tolerability in myoclonic seizures.

OBJECTIVES: Perampanel is an antiepileptic drug (AED) approved for add-on treatment of focal seizures (with or without generalization) and primary generalized tonic-clonic (GTC) seizures. Our objective was to explore the effectiveness and tolerability of adjunctive perampanel in patients with drug-resistant myoclonic seizures, after failure of other AEDs. MATERIALS AND METHODS: Retrospective, multicenter, observational study. Data were collected from individual patient clinical files and analysed using appropriate descriptive statistics and inferential analyses. RESULTS: Data are reported for 31 patients with mean age 36.4 years, who had an average epilepsy duration of 18 years, previously taken an average of 5.03 AEDs, and were taking an average of 2.4 AEDs on perampanel initiation. Patients exhibited myoclonic, GTC, absence, tonic and focal seizures, and most had associated cognitive decline and/or ataxia. Median time on perampanel was 6 months, most common dose was 6 mg, and overall retention rate was 84%. The responder rate for myoclonic seizures was defined via reduction of days with myoclonic seizures per month. At 6 months, 15 (48.4%) of the 31 patients were classed as myoclonic seizure responders, 10 (32.3%) were myoclonic seizure free, and 39% saw improvements in functional ability. Of 17 patients with GTC seizures at baseline, 9 (53%) were responders at 6 months, and 8 (47.1%) were seizure free. The most frequent side effects were psychiatric disorders, instability, dizziness and irritability, and mostly resolved with dose reduction. Five patients discontinued perampanel due to side effects. CONCLUSIONS: Perampanel caused clinically meaningful improvements in patients with drug-resistant myoclonic seizures. It was generally well tolerated, but psychiatric and neurological side effects sometimes required follow-up and dose reduction.

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

OBJECTIVES: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. METHODS: Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. RESULTS: Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. CONCLUSIONS: Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.

Synthesis of functionalized alkyl substituted benzoquinones by Rh-catalyzed additions of boronic acids.

A general synthetic route to γ-oxo alkyl or α-hydroxy benzyl 2-substituted benzoquinones has been developed through a one-pot Rh-catalyzed C-C bond formation/oxidative demethylation sequence from 2,5-dimethoxy aryl boronic acids and several electron deficient alkenes or aldehydes. The process allows rapid access to functionalized benzoquinones under very mild conditions and good yields. We disclose the first example of a Rh-catalyzed 1,4-addition reaction of benzoquinonyl boronic acid to methyl vinyl ketone and other conjugate acceptors, which allows the direct synthesis of 2-(γ-functionalized alkyl) substituted benzoquinones.

VNS and pregnancy: A multicentric experience of four cases.

BACKGROUND: Vagus nerve stimulation system (VNS) has been employed worldwide as adjunctive therapy in drug-resistant epileptic patients. Only nine previous pregnancies with six-positive outcomes have been reported in women with epilepsy treated with VNS since 1998. AIMS OF THE STUDY: To communicate the experience of pregnancies in women treated with VNS in our country. METHODS: Clinical data of four female patients treated with VNS during pregnancy and delivery in five gestations is described. RESULTS: Four pregnancy outcomes were positive and one ended in spontaneous abortion, probably more related to the use antiepileptic drugs than VNS itself. Two births were vaginal and the other two with cesarean section. None of the complications during delivery were attributed to VNS. No teratogenicity was documented. CONCLUSIONS: Based on our experience VNS constitutes a safe therapy for the treatment of drug-resistant epilepsy in women of childbearing potential and during pregnancy and delivery. Larger series will be useful to confirm this finding.

Accuracy of arterial spin labeling magnetic resonance imaging (MRI) perfusion in detecting the epileptogenic zone in patients with drug-resistant neocortical epilepsy: comparison with electrophysiological data, structural MRI, SISCOM and FDG-PET.

BACKGROUND AND PURPOSE: Locating the epileptogenic zone (EZ) in patients with neocortical epilepsy presents major challenges. Our aim was to assess the accuracy of arterial spin labeling (ASL), an emerging non-invasive magnetic resonance imaging (MRI) perfusion technique, to locate the EZ in patients with drug-resistant neocortical epilepsy. METHODS: Twenty-five consecutive patients with neocortical epilepsy referred to our epilepsy unit for pre-surgical evaluation underwent a standardized assessment including video-electroencephalography (EEG) monitoring, structural MRI, subtraction ictal single-photon emission computed tomography co-registered to MRI (SISCOM) and fluorodeoxyglucose positron emission tomography (FDG-PET) studies. An ASL sequence was included in the MRI studies. Areas of hypoperfusion or hyperperfusion on ASL were classified into 15 anatomic-functional cortical regions; these regional cerebral blood flow maps were compared with the EZ determined by the other tests and the strength of concordance was assessed with the kappa coefficient. RESULTS: Of the 25 patients [16 (64%) women; mean age 32.4 (±13.8) years], 18 (72%) had lesions on structural MRI. ASL abnormalities were seen in 15 (60%) patients (nine hypoperfusion, six hyperperfusion). ASL had a very good concordance with FDG-PET (k = 0.84), a good concordance with structural MRI (k = 0.76), a moderate concordance with video-EEG monitoring (k = 0.53) and a fair concordance with SISCOM (k = 0.28). CONCLUSION: Arterial spin labeling might help to confirm the location and extent of the EZ in the pre-surgical workup of patients with drug-resistant neocortical epilepsy.

Home management of acute medical complications in cancer patients: a prospective pilot study.

BACKGROUND: The development of reliable alternatives to conventional hospitalization in patients with cancer would have great clinical and economical value. The aim of the present study was to assess the feasibility of a home-based nursing intervention model as a safe alternative for the management of acute medical complications in cancer patients who would otherwise require conventional hospitalization. PATIENTS AND METHODS: From October 2013 to October 2014, we prospectively evaluated the outcomes of consecutive acute medical episodes treated at home under the home-based intervention program named the Bridge Project (BP). Episodes were classified as "avoided hospitalization in outpatients" (AHO) vs. "reduced hospitalization in inpatients" (RHI). The primary end-point was to assess the rate and causes of BP intervention failure (unplanned hospital readmission or death). RESULTS: Two hundred and forty-six consecutive episodes (52 % AHO and 48 % RHI) involving 203 patients (55 % male; mean age 63 years) were enrolled. The main conditions managed at home were non-neutropenic infections (40 %), febrile neutropenia (20 %), and cancer-related complications (28 %). The median duration of the BP intervention was 5 days (range 1-16 days). No deaths were reported at home. Unplanned hospital readmissions occurred in 9 % of episodes (14 % in AHO vs. 4 % in RHI; p = 0.001). Five of the 22 readmitted patients (22.7 % of the BP failures; 2.5 % of the whole series) died during hospitalization. The BP intervention burden was 1353 days, representing a potential saving of 14 % of days of hospitalization during the study period. CONCLUSIONS: The BP is a safe intervention which can potentially avoid or reduce the length of hospitalization in selected cancer patients with acute medical complications. Our findings support further development of innovative home-based clinical approaches to promote potentially avoidable hospitalization in this setting.

Directional random laser source consisting of a HC-ARROW reservoir connected to channels for spectroscopic analysis in microfluidic devices.

Light sources are used in optofluidic devices for real-time system control and quantitative analysis of important process parameters. In this work, we present a random laser source using a hollow-core antiresonant reflecting optical waveguide (HC-ARROW) containing the gain media inside a reservoir to reduce dye bleaching, which is connected to microchannel waveguides to increase beam directionality. The device is pumped externally and emits a highly coherent and collimated laser beam.

EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis.

INTRODUCTION: The anti-NMDA receptor (NMDAr) encephalitis-associated syndrome includes neuropsychiatric symptoms, impaired consciousness, seizures, autonomic instability, and hypoventilation. The electroencephalographic (EEG) activity throughout the course of the disease has still not been well documented. We reviewed electroclinical data of patients with NMDAr encephalitis to characterize their EEG and its clinical correlation. MATERIAL AND METHODS: We retrospectively identified 16 patients with NMDAr encephalitis from 8 Spanish medical centers, 15 of whom underwent video-EEG in the acute phase. RESULTS: In 15 patients (11 females, median age: 37.4, range: 14-87 years), seizures occurred in 9 (60%) and status epilepticus (SE) in 5 (33.3%). Magnetic resonance imaging (MRI) was abnormal in 10 (66.6%), and CSF (cerebrospinal fluid) was normal in 3 and abnormal in 12, with positive PCR (polymerase chain reaction) for Mycoplasma pneumoniae (1/15) and herpes simple virus (1/15). An ovarian teratoma was found in 1 patient and other malignancies (small cell lung carcinoma) in 1 patient. The EEG was abnormal in the acute phase in 14/15 (93.3%). Extreme delta brush (EDB) was observed in 5 (33.3%), and the presence of EDB was associated with SE in all cases. Rhythmic delta activity without EDB was observed in 5 (33.3%), while excessive beta activity was present in 4 (26.6%). Extreme delta brush can follow a pattern of well-characterized electroclinical seizures. CONCLUSIONS: Almost invariably, patients with NMDAr encephalitis had abnormal EEG. The presence of EDB, which can follow a pattern of well-characterized electroclinical seizures, in our patients was associated with seizures and SE. These findings suggest that EDB could be an evolutive pattern of an SE in NMDAr encephalitis. This article is part of a Special Issue entitled "Status Epilepticus".

Control of the helical chirality of enantiopure sulfinyl (Z)-azobenzene-based photoswitches.

A new class of enantiopure ortho,ortho-disubstituted azobenzene photoswitches has been synthesized from (S)-2-(p-tolylsulfinyl)benzoquinone and arylhydrazines. The sulfoxide acts as a unidirectional controller of the helical chirality that arises in the Z isomer after photoisomerization. Highly congested E-azobenzenes 5 c showed two atropisomeric diastereoconformers in the solid state that converged upon irradiation into a unique Z isomer with defined helicity (M), as evident in the X-ray structure. The chiroptical properties of this three-state enantiopure switch can be externally tuned both photochemically and/or thermally. Theoretical CD spectra calculated by using time-dependent DFT methods support the existence of two atropoisomeric E isomers and only one Z isomer with (M) helicity. Complementary to the classical azobenzene-based switches, the photoswiching event is promoted under green/blue light and do not occur under UV irradiation.

Enantioselective synthesis of helicenequinones and -bisquinones.

A convergent approach based on Diels-Alder reactions between polycyclic dienes and benzoquinones has emerged as a powerful tool for the construction of helicenequinones and bisquinones. Chemical resolution and asymmetric Diels-Alder reactions with sulfinyl quinones provide direct access to enantiopure derivatives. Biaryl or ferrocenyl dienes can be resolved leading to helicenequinones having additional axial or planar chirality.

Computer visual syndrome in university students in times of pandemic.

INTRODUCTION: One of the consequences of prolonged use of bright screens such as those of the computer or cell phone, is the computer visual syndrome where characteristic symptoms are presented that normally disappear after a couple of hours when you stop using electronic devices. The prevalence is high due to multiple risk factors. OBJECTIVE: To determine the prevalence of computer vision syndrome in medical students at the University of Boyacá in times of pandemic. METHODOLOGY: Descriptive and cross-sectional observational study. The study population were medical students, the data were collected in September and October of the year, an electronic survey was carried out for data collection. RESULTS: A total of 300 participants were invited to participate in the study. 78% (234) of participating students suffer from SVI. 67.09% (157) of the participants who reported suffering from SVI were female and 32.91% (77) were male. CONCLUSIONS: Computer visual syndrome is very common among medical students at the University of Boyacá. This study has shown that the presence of SVI has been significantly associated with exposure factors that were triggered during the pandemic period, where frequent virtual classes and long hours led to high exposure to screens. In addition, in the era of virtuality, communication through social networks increased the use of cell phones, which increases the possibility of the appearance of this syndrome.

Prevalence and immunological spectrum of temporal lobe epilepsy with glutamic acid decarboxylase antibodies.

BACKGROUND AND PURPOSE: High levels of glutamic acid decarboxylase (GAD)-ab were initially described in patients with stiff person syndrome, and have since also been observed in patients with other neurological diseases. Temporal lobe epilepsy (TLE) seems to be specially associated. Our purpose is to describe the prevalence of GAD-ab in patients with TLE, and to characterize the clinical-immunological profile of TLE patients with high levels of GAD-ab. METHODS: An immunological profile including GAD-ab and antinuclear, anti-DNA, anti-cardiolipin, anti-transglutaminase and antithyroid antibodies was determined in a consecutive series of patients with TLE. As adulthood onset is the least common onset in TLE + hipocampal sclerosis and febrile seizures, we selected patients whose onset was after 30 years of age, to expand the spectrum of aetiologies. Patients were divided into two groups: known aetiology, 19 patients (45%) and unknown aetiology, 23 (55%). The clinical-immunological study included TLE patients with high GAD-ab levels (>1000 IU). RESULTS: Amongst 42 patients, serum GAD-ab levels were positive in 5 (152-11, 963 IU/ml), all from the unknown aetiology group. Thus, GAD-ab levels were positive in 21.7% and high in 8.7% of the unknown aetiology group. The immunological profile study included nine patients (seven pharmacoresistant), of whom six were women (66%) with mean age 41 years. Three patients reported acute debut, four (44%) insulin-dependent diabetes mellitus, five (55%) other concomitant autoimmune diseases, four (44%) memory impairment and four moderate-to-severe mood disturbance. Intrathecal synthesis of GAD-ab was observed in seven patients (77%). CONCLUSIONS: Temporal lobe epilepsy with GAD-ab is not a rare condition. In the subgroup of patients with high titres, this epilepsy is often pharmacoresistant and associated with memory impairment, depression and other autoimmune diseases.

Successful outcome of episodes of status epilepticus after vagus nerve stimulation: a multicenter study.

BACKGROUND AND PURPOSE: Vagus nerve stimulation (VNS) has been reported to be a safe and effective treatment for drug-resistant epilepsy. The aim of this study is to describe the effect of VNS in patients with a history of repeated episodes of status epilepticus (SE) before implantation. METHODS: From a total of 83 adult patients with drug-resistant epilepsy who had VNS implanted in four tertiary centers in Spain between 2000 and 2010, eight had a previous history of repeated episodes of SE. We performed a retrospective observational study analyzing the outcome of seizures and episodes of SE after implantation. Stimulation was started at the usual settings, and intensity increased according to clinical response and tolerability. RESULTS: Regarding the eight patients with a history of SE, the mean age at time of VNS implantation was 25.1 [14-40] years. Duration of epilepsy until the implantation was 21.7 [7-39.5] years, and they had been treated with a mean of 12 antiepileptic drugs [10-16]. Mean follow-up since implantation was 4.15 [2-7.5] years. Average seizure frequency decreased from 46 to 8.2 per month. Interestingly, four of the eight patients remained free of new episodes of SE after implantation, and in two additional patients, the frequency decreased by >75%. Adverse effects were mild or moderate in intensity and included mainly coughing and dysphonia. CONCLUSION: In those patients with refractory epilepsy and history of SE who are not surgical candidates, VNS is a safe and effective method to reduce seizure frequency and episodes of SE.

Versatile bottom-up approach to stapled π-conjugated helical scaffolds: synthesis and chiroptical properties of cyclic o-phenylene ethynylene oligomers.

Spring loaded: the smallest members of a family of carbon nanocoils (CNCs), adopting a fixed helical structure, have been synthesized by introduction of one or two staples in o-phenylene ethynylene oligomers. The chiroptical responses of the systems having enantiopure L-tartrate-derived staples confirmed the induced helicity. Theoretical studies suggest that these CNCs are pseudoelastic.

Testing an Adapted Auditory Verbal Learning Test Paradigm for fMRI to Lateralize Verbal Memory in Patients with Epilepsy.

BACKGROUND AND PURPOSE: fMRI is a noninvasive tool for predicting postsurgical deficits in candidates with pharmacoresistant temporal lobe epilepsy. We aimed to test an adapted paradigm of the Rey Auditory Verbal Learning Test to evaluate differences in memory laterality indexes between patients and healthy controls and its association with neuropsychological scores. MATERIALS AND METHODS: We performed a prospective study of 50 patients with temporal lobe epilepsy and 22 healthy controls. Participants underwent a block design language and memory fMRI. Laterality indexes and the hippocampal anterior-posterior index were calculated. Language and memory lateralization was organized into typical and atypical on the basis of laterality indexes. A neuropsychological assessment was performed with a median time from fMRI of 8 months and was compared with fMRI performance. RESULTS: We studied 40 patients with left temporal lobe epilepsy and 10 with right temporal lobe epilepsy. Typical language occurred in 65.3% of patients and 90.9% of healthy controls (P = .04). The memory fMRI laterality index was obtained in all healthy controls and 92% of patients. The verbal memory laterality index was bilateral (24.3%) more frequently than the language laterality index (7.69%) in patients with left temporal lobe epilepsy. Atypical verbal memory was greater in patients with left temporal lobe epilepsy (56.8%) than in healthy controls (36.4%), and the proportion of bilateral laterality indexes (53.3%) was larger than right laterality indexes (46.7%). Atypical verbal memory might be associated with higher cognitive scores in patients. No relevant differences were seen in the hippocampal anterior-posterior index according to memory impairment. CONCLUSIONS: The adapted Rey Auditory Verbal Learning Test paradigm fMRI might support verbal memory lateralization. Temporal lobe epilepsy laterality influences hippocampal memory laterality indexes. Left temporal lobe epilepsy has shown a higher proportion of atypical verbal memory compared with language, potentially to memory functional reorganization.

The effect of sulfoxides on the stereoselective construction of tetrahydrofurans: total synthesis of (+)-goniothalesdiol.

Good to excellent stereoselectivities were achieved in the reductive cyclization (with Et(3)SiH/trimethylsilyl trifluoromethanesulfonate (TMSOTf)) of enantiopure hydroxy sulfinyl ketones en route to 2,5-cis-disubstituted tetrahydrofuran skeletons. Electrostatic effects of the exocyclic sulfoxide, which stabilized the reactive intermediate oxocarbenium conformations, were responsible for the observed stereocontrol. A model is proposed to explain the results. The use of this reaction and the asymmetric ß-ketosulfoxide reduction as key steps facilitated the total enantioselective synthesis of the natural ß-C-aryl glycoside (+)-goniothalesdiol.

Stereoselective synthesis of the C15-C26 fragment of the antitumor agent (-)-dictyostatin.

The synthesis of the C15-C26 fragment of (-)-dictyostatin is reported in 10 steps and 28% overall yield. The key steps are the two stereoselective sulfoxide-directed processes: a Reformatsky-type reaction and a ß-keto sulfoxide reduction.