Protocol for combined N-of-1 trials to assess cerebellar neurostimulation for movement disorders in children and young adults with dyskinetic cerebral palsy.

BACKGROUND: Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders. METHODS: Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS. DISCUSSION: Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT06122675, first registered November 7, 2023.

One-year efficacy of a lifestyle behavioural intervention on physical and mental health in people with severe mental disorders: results from a randomized controlled trial.

This multicentric randomized controlled trial (RCT), carried out in six Italian University mental health sites, aims to test the efficacy of a six-month psychosocial intervention (LYFESTYLE) on Body Mass Index (BMI), body weight, waist circumference, fasting glucose, triglycerides, cholesterol, Framingham and HOmeostasis Model Assessment of insulin resistance (HOMA-IR) indexes in patients with schizophrenia, bipolar disorder, and major depression. Moreover, the efficacy of the intervention has also been tested on several other physical and mental health domains. Patients were randomly allocated to receive the six-month experimental intervention (LIFESTYLE) or a behavioural control intervention. All enrolled patients were assessed at baseline and after one year. We recruited 401 patients (206 in the experimental and 195 in the control group) with a diagnosis of schizophrenia or other psychotic disorder (29.9%), bipolar disorder (43.3%), or major depression (26.9%). At one year, patients receiving the experimental intervention reported an improvement in body mass index, body weight, waist circumference, HOMA-IR index, anxiety and depressive symptoms and in quality of life. Our findings confirm the efficacy of the LIFESTYLE intervention in improving physical and mental health-related outcomes in patients with severe mental illnesses after one year.

Endoscopic endonasal marsupialization of rathke cleft cysts: clinical outcomes and risk factors analysis of visual impairment, pituitary dysfunction, and CSF leak.

OBJECTIVE: This paper assesses the clinical and imaging characteristics, histopathological findings, and treatment outcomes of patients with Rathke's cleft cyst (RCC), as well as identifies potential risk factors for preoperative visual and pituitary dysfunction, intraoperative cerebrospinal fluid (CSF) leak, and recurrence. Through analyzing these factors, the study aims to contribute to the current understanding of the management of RCCs and identify opportunities for improving patient outcomes. METHODS: We performed a retrospective analysis of 45 RCC patients between ages 18-80 treated by Endoscopic Endonasal Approach (EEA) and cyst marsupialization between 2010 and 2022 at a single institution. RESULTS: The median patient age was 34, and 73% were female. The mean follow-up was 70 ± 43 months. Preoperative visual impairment correlated with cyst diameter (OR = 1.41, 95% CI = 1.07 to 1.85, p-value = 0.01) and older age (OR = 1.06, 95% CI = 1.01 to 1.11, p-value = 0.02). Intraoperative CSF leaks were 11 times more likely for cysts ≥ 2 cm (OR = 11.3, 95% CI = 1.25 to 97.37, p-value = 0.03), with the odds of leakage doubling for every 0.1 cm increase in cyst size (OR = 1.41, 95% CI = 1.08 to 1.84, p-value = 0.01). Preoperative RCC appearing hypointense on T1 images demonstrated significantly higher CSF leak rates than hyperintense lesions (OR = 122.88, 95% CI = 1.5 to 10077.54, p-value = 0.03). Preoperative pituitary hypofunction was significantly more likely in patients with the presence of inflammation on histopathology (OR = 20.53, 95% CI = 2.20 to 191.45, p-value = 0.008 ) and T2 hyperintensity on magnetic resonance imaging (MRI) sequences (OR = 23.2, 95% CI = 2.56 to 211.02, p-value = 0.005). Notably, except for the hyperprolactinemia, no postoperative improvement was observed in pituitary function. CONCLUSION: Carefully considering risk factors, surgeons can appropriately counsel patients and deliver expectations for complications and long-term results. In contrast to preoperative visual impairment, preoperative pituitary dysfunction was found to have the least improvement post-surgery. It was the most significant permanent complication, with our data indicating the link to the cyst signal intensity on T2 MR and inflammation on histopathology. Earlier surgical intervention might improve the preservation of pituitary function.

Anti-inflammatory, antinociceptive, and vasorelaxant effects of a new pyrazole compound 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole: role of NO/cGMP pathway and calcium channels.

Molecular modification of compounds remains important strategy towards the discovery of new drugs. In this sense, this study presents a new pyrazole derivative 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole (LQFM039) and evaluated the anti-inflammatory, analgesic, and vasorelaxant effects of this compound as well the mechanisms of action involved in the pharmacological effects. For this, mice were orally treated with LQFM039 (17.5, 35, or 70 mg/kg) prior acetic acid-induced abdominal writhing, formalin, tail flick, and carrageenan-induced paw edema protocols. In addition, vascular reactivity protocols were made with aortic rings contraction with phenylephrine and stimulated with graded concentrations of LQFM039. Abdominal writhing and licking time in both neurogenic and inflammatory phases of formalin were reduced with LQFM039 without altering latency to nociceptive response in the tail flick test. Carrageenan-induced paw edema showed that LQFM039 reduces edema and cell migration. In addition, the mechanism of action of LQFM039 involves NO/cGMP pathway and calcium channels, since this new pyrazole derivate elicited concentration-dependent relaxation attenuated by Nω-nitro-l-arginine methyl ester and 1H-[1,2,4] oxadiazolo [4,3-alpha]quinoxalin-1-one, and blockade of CaCl2-induced contraction. Altogether, our finding suggests anti-inflammatory, antinociceptive, and vasorelaxant effect of this new pyrazole derivative with involvement of NO/cGMP pathway and calcium channels.

The Patient's Clinical Profile From a Neuro-Ophthalmology Center in Brazil: A Retrospective Study.

BACKGROUND: Neuro-ophthalmology (NO) is a subspeciality of Ophthalmology, which represents more than an intersection of Neurology and Ophthalmology. The present report highlights the increasing importance of the subspeciality in Brazil and provides a unique retrospective study of the patient's clinical profile of a NO reference center. METHODS: Our study was retrospectively planned aiming to identify all neuro-ophthalmic cases of Instituto de Olhos of the Medical School Faculdade Ciências Médicas de Minas Gerais from August 2013 to March 2022.The first clinical diagnostic impression was selected from a predetermined list of 18 neuro-ophthalmologic conditions. Some NO conditions were eventually reclassified during the follow-up as the final clinical diagnosis impression. The concordance between the first and final clinical impressions was also investigated, as well as the patient's referral source. RESULTS: The sample comprised 903 patients from which 56.4% were female. The mean age was 51.48 ± 20.93 years. Males were more frequent in lower age groups <1 year (n = 3, 100%) and 1-9 years (n = 19/37, 51.4%). An external referral source represented 23.1%, and patients referred after basic ophthalmic consultation and from glaucoma service were 30.3% and 23.2%, respectively. The most encountered first clinical diagnostic impressions were isolated optic atrophy (13.1%), non-neuro-ophthalmic disease (11.7%), optic disc abnormalities (10.4%), ischemic optic neuropathies/retinal vascular occlusions (10.2%), and other visual field defects (9.0%). The kappa concordance coefficient among the first and final clinical diagnostic impressions was 0.53 (95% CI 0.48-0.59), indicating a moderate concordance level. The concordance among the most frequent diagnoses was lower in isolated optic atrophy (33%), other visual field defects (41%), and idiopathic optic neuritis (40%). CONCLUSIONS: Due to the limited number of epidemiology studies in neuro-ophthalmology, we highlight the importance of a NO service in the public health system in Brazil. It may certainly contribute to better strategy plan assistance among professionals and health care managers. This report should seemingly stimulate other studies regarding the relevant and unique features of this subspeciality, which is undoubtedly increasing its importance among patients, and in the scientific community worldwide.

Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties.

Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities. The resulting peptide, mast-MO, adopted an α-helical structure as determined by NMR, exhibited increased antibacterial properties comparable to standard-of-care antibiotics both in vitro and in vivo, and potentiated the activity of different classes of antibiotics. Mechanism-of-action studies revealed that mast-MO targets bacteria by rapidly permeabilizing their outer membrane. In animal models, the peptide displayed direct antimicrobial activity, led to enhanced ability to attract leukocytes to the infection site, and was able to control inflammation. Permutation studies depleted the remaining toxicity of mast-MO toward human cells, yielding derivatives with antiinfective activity in animals. We demonstrate a rational design strategy for repurposing venoms into promising antimicrobials.

CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness.

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.

Low numbers of large microplastics on environmentally-protected Antarctic beaches reveals no widespread contamination: insights into beach sedimentary dynamics.

Microplastics are ubiquitous contaminants of marine ecosystems around the world and Antarctica is no exception. Microplastics can be influenced by sedimentary dynamics mainly on coastal areas where they are more abundant in Antarctica. This study evaluated microplastic contamination in beach environments from two Antarctic Specially Protected Areas, aiming to identify relationships between microplastic numbers and sedimentological parameters on beach sediments. Low numbers of microplastics were found (> 0.5 mm; fibers excluded) - one particle per sample in 4 of 15 samples analyzed - and there is no evidence of widespread contamination. Sedimentological parameters reveal differences between sampled environments, but low numbers of microplastics impaired statistical comparison. All sediment samples are coarse, denoting highenergy depositional environments that are likely little susceptible to microplastic accumulation. Microplastic contamination in the Antarctic coastal ecosystem is heterogeneous, and their detailed characterization assisted by a systematization of methods can improve the understanding of microplastics distribution patterns in the cold coastal ecosystem.

First Report of Tomato Spotted Wilt Virus infecting Lettuce in Yuma, Arizona.

Tomato spotted wilt virus (TSWV, family Tospoviridae, genus Orthotospovirus) is a thrips-vectored pathogen that infects lettuce (Lactuca sativa) and many vegetable crops (Kuo et al. 2014, Hasegawa et al. 2022). Another thrips-borne pathogen of lettuce, impatiens necrotic spot virus (INSV, Tospoviridae, Orthotospovirus), was first reported in 2021 in Yuma, Arizona (Hasegawa et al. 2022). Symptoms of both viruses in lettuce are similar and include necrotic spotting, leaf chlorosis and plant stunting (Kuo et al. 2014). Beginning February through April of 2022, lettuce displaying symptoms of orthotospovirus infection was collected from romaine lettuce (var. longifolia) fields in three regions of Yuma County. A total of 96 plants were collected (5 from Tacna on 2/21, 5 from Wellton on 2/21, 15 from Wellton on 3/23, 30 from Tacna on 4/4, 20 from Wellton on 4/4, and 21 from Yuma Valley on 4/4). The area of the fields ranged from 10 to 18 acres, and the percent disease incidence ranged from 0.8% (Tacna on 4/4) to 2.75% (Tacna on 2/21). Thrips vector were present in all fields were symptomatic plants were observed. One leaf disk per plant (8 mm in diameter) was sampled with a cork borer and grounded individually with a micro pestle in a 1.7 ml microcentrifuge tube with 150 ul of Tri-reagent (Molecular Research Center). Total RNA was extracted from each sample using the Zymo Direct-zol-96 kit (Zymo Research). Samples were diluted with water to a ratio of 1:10 after RNA extraction. RT-qPCR was performed in 20 ul reactions with 5 ul of input RNA using the PCR Biosystems qPCRBIO Probe 1-Step Go No-ROX for the cDNA/qPCR master mix. RT-qPCR assays were carried out in multiplex reactions using primers specific for TSWV and INSV, in addition to a lettuce internal control gene (LOC111918243), along with negative controls. Primer and probe sequence details are reported in supplemental Table 1. We used a cycle threshold (ct) < 40 to indicate a positive result for both INSV and TSWV (Chen et al. 2013; Boonham et al. 2002). RT-qPCR successfully amplified INSV in 90 out of 96 samples and TSWV in 8 out of 96 samples. These 8 samples tested positive for both TSWV and INSV, showing that INSV and TSWV co-infected lettuce plants. Thus overall, ∼ 95% of symptomatic plants were infected with INSV alone, and ∼ 8% were co-infected with TSWV and INSV. Amplicons of 4 samples testing positive for TSWV were sent for Sanger sequencing (Eurofins Genomics, Louisville, KY). All were identified as TSWV. One amplicon with TSWV was sequenced for INSV and double infection was confirmed. BLAST results from the NCBI nt database show 100% (138 bp) identity to TWSV (MW519211) for the 4 TWSV amplicons and 99.22% (137 bp) identity to INSV (KX790323) for the INSV amplicon. Sanger sequence data are in the GenBank (accession: OQ685940-OQ685944). Based on RT-qPCR results, all TSWV infected plants were also infected with INSV. INSV may have been introduced to Yuma by infected plants or thrips from lettuce transplants produced in California (Hasegawa et al. 2022). TSWV could have been introduced similarly. To our knowledge, this is the first report of TSWV infecting lettuce in Yuma and the first report of INSV and TSWV co-infecting lettuce. TSWV and INSV infections have remained low since their discovery in Yuma, in part due to effective cultural and chemical management by lettuce growers (Palumbo, 2022). However, an increase in disease incidence and severity in the future could have a significant negative impact on production of romaine lettuce in the region.

Detecting and Characterizing Inferior Vena Cava Filters on Abdominal Computed Tomography with Data-Driven Computational Frameworks.

Two data-driven algorithms were developed for detecting and characterizing Inferior Vena Cava (IVC) filters on abdominal computed tomography to assist healthcare providers with the appropriate management of these devices to decrease complications: one based on 2-dimensional data and transfer learning (2D + TL) and an augmented version of the same algorithm which accounts for the 3-dimensional information leveraging recurrent convolutional neural networks (3D + RCNN). The study contains 2048 abdominal computed tomography studies obtained from 439 patients who underwent IVC filter placement during the 10-year period from January 1st, 2009, to January 1st, 2019. Among these, 399 patients had retrievable filters, and 40 had non-retrievable filter types. The reference annotations for the filter location were obtained through a custom-developed interface. The ground truth annotations for the filter types were determined based on the electronic medical record and physician review of imaging. The initial stage of the framework returns a list of locations containing metallic objects based on the density of the structure. The second stage processes the candidate locations and determines which one contains an IVC filter. The final stage of the pipeline classifies the filter types as retrievable vs. non-retrievable. The computational models are trained using Tensorflow Keras API on an Nvidia Quadro GV100 system. We utilized a fine-tuning supervised training strategy to conduct our experiments. We find that the system achieves high sensitivity on detecting the filter locations with a high confidence value. The 2D + TL model achieved a sensitivity of 0.911 and a precision of 0.804, and the 3D + RCNN model achieved a sensitivity of 0.923 and a precision of 0.853 for filter detection. The system confidence for the IVC location predictions is high: 0.993 for 2D + TL and 0.996 for 3D + RCNN. The filter type prediction component of the system achieved 0.945 sensitivity, 0.882 specificity, and 0.97 AUC score with 2D + TL and 0. 940 sensitivity, 0.927 specificity, and 0.975 AUC score with 3D + RCNN. With the intent to create tools to improve patient outcomes, this study describes the initial phase of a computational framework to support healthcare providers in detecting patients with retained IVC filters, so an individualized decision can be made to remove these devices when appropriate, to decrease complications. To our knowledge, this is the first study that curates abdominal computed tomography (CT) scans and presents an algorithm for automated detection and characterization of IVC filters.

LQFM289: Electrochemical and Computational Studies of a New Trimetozine Analogue for Anxiety Treatment.

This study employs electrochemical and Density Functional Theory (DFT) calculation approaches to investigate the potential of a novel analogue of trimetozine (TMZ) antioxidant profile. The correlation between oxidative stress and psychological disorders indicates that antioxidants may be an effective alternative treatment option. Butylatedhydroxytoluene (BHT) is a synthetic antioxidant widely used in industry. The BHT-TMZ compound derived from molecular hybridization, known as LQFM289, has shown promising results in early trials, and this study aims to elucidate its electrochemical properties to further support its potential as a therapeutic agent. The electrochemical behavior of LQFM289 was investigated using voltammetry and a mechanism for the redox process was proposed based on the compound's behavior. LQFM289 exhibits two distinct oxidation peaks: the first peak, Ep1a ≈ 0.49, corresponds to the oxidation of the phenolic fraction (BHT), and the second peak, Ep2a ≈ 1.2 V (vs. Ag/AgCl/KClsat), denotes the oxidation of the amino group from morpholine. Electroanalysis was used to identify the redox potentials of the compound, providing insight into its reactivity and stability in different environments. A redox mechanism was proposed based on the resulting peak potentials. The DFT calculation elucidates the electronic structure of LQFM289, resembling the precursors of molecular hybridization (BHT and TMZ), which may also dictate the pharmacophoric performance.

Pharmacological evaluation of antinociceptive and anti-inflammatory activities of LQFM202: a new piperazine derivative.

Advances have been made in the search for new multi-target modulators to control pain and inflammation. Therefore, compound 3,5-di-tert-butyl-4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (LQFM202) was synthesised and evaluated. First, in vitro assays were performed for COX-1, COX-2, and 5-LOX enzymes. Subsequently, adult female Swiss albino mice treated orally with LQFM202 at doses of 25-200 mg/kg were subjected to acetic acid-induced writhing, formalin-induced pain, carrageenan-induced hyperalgesia, carrageenan- or zymosan-induced paw oedema, or pleurisy. LQFM202 inhibited COX-1, COX-2, and LOX-5 (IC50 = 3499 µM, 1565 µM, and 1343 µM, respectively). In acute animal models, LQFM202 (50, 100, or 200 mg/kg) decreased the amount of abdominal writhing (29%, 52% and 48%, respectively). Pain in the second phase of the formalin test was reduced by 46% with intermediate dose. LQFM202 (100 mg/kg) reduced the difference in nociceptive threshold in all 4 h evaluated (46%, 37%, 30%, and 26%, respectively). LQFM202 (50 mg/kg) decreased the carrageenan-oedema from the second hour (27%, 31% and 25%, respectively); however, LQFM202 (100 mg/kg) decreased the carrageenan-oedema in all hours evaluated (35%, 42%, 48% and 50%, respectively). When using zymosan, LQFM202 (50 mg/kg) decreased the oedema in all hours evaluated (33%, 32%, 31% and 20%, respectively). In the carrageenan-pleurisy test, LQFM202 (50 mg/kg) reduced significantly the number of polymorphonuclear cells (34%), the myeloperoxidase activity (53%), TNF-α levels (47%), and IL-1ß levels (58.8%). When using zymosan, LQFM202 (50 mg/kg) reduced the number of polymorphonuclear and mononuclear cells (54% and 79%, respectively); and the myeloperoxidase activity (46%). These results suggest antinociceptive and anti-inflammatory effects of LQFM202.

Anti-inflammatory and antinociceptive effects, and safety toxicological profile of a new paracetamol analog, LQFM291.

In the scope of a research program with the goal of developing treatments for inflammatory diseases, the pharmacological evaluation of LQFM291, designed by molecular hybridization from butylated hydroxytoluene and paracetamol, was described. The antioxidant profile of LQFM291 was evaluated by electrochemical measurement. Also, acute or repeated treatments with equimolar doses to paracetamol were used to evaluate the antinociceptive and/or anti-inflammatory activities of LQFM291 in animal models. The toxicologic potential of LQFM291 was also evaluated and compared to paracetamol through biochemical and histopathological analysis after the repeated treatment schedule. As a result of the acute treatment, paracetamol showed a similar antinociceptive effect in formalin test compared to LQFM291. Whereas, after the repeated treatment, when carrageenan-induced hyperalgesia and edema tests were performed, paracetamol showed a delayed antinociceptive and anti-inflammatory effect compared to LQFM291. Furthermore, as other advantages the LQFM291 showed a high redox capacity, a gastroprotective activity and a safety pharmacological profile without any liver or kidney damage. These effects can be related to the prevention of oxidative stress by reduction of protein and lipid peroxidation in gastric tissue, maintenance of glutathione levels in hepatic homogenate, and a systemic reduction of pro-inflammatory cytokine levels, which may characterize the LQFM291 as a more viable and effective alternative to relief pain and inflammatory signs in patients with chronic disorders.

Direct binding of benzoate derivatives to two chemoreceptors with Cache sensor domains in Halomonas titanicae KHS3.

Halomonas titanicae KHS3, isolated from a hydrocarbon-contaminated sea harbor in Argentina, is able to grow on aromatic hydrocarbons and displays chemotaxis toward those compounds. This behavior might contribute to the efficiency of its degradation capacity. Using high throughput screening, we identified two chemoreceptors (Htc1 and Htc2) that bind benzoate derivatives and other organic acids. Whereas Htc1 has a high affinity for benzoate (Kd 112 µM) and 2-hydroxybenzoate (Kd 83 µM), Htc2 binds 2-hydroxybenzoate with low affinity (Kd 3.25 mM), and also C3/C4 dicarboxylates. Both chemoreceptors are able to trigger a chemotactic response of E. coli cells to the specific ligands. A H. titanicae htc1 mutant has reduced chemotaxis toward benzoate, and is complemented upon expression of the corresponding receptor. Both chemoreceptors have a Cache-type sensor domain, double (Htc1) or single (Htc2), and their ability to bind aromatic compounds is reported here for the first time.

A Method for Statistical Processing of Magnetic Field Sensor Signals for Non-Invasive Condition Monitoring of Synchronous Generators.

Condition monitoring of synchronous generators through non-invasive methods is widely requested by maintenance teams for not interfering the machine operation. Among the techniques used, external magnetic field monitoring is a recent strategy with great potential for detecting incipient faults. In this context, this paper proposes the application of a simple strategy with low computational cost to process data of external magnetic field time derivative signals for the purposes of condition monitoring and fault detection in synchronous machines. The information of interest is extracted from changes in the magnetic signature of the synchronous generator, obtained from frequency spectra of monitored signals using induction magnetic field sensors. The process forms a set of time series that reflects constructive and operational characteristics of the machine. The Shewhart control chart method is applied for anomaly detection in these time series, allowing the detection of changes in the machine magnetic signature. This method is employed in an algorithm for continuous condition monitoring of synchronous generators, presenting as output a global change indicator for the multivariable problem associated with magnetic signature monitoring. Correlation matrices are used to improve the algorithm response, filtering series with similar variation patterns associated with detected events. The proposed method is validated through tests on an experimental bench that allows the controlled imposition of faults in a synchronous generator. The proposed global change indicator allows the automatic detection of stator and rotor faults with the machine synchronized with the commercial power grid. The proposed methodology is also applied on data obtained from an equipment installed in a 305 MVA synchronous generator of a hydroelectric power plant where the evolution of an incipient fault, i.e., a mechanical vibration fault, has been detected.

Improvement in Solubility-Permeability Interplay of Psoralens from Brosimum gaudichaudii Plant Extract upon Complexation with Hydroxypropyl-ß-cyclodextrin.

Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-ß-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-ß-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (Kc < 500 M−1). PSO and 5-MOP permeability rate decreased after adding HP-ß-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-ß-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-ß-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.

Gene expression and alternative splicing dynamics are perturbed in female head transcriptomes following heterospecific copulation.

BACKGROUND: Despite the growing interest in the female side of copulatory interactions, the roles played by differential expression and alternative splicing mechanisms of pre-RNA on tissues outside of the reproductive tract have remained largely unknown. Here we addressed these questions in the context of con- vs heterospecific matings between Drosophila mojavensis and its sister species, D. arizonae. We analyzed transcriptional responses in female heads using an integrated investigation of genome-wide patterns of gene expression, including differential expression (DE), alternative splicing (AS) and intron retention (IR). RESULTS: Our results indicated that early transcriptional responses were largely congruent between con- and heterospecific matings but are substantially perturbed over time. Conspecific matings induced functional pathways related to amino acid balance previously associated with the brain's physiology and female postmating behavior. Heterospecific matings often failed to activate regulation of some of these genes and induced expression of additional genes when compared with those of conspecifically-mated females. These mechanisms showed functional specializations with DE genes mostly linked to pathways of proteolysis and nutrient homeostasis, while AS genes were more related to photoreception and muscle assembly pathways. IR seems to play a more general role in DE regulation during the female postmating response. CONCLUSIONS: We provide evidence showing that AS genes substantially perturbed by heterospecific matings in female heads evolve at slower evolutionary rates than the genome background. However, DE genes evolve at evolutionary rates similar, or even higher, than those of male reproductive genes, which highlights their potential role in sexual selection and the evolution of reproductive barriers.

Human splenic myeloid derived suppressor cells: Phenotypic and clustering analysis.

Myeloid derived suppressor cells (MDSCs) can be subset into monocytic (M-), granulocytic (G-) or polymorphonuclear (PMN-), and immature (i-) or early MDSCs and have a role in many disease states. In cancer patients, the frequencies of MDSCs can positively correlate with stage, grade, and survival. Most clinical studies into MDSCs have been undertaken with peripheral blood (PB); however, in the present studies, we uniquely examined MDSCs in the spleens and PB from patients with gastrointestinal cancers. In our studies, MDSCs were rigorously subset using the following markers: Lineage (LIN) (CD3, CD19 and CD56), human leukocyte antigen (HLA)-DR, CD11b, CD14, CD15, CD33, CD34, CD45, and CD16. We observed a significantly higher frequency of PMN- and M-MDSCs in the PB of cancer patients as compared to their spleens. Expression of the T-cell suppressive enzymes arginase (ARG1) and inducible nitric oxide synthase (i-NOS) were higher on all MDSC subsets for both cancer patients PB and spleen cells as compared to MDSCs from the PB of normal donors. Similar findings for the activation markers lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), program death ligand 1 (PD-L1) and program cell death protein 1 (PD-1) were observed. Interestingly, the total MDSC cell number exported to clustering analyses was similar between all sample types; however, clustering analyses of these MDSCs, using these markers, uniquely documented novel subsets of PMN-, M- and i-MDSCs. In summary, we report a comparison of splenic MDSC frequency, subtypes, and functionality in cancer patients to their PB by clustering and cytometric analyses.

Neck CT imaging and correlation with thyroid cancer incidence across age, gender and race.

OBJECTIVE: Incidental detection of thyroid cancers has been proposed as a cause of thyroid cancer increases over past decades, but few studies assess the impact of imaging utilization on thyroid cancer incidence. This study quantifies neck CT prevalence and its relationship with thyroid cancer incidence as a function of age, sex and race. DESIGN AND PATIENTS: Medical records of over 1 million patients at our institution were retrospectively analysed to quantify neck CT prevalence from 2004 to 2011 (study period). A national cancer database was used to compute thyroid cancer incidences over the study period and a reference period (1974-81) and to calculate change in thyroid incidence between the two periods. Both populations were partitioned into demographic subgroups of varying age, sex and race. Linear correlation between neck imaging and thyroid cancer incidence changes among subgroups was assessed using Pearson's correlation. RESULTS: Neck CT imaging and change in thyroid cancer incidence varied across all examined demographic variables, particularly age. When stratifying by age, CT use correlated strongly with recent national thyroid cancer incidence (R = .97) and with 30-year change in thyroid cancer incidence (R = .87). Across all demographic subgroups, CT prevalence correlated strongly and positively with change in thyroid cancer incidence (R = .60), greater for whites (R = .60) and blacks (R = .70) than other races (R = .28). CONCLUSION: Differences in neck CT usage strongly and positively correlates with the variation in thyroid cancer trends based on age, gender and race.

Predicting Mental Decline Rates in Mild Cognitive Impairment From Baseline MRI Volumetric Data.

PURPOSE: In mild cognitive impairment (MCI), identifying individuals at high risk for progressive cognitive deterioration can be useful for prognostication and intervention. This study quantitatively characterizes cognitive decline rates in MCI and tests whether volumetric data from baseline magnetic resonance imaging (MRI) can predict accelerated cognitive decline. METHODS: The authors retrospectively examined Alzheimer Disease Neuroimaging Initiative data to obtain serial Mini-Mental Status Exam (MMSE) scores, diagnoses, and the following baseline MRI volumes: total intracranial volume, whole-brain and ventricular volumes, and volumes of the hippocampus, entorhinal cortex, fusiform gyrus, and medial temporal lobe. Subjects with <24 months or <4 measurements of MMSE data were excluded. Predictive modeling of fast cognitive decline (defined as >0.6/year) from baseline volumetric data was performed on subjects with MCI using a single hidden layer neural network. RESULTS: Among 698 baseline MCI subjects, the median annual decline in the MMSE score was 1.3 for converters to dementia versus 0.11 for stable MCI (P<0.001). A 0.6/year threshold captured dementia conversion with 82% accuracy (sensitivity 79%, specificity 85%, area under the receiver operating characteristic curve 0.88). Regional volumes on baseline MRI predicted fast cognitive decline with a test accuracy of 71%. DISCUSSION: An MMSE score decrease of >0.6/year is associated with MCI-to-dementia conversion and can be predicted from baseline MRI.