Predicting outcome of chronic pain treatment via a modified self-efficacy scale.
This study utilized a modified self-efficacy scale and examined the relationship of perceived self-efficacy to treatment outcome in a chronic, intractable, benign pain population (N = 62). In two separate studies a self-efficacy scale was given to inpatients in a combined cognitive-behavioral and medical treatment program. The scale categories consisted of (1) walking distance, (2) lifting ability, (3) pain coping, (4) working ability, and (5) social and recreational engagement. Self-efficacy beliefs were found to be associated with the level of functioning of these patients and their response to treatment. Patients with higher self-efficacy scores following treatment rated themselves as more improved and demonstrated better overall functioning with greater reductions in chronic illness behavior at followup. These observations support the merits of self-efficacy measures as predictors of treatment outcome in chronic pain patients.


The effect of changes to Australian Capital Territory mental health legislation on rates of emergency detention.
The Australian Capital Territory (ACT) changed from the Mental Health (Treatment and Care) Act 1994 (ACT) to the Mental Health Act 2015 (ACT) on 1 March 2016. The objective was to find the association between legislative changes and detention rates. A cross-sectional study of involuntary order rates in the period 3 years before the legislative change was undertaken. Chi-squared analysis was performed to compare proportions. There was a statistically significant decrease in the proportion of Psychiatric Treatment Orders (PTOs) over the two periods, which could be impacted by the change from a period of detention for 7 days to a period of detention of 11 days in Period 2. On the other hand, the total number of Emergency Actions (EAs) increased in Period 2, where ambulance officers could detain patients. The change in mental health legislation in the ACT was associated with a change in detention rates, in particular a decrease in the proportion of PTOs and an increase in EAs. Further study needs to be undertaken, given changes to frontline supports since the study period ended.


Wheat flour peroxidase is a prominent allergen associated with baker's asthma.
Putative wheat allergens with molecular sizes around 35kDa have been repeatedly detected in immunoblots using sera from patients with baker's asthma. However, none of these allergens had been previously isolated. To purify and characterize a major component of the 35 kDa allergenic band which seems to be present in flour from diploid, tetraploid (pasta) and hexaploid (bread) wheats. Gel-filtration chromatography followed by RP-HPLC have allowed the purification of a new wheat allergen. Immunodetection with sera from allergic patients and with a specific serum for asparagine-linked complex glycans, as well as amino acid sequencing, were used to identify the isolated protein. A 36 kDa allergen has been purified from wheat flour. Its N-terminal and internal sequences, N-linked glycans, and enzymatic activity indicated that this allergen is a seed-specific peroxidase. Sera from six out of 10 patients hypersensitive to wheat flour displayed positive reactions when assayed against the purified dot-blotted allergen. Seed-specific peroxidases from cereals (flours) seem to be important allergens in hypersensitive diseases associated with the manipulation of these plant materials. A new enzyme has thus been involved in IgE-mediated diseases.


Contribution of a lectin, LecM, to the quorum sensing signalling pathway of Ralstonia solanacearum strain OE1-1.
The soil-borne bacterium Ralstonia solanacearum invades the roots and colonizes the intercellular spaces and then the xylem. The expression of lecM, encoding a lectin LecM, is induced by an OmpR family response regulator HrpG in R. solanacearum strain OE1-1. LecM contributes to the attachment of strain OE1-1 to the host cells of intercellular spaces. OE1-1 produces methyl 3-hydroxymyristate (3-OH MAME) through a methyltransferase (PhcB) and extracellularly secretes the chemical as a quorum sensing (QS) signal, which activates QS. The expression of lecM is also induced by the PhcA virulence regulator functioning through QS, and the resulting LecM is implicated in the QS-dependent production of major exopolysaccharide EPS I and the aggregation of OE1-1 cells. To investigate the function of LecM in QS, we analysed the transcriptome of R. solanacearum strains generated by RNA sequencing technology. In the lecM mutant, the expression of positively QS-regulated genes and negatively QS-regulated genes was down-regulated (by >90%) and up-regulated (by ~60%), respectively. However, phcB and phcA in the lecM mutant were expressed at levels similar to those in strain OE1-1. The lecM mutant produced significantly less ralfuranone and exhibited a significantly greater swimming motility, which were positively and negatively regulated by QS, respectively. In addition, the extracellular 3-OH MAME content of the lecM mutant was significantly lower than that of OE1-1. The application of 3-OH MAME more strongly increased EPS I production in the phcB-deleted mutant and strain OE1-1 than in the lecM mutant. Thus, the QS-dependent production of LecM contributes to the QS signalling pathway.


Capgras syndrome and confabulation unfurling anti NMDAR encephalitis with classical papillary thyroid carcinoma: First reported case.
Anti NMDA Receptor encephalitis (ANMDARE) is an immune mediated disease of the central nervous system, caused by circulating antibodies against the NMDA receptor present on neuronal surface. It is known to cause a spectrum of disease ranging from mild behavioral and psychiatric manifestations to full blown seizures, dyskinesias and altered sensorium. It can also be paraneoplastic presentation of a hidden tumor, most commonly ovarian teratoma. Here we present a case of ANMDARE with intriguing presentation of Capgras syndrome and confabulations, who was found to have a malignant papillary thyroid carcinoma, which has been rarely reported.


Evaluating the Role of Major Lower Extremity Amputation in Nonagenarians.
Elderly patients with critical limb ischemia are an especially frail and vulnerable group of patients. There is little literature investigating outcomes and resource utilization in nonagenarians undergoing major lower extremity amputation (MLEA). This study aims to elucidate the outcomes of this unique set of patients for whom amputation may often be considered a "palliative" intervention. Analyzing over 16,000 records from the Vascular Quality Initiative (VQI) database, we collected demographic, operative, and postoperative data on all patients who underwent an MLEA. We performed univariate analysis comparing nonagenarians to younger patients examining both short-term and long-term outcomes. Multimodel inference was used to analyze the effect of age on clinically meaningful outcomes: mortality and long-term living disposition. With 392 nonagenarians and 16,349 patients under the age of 90, we found nonagenarians were less comorbid and less likely to have a prior bypass or amputation. Despite experiencing lower rates of reoperation and individual postoperative complications, nonagenarians suffered higher long-term mortality (46% vs. 22%, P < 0.0005) and were more likely to be living in a facility at follow-up (34% vs. 15%, P < 0.0005). Incorporating important demographic and clinical factors, multimodel inference demonstrated that, the nonagenarian age group was a critical predictor of nonhome living status (Akaike Importance weight 0.99). Although nonagenarians were less comorbid than their younger counterparts and suffered fewer perioperative complications, MLEA leads to a poorer outcome with significant mortality and a higher likelihood of residing in a facility at long-term follow-up. These findings underscore the importance of frank goals of care discussions in nonagenarians considering major amputation.


Pulsed Doppler flow-velocity waveforms in the prediction of fetal hematocrit of the severely isoimmunized pregnancy.
We previously reported a significant relationship between the hematocrit levels of anemic fetuses and information derived from ultrasonographic and Doppler flow-velocity waveforms. In this study we prospectively tested two formulas for the prediction of hematocrit values, by use of gestational age, presence or absence of hydrops, and Doppler indices. Although one of the two formulas predicted hematocrit values significantly, the only component of the formula that made a significant contribution was fetal hydrops. We conclude that currently available fetal Doppler measurements are unable to be applied in the prospective prediction of hematocrit values in anemic fetuses of isoimmunized pregnancies.


How should I fixate the subscapularis in total shoulder arthroplasty? A systematic review of pertinent subscapularis repair biomechanics.
The present study aimed to review the biomechanical outcomes of subscapularis repair techniques during total shoulder arthroplasty (TSA) to assist in clinical decision making. A systematic review of multiple databases was performed by searching PubMed, Scopus, Cochrane Library, Google Scholar, and all databases within EBSCOhost to find biomechanical studies of subscapularis repair techniques in cadaveric models of TSA. Nine studies met the inclusion criteria. In the majority of studies, lesser tuberosity osteotomy (LTO) techniques had greater load to failure and less cyclic displacement compared to subscapularis tenotomy or peel methods. LTO repairs with sutures wrapped around the humeral stem demonstrated superior biomechanical outcomes compared to techniques using only a tension band. In terms of load to failure, the strongest repair of any study was a dual-row fleck LTO using four sutures wrapped around the stem. Several cadaveric studies have shown superior biomechanical outcomes with LTO techniques compared to tenotomy. In the majority of studies, the strongest subscapularis repair technique in terms of biomechanical outcomes is a compression LTO. Using three or more sutures wrapped around the implant and the addition of a tension suture may increase the biomechanical strength of the LTO repair.


Nematode predatory ability of the fungus Duddingtonia flagrans affected by in vitro sequential exposure to ovine gastrointestinal tract.
Duddingtonia flagrans is a nematophagous fungus employed as a biocontrol agent of gastrointestinal nematodes in ruminants. After oral ingestion and passage through the digestive tract of animals, this microorganism captures the nematodes in the feces. The drastic conditions of ruminant digestive tract could affect fungi chlamydospores and therefore biocontrol activity. The aim of this study was to evaluate in vitro the effect of four ruminant digestive segments on the concentration and nematode predatory ability of a Colombian native strain of D. flagrans. The sequential four-step methodology proposed evaluated conditions of the oral cavity, rumen, abomasum, and small intestine such as pH (2, 6, 8), enzymes (pepsin, pancreatin), temperature (39 °C), and anaerobiosis comparing short (7 h) and long (51 h) exposure times. The results showed that the nematode predatory ability of the fungi is affected by sequential exposure to gastrointestinal segments and this effect depends on the exposure time to those conditions. After short exposure (7 h) through the four ruminant digestive segments, the fungi had a nematode predatory ability of 62%, in contrast, after long exposure (51 h) the nematode predatory ability was lost (0%). Moreover, the number of broken chlamydospores was higher in the long-exposure assay.


Immunity in acute bacterial infections.
A brief survey of the ways in which humoral and cellular immune responses deal with bacteria and their products shows that a variety of effector mechanisms is involved. Their efficiency varies, partly in relation to the kind of bacterial attack with which they have to deal. Some bacterial factors though not crudely toxic can interfere with specific host defences.


Structure-activity relationship analysis of activity-based probes targeting HTRA family of serine proteases.
High temperature requirement A serine proteases (HTRA) are ubiquitously expressed and participate in protein quality control and cellular stress responses. They are linked to several clinical illnesses, including bacterial infection, cancer, age-related macular degeneration, and neurodegenerative diseases. In addition, several recent studies have revealed HTRAs as important biomarkers and potential therapeutic targets, necessitating the development of an effective detection method to evaluate their functional states in various disease models. We developed a new series of HTRA-targeting activity-based probes with enhanced subtype selectivity and reactivity. In conjunction with our previously developed tetrapeptide probes, we established the structure-activity relationship of the new probes for different HTRA subtypes. Our probes are cell-permeable and have potent inhibitory effects against HTRA1 and HTRA2, making them valuable for identifying and validating HTRAs as an important biomarker.


Stereotactic removal of intracranial foreign bodies: review and case report.
A 13-year-old boy presented himself with an airgun injury with a track from an entry wound in the left temporal region to the right thalamic pulvinar. The patient made a good recovery following stereotactic removal of the pellet. The literature is reviewed and the indications for stereotactic removal of intracranial foreign bodies discussed.


Cost Analysis in Helicobacter pylori Eradication Therapy Based on a Database of Health Insurance Claims in Japan.
Cost-benefit is an important consideration for Helicobacter pylori (H. pylori) eradication in Japan, where 1.5 million patients were reported to receive first-line eradication annually. This study aimed to identify the optimal cost-saving triple therapy regimen for H. pylori eradication in Japan. This retrospective observational study used data from a large-scale, nationwide health insurance claims database (2015‒2018). Using success rates of first-line eradication, mean total costs of first-line and second-line eradications per patient were compared between regimens including a potassium-competitive acid blocker (P-CAB) or a proton pump inhibitor (PPI), and between two clarithromycin (CAM) doses (400 and 800 mg/day). Subgroup analyses by smoking habit or body mass index (BMI) were performed. Among propensity score (age, gender, CAM dose, disease name)-matched patients (P-CAB regimen, n=22,002; PPI regimen, n=22,002), total costs were lower with the P-CAB than the PPI regimen (Japanese yen [JPY] 12,952 vs 13,146) owing to significantly higher first-line eradication rates with the P-CAB regimen (93.6% vs 79.7%; p<0.001). For both regimens, even among current smokers or patients with BMI ≥25 kg/m2, eradication rates did not differ by CAM dose, and total costs were approximately JPY1000 lower with CAM 400 mg/day than with CAM 800 mg/day. High success rate of first-line eradication contributes to saving in total eradication costs by reducing costs of subsequent therapy, irrespective of patients' smoking status or BMI class. The combination of more potent acid-inhibitory medicine and low-dose CAM may be the optimal regimen in terms of efficacy and cost-benefit in Japan.


Effect of alkalosis on plasma epinephrine responses to high intensity cycle exercise in humans.
The purpose of this study was to determine the effects of alkalosis on epinephrine concentrations in response to a 90 s maximal exercise test. A group of ten healthy men ingested either a bicarbonate (BS) supplement (0.3 g x kg(-1) of body mass of sodium bicarbonate) or placebo mixture (P) prior to performing a 90 s maximal cycle ergometer test. An indwelling Teflon cannula was placed in the antecubital vein and blood samples were drawn at three times at rest separated by 10 min, immediately following the protocol, and at 2.5, 5, and 10 min post exercise to determine plasma epinephrine concentrations. Sodium bicarbonate ingestion significantly ( P<0.05) induced alkalosis both at rest [mean (SD) pH=7.42 (0.02) BS, 7.38 (0.02) P] and after the exercise protocol [pH=7.16 (0.02) BS, 7.12 (0.02) P]. Plasma epinephrine concentrations were not significantly different immediately post exercise between the two conditions [4.2 (0.6) compared to 4.2 (0.7) pmol x ml(-1) in BS and P, respectively]. Work performed and power output attained were not significantly different between the two treatment conditions [mean power=258.7 (35.1) W BS, 260.3 (35.4) W P; peak power=534.7 (61.6) W BS, 535.7 (54.4) W P]. The primary finding of this investigation was that orally-induced alkalosis does not significantly affect plasma epinephrine concentrations or performance following 90 s of maximal cycle exercise in untrained men.


Comparison of Perioperative Outcomes between Open, Laparoscopic, and Robotic Distal Pancreatectomy: an Analysis of 1815 Patients from the ACS-NSQIP Procedure-Targeted Pancreatectomy Database.
Robotic surgery is gaining acceptance for distal pancreatectomy (DP). Nevertheless, no multi-institutional data exist to demonstrate the ideal clinical circumstances for use and the efficacy of the robot compared to the open or laparoscopic techniques, in terms of perioperative outcomes. The 2014 ACS-NSQIP procedure-targeted pancreatectomy data for patients undergoing DP were analyzed. Demographics and clinicopathological and perioperative variables were compared between the three approaches. Univariate and multivariable analyses were used to evaluate outcomes. One thousand eight hundred fifteen DPs comprised 921 open distal pancreatectomies (ODPs), 694 laparoscopic distal pancreatectomies (LDPs), and 200 robotic distal pancreatectomies (RDPs). The three groups were comparable with respect to demographics, ASA score, relevant comorbidities, and malignant histology subtype. Compared to the ODP group, patients undergoing RDP had lower T-stages of disease (P = 0.0192), longer operations (P = 0.0030), shorter hospital stays (P < 0.0001), and lower postoperative 30-day morbidity (P = 0.0476). Compared to the LDP group, RDPs were longer operations (P < 0.0001) but required fewer concomitant vascular resections (P = 0.0487) and conversions to open surgery (P = 0.0068). On multivariable analysis, neoadjuvant therapy (P = 0.0236), malignant histology (P = 0.0124), pancreatic reconstruction (P = 0.0006), and vascular resection (P = 0.0008) were the strongest predictors of performing an ODP. The open, laparoscopic, and robotic approaches to distal pancreatectomy offer particular advantages for well-selected patients and specific clinicopathological contexts; therefore, clearly demonstrating the most suitable use and superiority of one technique over another remains challenging.


Ocular complications following I-125 brachytherapy for choroidal melanoma.
Uveal melanoma has traditionally been treated with enucleation, plaque brachytherapy, or external beam radiation. Following the results of the multicenter Collaborative Ocular Melanoma Study (COMS), which established no significant difference in mortality rates between enucleation and brachytherapy, plaque brachytherapy has become the favoured modality given its potential for preservation of vision and the eye. Among the radioisotopes that have been used, iodine-125 (I-125) has become the increasingly popular choice in the United States. However, I-125 brachytherapy is associated with complications, including keratitis, iris neovascularization, neovascular glaucoma, radiation retinopathy, and optic neuropathy. The purpose of this review is to discuss the pathogenesis, clinical presentation, and management of complications related to I-125 plaque brachytherapy for choroidal melanoma.


Repurposing Belinostat for Alleviation of Atopic Dermatitis.
Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease that is characterized by intense pruritus, seriously affecting patients' quality of life. Its pathophysiology, which involves both the adaptive and innate immune responses as well as skin barrier defects, is still poorly understood. We recently identified a microRNA, miR-335, as a key driver of keratinocyte differentiation and cornification, which is essential for the establishment of a healthy skin barrier. However, expression of miR-335 is lost in AD, leading to barrier defect. We further demonstrated how belinostat, a histone deacetylase inhibitor, can effectively restore miR-335 and resolve the barrier defect in a dry skin model. Here, in this commentary, we highlight the role of belinostat in the treatment of AD and discuss the need for more research into crosstalk between epigenetic and non-coding RNA-based regulation, as well as possible therapeutic strategies targeting the epigenome.


VEGF165 gene-modified human umbilical cord blood mesenchymal stem cells protect against acute liver failure in rats.
Human umbilical cord blood mesenchymal stem cells (HUCB-MSCs) can exert a protective effect in rat models of acute liver failure (ALF). Vascular endothelial growth factor 165 (VEGF165 ) is the predominant VEGF isoform and possesses a strong pro-angiogenic function. In the present study, HUCB-MSC served as the gene delivery vehicle for the VEGF165 gene, and we explored the therapeutic effects of this system on ALF. HUCB-MSCs were infected with an adenovirus expressing green fluorescent protein (GFP)-VEFG fusion protein (Ad-VEGF165 ) to overexpress VEGF165 or an adenovirus expressing GFP (Ad-GFP) as control. The control and modified HUCB-MSCs were then transplanted into ALF model rats. Liver function and liver pathological changes were assessed by biochemical tests and liver histology. Immunohistochemistry was carried out to determine the expression of, CD34, Ki67 and VEGF. VEGF165 overexpression enhanced the multipotency of HUCB-MSCs and promoted the homing and colonization of HUCB-MSC in the liver tissues of ALF rats. Furthermore, although HUCB-MSC transplantation ameliorated liver damage and promoted liver regeneration to some extent in ALF rats, Ad-VEGF165 -HUCB-MSC transplantation showed stronger therapeutic effects on ALF. In summary, transplantation of VEGF165 -modified HUCB-MSCs exert stronger therapeutic effects on ALF than HUCB-MSCs. The present study provides a novel therapeutic approach for ALF.


A mass spectrometry-based approach to host cell protein identification and its application in a comparability exercise.
Host cell proteins (HCPs) are process-related impurities present in biopharmaceuticals and are generally considered to be critical quality attributes. Changes in a biopharmaceutical production process may result in qualitative shifts in the HCP population. These shifts are not necessarily detectable when overall HCP levels are measured with traditional approaches such as enzyme-linked immunosorbent assays (ELISAs). Thus, the development of techniques that complement the ELISA's functionality is desirable. Here, a mass spectrometry (MS)-based approach for the analysis of HCP populations in biopharmaceuticals is presented. It consists of (i) the generation of exclusion lists that represent the masses of the active pharmaceutical ingredient (API), (ii) the compilation of inclusion lists based on an HCP catalog derived from the analysis of protein A-purified samples, and (iii) the analysis of purified biopharmaceuticals using the generated exclusion and inclusion lists. With this approach, it was possible to increase sensitivity for HCP detection compared with a standard liquid chromatography tandem MS (LC-MS/MS) run. The workflow was successfully implemented in a comparability exercise assessing HCP populations in drug substance samples before and after a process change. Furthermore, the results suggest that size can be an important factor in the copurification of HCPs and API.


Prevalence and characterization of frailty, depression, and cognitive impairment in patients listed for heart transplantation: Results of the FELICITAR prospective registry.
It is recommended to assess frailty prior to heart transplantation (HT). Our objective was to assess the prevalence of frailty in patients listed for HT. The FELICITAR registry (Frailty Evaluation after List Inclusion, Characteristics and Influence on TrAnsplantation And Results) is a prospective registry that includes patients listed for HT in three centers, from January 2017 to April 2019. We assessed the presence of frailty, depression, cognitive impairment, and quality of life when included. Ninety-nine patients were included. Of this group, 30.6% were frail, 55 (56.1%) had depression (treated only in nine patients), and 51 (54.8%) had cognitive impairment. Compared with non-frail patients, frail patients were more frequently hospitalized when included in HT waiting list (P = .048), had a lower upper-arm circumference (P = .026), had a lower Barthel index (P = .001), more anemia (P = .010), higher rates of depression (P = .001), poorer quality of life (P = .001), and lower hand-grip strength (P < .001). In multivariate analysis hand-grip strength (odds ratio .91; 95% confidence interval .87-.96, P < .001) and Barthel index (odds ratio .90; 95% confidence interval .82-.99, P = .024) were associated with frailty. Frailty, depression, and cognitive impairment are common in patients included in HT waiting list. Frailty is strongly associated with hand-grip strength.


Uveitis in Behçet disease in a tertiary center over 25 years: the KKESH Uveitis Survey Study Group.
To describe the features of Behçet-associated uveitis over a 25-year period. Retrospective observational case series. A chart review of patients with Behçet-associated uveitis who were evaluated from January 1986 to December 2011 at King Khaled Eye Specialist Hospital, Saudi Arabia. Demographic data, symptoms, type of uveitis, treatment, and complications were evaluated. The main outcome measures were presenting symptoms, types of uveitis, treatment, and complications. There were 132 patients (232 eyes; 102 male [77.3%]) evaluated with age of onset of 36.9 ± 11.4 years. Panuveitis was the most common presentation, affecting 118 patients (89.4%). Episodes were bilateral in 100 patients (75.8%). Baseline best-corrected visual acuity (BCVA) was 20/125 in both eyes. Retinal vasculitis at presentation occurred in 61 eyes (26.3%), occlusive vasculitis in 59 eyes (25.4%), and macular edema in 42 eyes (18.1%). Common therapeutic management included oral corticosteroids in 123 patients (93.2%), intravenous steroid therapy in 35 patients (26.5%), cyclosporine in 98 patients (74.2%), and azathioprine in 65 patients (49.2%). Common anterior segment complications included glaucoma (44 eyes, 19%) and cataracts (34 eyes, 14.7%). The most common posterior segment complication was optic nerve atrophy. Cataract surgery was the most common surgery. At last visit, BCVA was better than 20/50 in 131 eyes (56.5%). Behçet-associated uveitis predominantly affects young men in Saudi Arabia. Bilateral panuveitis associated with retinal vasculitis was the most common manifestation. More than 50% of patients maintained 20/50 or better BCVA at final follow-up and were primarily managed with oral corticosteroids and other immunosuppressive agents.


Inhibitory effect of neurotensin on gastric acid secretion in rats. Development of a bioassay model.
Neurotensin has been shown to inhibit gastric acid secretion when administered in pharmacological doses, but no information has been available concerning its possible dose-related effect during intravenous infusion. In this study, a dose-related and reversible inhibitory effect of neurotensin was demonstrated in pentobarbital-anesthetized female Sprague-Dawley rats. The rats underwent continuous gastric perfusion with saline, 1 ml/min, and intravenous infusion of both pentagastrin and neurotensin. Inhibition of acid secretion did not depend upon the occurrence of hypotension, and ranged from 35 +/- 7% of maximal acid output at 0.24 nmol/kg/hr to 60 +/- 10% at 7.2 nmol/kg/hr of neurotensin. Blood levels of C-terminal neurotensin-like immunoreactivity were proportional to the dose of peptide infused and were 52 fmol/ml during infusion of 0.24 nmol/kg/hr, a dose that significantly inhibited pentagastrin-induced acid secretion. Thus, a model has been developed to study the effect of neurotensin infusion on acid secretion; the concentration of plasma neurotensin-like immunoreactivity at which inhibition occurs in this model is similar to the concentration reported to occur after a nutrient stimulus.


Corrigendum: Morphophysiology of Potato (Solanum tuberosum) in Response to Drought Stress: Paving the Way Forward.
[This corrects the article DOI: 10.3389/fpls.2020.597554.].


Exploiting the gain-modulation mechanism in parieto-motor neurons: application to visuomotor transformations and embodied simulation.
The so-called self-other correspondence problem in imitation demands to find the transformation that maps the motor dynamics of one partner to our own. This requires a general purpose sensorimotor mechanism that transforms an external fixation-point (partner's shoulder) reference frame to one's own body-centered reference frame. We propose that the mechanism of gain-modulation observed in parietal neurons may generally serve these types of transformations by binding the sensory signals across the modalities with radial basis functions (tensor products) on the one hand and by permitting the learning of contextual reference frames on the other hand. In a shoulder-elbow robotic experiment, gain-field neurons (GF) intertwine the visuo-motor variables so that their amplitude depends on them all. In situations of modification of the body-centered reference frame, the error detected in the visuo-motor mapping can serve then to learn the transformation between the robot's current sensorimotor space and the new one. These situations occur for instance when we turn the head on its axis (visual transformation), when we use a tool (body modification), or when we interact with a partner (embodied simulation). Our results defend the idea that the biologically-inspired mechanism of gain modulation found in parietal neurons can serve as a basic structure for achieving nonlinear mapping in spatial tasks as well as in cooperative and social functions.


Sex differences in Parkinson's disease: A transcranial magnetic stimulation study.
Demographic and clinical studies imply that female sex may be protective for PD, but pathophysiological evidence to support these observations is missing. In early PD, functional changes may be detected in primary motor cortex using transcranial magnetic stimulation. We hypothesised that if pathophysiology differs between sexes in PD, this will be reflected in differences of motor cortex measurements. Forty-one newly diagnosed PD patients (22 males, 19 females) were clinically assessed using MDS-UPDRS part III, and various measures of cortical excitability and sensorimotor cortex plasticity were measured over both hemispheres, corresponding to the less and more affected side, using transcranial magnetic stimulation. Twenty-three healthy (10 men, 13 women) participants were studied for comparison. Among patients, no significant differences between sexes were found in age, age of diagnosis, symptom duration, and total or lateralized motor score. However, male patients had disturbed interhemispheric balance of motor thresholds, caused by decreased resting and active motor thresholds in the more affected hemisphere. Short interval intracortical inhibition was more effective in female compared to male patients in both hemispheres. Female patients had a preserved physiological focal response to sensorimotor plasticity protocol, whereas male patients showed an abnormal spread of the protocol effect. The study provides one of the first neurophysiological evidences of sex differences in early PD. Female patients have a more favorable profile of transcranial magnetic stimulation measures, possibly reflecting a more successful cortical compensation or delayed maladaptive changes in the sensorimotor cortex. © 2019 International Parkinson and Movement Disorder Society.


Determination of organophosphorus pesticides and their transformation products in river waters by automated on-line solid-phase extraction followed by thermospray liquid chromatography-mass spectrometry.
The trace-level determination of ten priority organophosphorus (OP) pesticides (e.g., chlorpyrifos-methyl, diazinon, disulfoton, fenthion, fenamiphos) and various transformation products (TPs; e.g., disulfoton sulfoxide, fenthion sulfoxide etc.) using automated on-line solid-phase extraction (SPE) with C18 precolumns followed by LC-MS and thermospray interface with time-scheduled selected-ion monitoring (SIM) was developed. Two main ions (usually [M+H]+ and [M+NH4]+ or [M+CH3CN]+) were used for each pesticide in the positive ion (PI) detection mode, while [M-H]- and [M+HCOO]- ions were used in the negative ion (NI) mode. The proposed method requires 100 ml of sample for a limit of detection (LOD) of 0.01-0.1 microgram/l. Calibration graphs were constructed by preconcentrating 100 ml of water spiked with the pesticide mixture at various concentrations (from 0.025 to 2 microgram/l). Good linearity was observed for most of the analytes studied. The experimental setup described in this paper was applied to study the kinetics of degradation of ten organophosphorus pesticides in spiked river water samples. The different samples were first analyzed by an automated on-line precolumn exchange system (OSP-2) followed by LC with diode array detection. To confirm the identity of the organophosphorus pesticides detected, the samples were then analyzed by automated on-line SPE-LC-MS. The method permitted unequivocal identification of many of the TPs formed during the experiments, e.g., the oxo-derivatives of chlorpyrifos-methyl, temephos and pyridafenthion, fenamiphos sulfoxide. Many of these TPs are here reported for the first time since previously used MS-based techniques were not sensitive enough.


Exploring the potential benefits of pharmacogenomics in chronic respiratory diseases.
Tweetable abstract Opportunities for pharmacogenetics implementation in chronic respiratory diseases through the employment of genotype-guided prescriptions in treating nonrespiratory comorbidities.


Safety guidelines for radiolocalised sentinel node resection.
Sentinel node radiolocalisation procedures are associated with low levels of radiation exposure. Radioactive material is present in the operating theatre and pathology laboratory. In most hospitals there are no official regulations in place for sentinel node radiation exposure. To establish guidelines on the safety of sentinel node mapping with emphasis on the management of radioisotopes. The current literature regarding sentinel node procedures and radiation safety was reviewed. EU and US radiation safety regulations were scrutinised. Personnel involved in sentinel node procedures are exposed to low levels of radiation. These levels are not high enough to require designated radiation workers in the theatre and pathology laboratory. Awareness of radiation safety and certain precautions during the procedure and processing of the specimen can further reduce levels of exposure. Although low levels of radiation exposure are associated with sentinel node procedures, awareness of radiation safety and adherence to regulations, along with close interdepartmental co-operation, are recommended for further reduction in radiation exposure and safe application of this technique.


Acute and subacute anterior cruciate ligament reconstructions are associated with a higher risk of revision and reoperation.
(1) Report concomitant cartilage and meniscal injury at the time of anterior cruciate ligament reconstruction (ACLR), (2) evaluate the risk of aseptic revision ACLR during follow-up, and (3) evaluate the risk of aseptic ipsilateral reoperation during follow-up. Using a United States integrated healthcare system's ACLR registry, patients who underwent primary isolated ACLR were identified (2010-2018). Multivariable Cox proportional-hazards regression was used to evaluate the risk of aseptic revision, with a secondary outcome evaluating ipsilateral aseptic reoperation. Outcomes were evaluated by time from injury to ACLR: acute (< 3 weeks), subacute (3 weeks-3 months), delayed (3-9 months), and chronic (≥ 9 months). The final sample included 270 acute (< 3 weeks), 5971 subacute (3 weeks-3 months), 5959 delayed (3-9 months), and 3595 chronic (≥ 9 months) ACLR. Medial meniscus [55.4% (1990/3595 chronic) vs 38.9% (105/270 acute)] and chondral injuries [40.0% (1437/3595 chronic) vs 24.8% (67/270 acute)] at the time of ACLR were more common in the chronic versus acute groups. The crude 6-year revision rate was 12.9% for acute ACLR, 7.0% for subacute, 5.1% for delayed, and 4.4% for chronic ACLR; reoperation rates a 6-year follow-up was 15.0% for acute ACLR, 9.6% for subacute, 6.4% for delayed, and 8.1% for chronic ACLR. After adjustment for covariates, acute and subacute ACLR had higher risks for aseptic revision (acute HR 1.70, 95% CI 1.07-2.72, p = 0.026; subacute HR 1.25, 95% CI 1.01-1.55, p = 0.040) and aseptic reoperation (acute HR 2.04, 95% CI 1.43-2.91, p < 0.001; subacute HR 1.31, 95% CI 1.11-1.54, p = 0.002) when compared to chronic ACLR. In this cohort study, while more meniscal and chondral injuries were reported for ACLR performed ≥ 9 months after the date of injury, a lower risk of revision and reoperation was observed following chronic ACLR relative to patients undergoing surgery in acute or subacute fashions.


A Simple Way to Apply Moisture Chamber Eyeglasses During Oculoplastic Surgery.
Proper eyelid closure and a normal blink reflex are essential to maintain a stable tear film and a healthy corneal surface. We present a simple technique to apply moisture chamber eyeglasses after oculoplastic surgery. The Opti-Gard® protective eyewear is faster, easily applicable and well performing. It can be used with different face shape, and it does not require any additional trimming or modification. This technical note explains a very simple, economical and less time-consuming method to prevent a postoperative dry keratoconjunctivitis. It may be applied to all procedures within the field of ophthalmic surgery, including oculoplastic surgery.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Autophosphorylation is crucial for CDK-activating kinase (Ee;CDKF;1) activity and complex formation in leafy spurge.
Ee;CDKF;1 protein is a leafy spurge (Euphorbia esula) CDK-activating kinase that is involved in a phosphorylation cascade linked to early stages of cell cycle progression. Yeast two-hybrid screening performed using Ee;CDKF;1 as a bait indicated that one of the interacting proteins was Ee;CDKF;1. Protein-protein interaction of Ee;CDKF;1 was further confirmed by yeast two-hybrid interaction and in vitro pull-down assays. Gel exclusion chromatography and/or native PAGE showed that GST-CDKF;1, MBP-CDKF;1, GST-CDKF;1 devoid of GST, and endogenous Ee;CDKF;1 were capable of forming homo protein complexes which are in dimer, trimer, and/or higher molecular-mass complex in its native state. In addition, Ee;CDKF;1 complexes were autophosphorylated and able to phosphorylate CDK. Moreover, mutant forms of Ee;CDKF;1 (106G/A, 166K/A), which lost autophosphorylation capability completely, were unable to form homo protein complexes in their native state. The result thus demonstrated that autophosphorylation of Ee;CDKF;1 is crucial for both kinase activity and complex formation.


[Pelvic injuries in childhood and adolescence: Retrospective analysis of 5-year data from a national trauma centre].
Pelvic fractures are uncommon injuries in paediatric trauma patients because of specific anatomical features. Due to the low incidence there is no standardized therapeutic algorithm. This retrospective review evaluates paediatric pelvic fractures of a Level I Trauma Centre over 5 years. In addition, we compared the data with adult pelvic fractures and reviewed the literature. A total of 37 pelvic fractures (≤16 years) were documented, with an incidence of 9.9% in the child with multiple injuries. The most common injury mechanisms were traffic accidents, followed by falls from heights. Type A injuries occurred in 50% (type B: 16%, type C: 27%, acetabular injuries: 11%). Osteosynthesis was performed in nine cases. Therapeutic intervention was necessary in three cases of haemodynamically relevant bleeding; 97% of all children had associated injuries (mean ISS: 38). Our data showed some differences to the literature. Pelvic fractures are predictors for high injury severity. Despite similar fracture pattern, in contrast to adults most injuries could be treated non-operatively. In unstable or dislocated fractures open reduction and stabilization must be performed.


PTSD is associated with accelerated transcriptional aging in World Trade Center responders.
Posttraumatic stress disorder (PTSD) is associated with shortened lifespan and healthspan, which suggests accelerated aging. Emerging evidence suggests that methylation age may be accelerated in PTSD. It is important to examine whether transcriptional age is also accelerated because transcriptome is highly dynamic, associated with age-related outcomes, and may offer greater insight into the premature aging in PTSD. This study is the first reported investigation of the relationship between transcriptional age and PTSD. Using RNA-Seq data from our previous study on 324 World Trade Center responders (201 never had PTSD, 81 with current PTSD, and 42 with past PTSD), as well as a transcriptional age calculator (RNAAgeCalc) recently developed by our group, we found that responders with current PTSD, compared with responders without a PTSD diagnosis, showed accelerated transcriptional aging (p = 0.0077) after adjustment for chronological age and race. We compared our results to the epigenetic aging results computed from several epigenetic clock calculators on matching DNA methylation data. GrimAge methylation age acceleration was also associated with PTSD diagnosis (p = 0.0097), and the results remained significant after adjustment for the proportions of immune cell types. PhenoAge, Hannum, and Horvath methylation age acceleration were not reliably related to PTSD. Both epigenetic and transcriptional aging may provide biological insights into the mechanisms underpinning aging in PTSD.


In vivo and in vitro experiments on relationships between PGA1 and glucose utilization.
The in vivo and in vitro effects of PGA1 on glucose utilization were investigated in normal rats and in rats with alloxan-diabetes (50 mg/kg i.v. administered 48 hrs before experiment). The animals were divided into two groups. The first group -- which included both normal and diabetic animals -- was submitted to an IVGIT after a 12-h fast and during a sodium chloride infusion. In the second group -- which equally included normal and diabetic rats -- the same GTT was performed during a sodium chloride infusion in which PGA1 had been diluted, so that a dose of 0.5 g/kg/min was administered. This dose is devoid of any effect on cardiovascular activity. For in vitro experiments, glucose utilization was studied in the rat diaphragm incubated with insulin (200 muU/ml) and PGA1 (10 and 100 ng): results demonstrated that PGA1 enhances the insulin effect on glucose utilization and the enhancement is dose-dependent. The same results were observed also in the in vivo experiments: in normal rats PGA1 really improves glucose utilization without any interference with insulin secretion from B-cells. On the other hand, PGA1 has no effect on this utilization in diabetic rats. From our experiments it can therefore be concluded that PGA1 improves glucose utilization, showing a synergic action with the increased quantity of insulin secreted in response to a glucose load. No effect is noted when insulin secretion from B-cells is reduced or absent.


Do Professionals Who Use the Voice in a Journalistic Context Benefit from Humming as a Semi-occluded Vocal Tract Exercise?
Many vocal enhancement and rehabilitation programs for voice professionals define vocal exercises without analyzing their effects on that specific population in which they will be applied, in the established dose and often without considering the presence and absence of vocal alteration. Journalists have sought the voice clinic due to new professional vocal demands and a vocal program is being elaborated. To determine the immediate effect of humming in professionals with and without voice disorders who work under high vocal demand in a journalistic context. Thirty-six individuals who completed the Dysphonia Risk Screening Protocol and underwent voice recording participated in the study. Three speech therapists defined the presence and/or absence of vocal changes by consensus. Subsequently, five repetitions of humming were proposed; the exercises lasted five seconds each and were separated by five seconds of complete silence, and recordings were made before and after the exercise (vowel and phrase). For the pre and post comparison between the groups with and without vocal changes, acoustic measurements and spectrogram, including the classification of the signal type, were performed. The sample had a similar distribution of men and women and a mean age of 39.9 years. Most of the professionals were journalists or reporters. The risk of dysphonia was high for half of the sample, and the presence of vocal changes, predominantly mild ones, was identified in 56%. After the exercise, a decrease in noise at low frequencies and an improvement in the series of harmonics and the signal type were observed in both groups; a decrease in irregularity was observed only in the participants without vocal changes. The proposed humming exercise had an immediate positive effect on the voice of professionals working in a journalistic context, and the changes were particularly evident in aspects of the voice that were initially altered.


[Correction of altered serotonin exchange in adolescents with functional disorders of digestive system].
With the purpose of search the ways of improvement treatment of functional pathologies of the system of digestion an author is studied the concentration and the role of serotonin in 180 adolescents. Got results of serotonin receptors 5HT1 agonists were used for patients with paroxysms of abdominal pain mainly at neurocirculatory disfunction and migraine.


Genomic characterization of Lactobacillus fermentum DSM 20052.
Lactobacillus fermentum, a member of the lactic acid bacteria complex, has recently garnered increased attention due to documented antagonistic properties and interest in assessing the probiotic potential of select strains that may provide human health benefits. Here, we genomically characterize L. fermentum using the type strain DSM 20052 as a canonical representative of this species. We determined the polished whole genome sequence of this type strain and compared it to 37 available genome sequences within this species. Results reveal genetic diversity across nine clades, with variable content encompassing mobile genetic elements, CRISPR-Cas immune systems and genomic islands, as well as numerous genome rearrangements. Interestingly, we determined a high frequency of occurrence of diverse Type I, II, and III CRISPR-Cas systems in 72% of the genomes, with a high level of strain hypervariability. These findings provide a basis for the genetic characterization of L. fermentum strains of scientific and commercial interest. Furthermore, our study enables genomic-informed selection of strains with specific traits for commercial product formulation, and establishes a framework for the functional characterization of features of interest.


The stability and characteristics of a DNA Holliday junction switch.
A Holliday junction (HJ) consists of four DNA double helices, with a branch point discontinuity at the intersection of the component strands. At low ionic strength, the HJ adopts an open conformation, with four widely spaced arms, primarily due to strong electrostatic repulsion between the phosphate groups on the backbones. At high ionic strength, screening of this repulsion induces a switch to a more compact (closed) junction conformation. Fluorescent labelling with dyes placed on the HJ arms allows this conformational switch to be detected optically using fluorescence resonance energy transfer (FRET), producing a sensitive fluorescent output of the switch state. This paper presents a systematic and quantitative survey of the switch characteristics of such a labelled HJ. A short HJ (arm length 8 bp) is shown to be prone to dissociation at low switching ion concentration, whereas an HJ of arm length 12 bp is shown to be stable over all switching ion concentrations studied. The switching characteristics of this HJ have been systematically and quantitatively studied for a variety of switching ions, by measuring the required ion concentration, the sharpness of the switching transition and the fluorescent output intensity of the open and closed states. This stable HJ is shown to have favourable switch characteristics for a number of inorganic switching ions, making it a promising candidate for use in nanoscale biomolecular switch devices.


Cytomegalovirus-Associated Nephrotic Syndrome in a Patient with Myasthenia Gravis Treated with Azathioprine: A Case Report.
BACKGROUND Patients taking azathioprine (AZA) are very susceptible to development of cytomegalovirus (CMV) infection. The symptoms of CMV infection are varied. In some rare cases, CMV infection can even result in nephrotic syndrome. CASE REPORT Here, we present a rare case of nephrotic syndrome associated with CMV infection, induced by azathioprine intake. The patient, diagnosed with myasthenia gravis, was initially treated with azathioprine for 2 years. Then, the patient was admitted to the hospital due to nephrotic syndrome and acute kidney injury. Minimal change disease with acute tubular necrosis were diagnosed through biopsy. After an initial good response to hemodialysis and steroids, the patient developed severe pneumonia and oral ulcers. Further anti-CMV IHC staining of kidney tissues showed positive cells in tubules, indicating nephrotic syndrome secondary to CMV infection. CONCLUSIONS This case reminded us that CMV may be an under-recognized cause of nephrotic syndrome. Patients treated with azathioprine are very susceptible to developing CMV infection. During the diagnosis of nephrotic syndrome, we should always take CMV infection into consideration, especially in patients with on azathioprine.


Exploring the appointment factors affecting pediatric patients with swallow disorders: Implications for speech and language pathology attendance.
Feeding and swallowing disorders have become increasingly prevalent among children, necessitating effective management to prevent long-term complications. Speech and language pathology (SLP) services play a crucial role in diagnosing and treating these disorders. The objective of this study was to explore the factors that influence patient attendance to SLP appointments for swallow disorders. This study was conducted at Boston Medical Center, involving 359 pediatric patients referred to SLP for swallow-related concerns. De-identified patient and appointment information was obtained from the electronic medical record. Various factors such as age, gender, race/ethnicity, primary language, appointment date/time, and COVID-19 lockdown status were analyzed to determine their impact on patient no-shows. Statistical analyses, including Chi-Square tests and binary logistic regression, were conducted using appropriate methodologies. 355 individual patient records were included in the analysis. Lockdown status and appointment time of day did not significantly affect patient no-shows. However, appointments conducted through telemedicine showed a significant difference in attendance. Patient referral department, gender, race, language, and being born at the medical center did not significantly influence patient attendance. Notably, having a primary care provider (PCP) at the medical center significantly affected patient attendance. Furthermore, previous appointment cancellations made a patient more likely to no-show. This study provides valuable insights into the factors influencing patient attendance at SLP appointments for pediatric swallowing disorders. Having a PCP at the medical center and utilizing telemedicine appointments were associated with higher attendance rates. Addressing appointment cancellations and investigating underlying reasons behind missed appointments should be prioritized in future research. Understanding these factors will facilitate the development of interventions to optimize patient attendance and improve the delivery of SLP services in pediatric populations.


Cerebral white matter lesions predict both ischemic strokes and myocardial infarctions in patients with established atherosclerotic disease.
Cerebral white matter lesions (WML) are regarded as manifestations of small vessel disease, but have also been associated with large vessel atherosclerosis. We investigated whether WML have a predictive value for future ischemic events. Two-hundred-thirty patients with proven atherosclerotic disease, recent ischemic stroke (IS, n=70), recent myocardial infarction (MI, n=71), or peripheral arterial disease (PAD, n=89) were included. The presence of periventricular lesions (PVL) and deep white matter lesions (DWML) on MRI at entry and ischemic events during follow-up were registered. During follow-up with a mean duration of 3.5+/-1.4 years 22 patients had a MI, 21 patients suffered an IS and 2 patients died suddenly. The frequency of ischemic events during follow-up was higher among patients with PVL than in those without PVL (IS: 18% versus 5%, p=0.001; MI: 15% versus 7%, p=0.03; any ischemic event: 36% versus 11%, p<0.001). DWML was associated only with the combined outcome any ischemic event (p=0.04). In multivariate regression analysis the presence of PVL was independently associated with IS (HR 3.2 (95%CI 1.3-8.4) and MI (HR 3.4 (95%CI 1.4-8.0)). We observed an association between WML, especially PVL, and future ischemic strokes and myocardial infarctions in patients with established atherosclerotic disease.


Oral dryness and moisture degree at the lingual but not buccal mucosa predict prognosis in end-of-life cancer patients.
The aim of this study is to investigate the association of oral dryness with overall survival and determine the threshold points of moisture degree for predicting 7-day survival in palliative care patients. A total of 147 consecutive palliative care patients were included between January 2017 and November 2018. Oral dryness at the lingual and buccal mucosa was measured using an oral moisture-checking device. Overall survival was compared between patients with and without oral dryness using Kaplan-Meier curves with a log-rank test. Prediction accuracy was evaluated by the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Median survival (95% confidence interval) in patients with oral dryness at the lingual mucosa was shorter than that in patients without oral dryness (17 [11-24] days vs. 28 [22-37] days, log-rank test, p <0.001), but not at the buccal mucosa. Time-dependent ROC revealed that the AUCs for 7-, 14-, 21-, and 28-day survival predictions were 0.72, 0.68, 0.61, and 0.59 with a cutoff value of 19.2%, respectively. The prevalence of performance status (PS) 4 and oxygen administration in the 7-day death group were higher than those in the non-7-day death group. A stratified analysis indicated that moisture degree <19.2% showed fair predictive performance with an AUC of 0.74 and 0.74, in the case of PS ≤3 or without oxygen administration. Oral dryness was associated with increased risk of mortality in palliative care patients. Moisture degree <19.2% at the lingual mucosa predicted less than 7-day survival.


Intraoperative evaluation of DRUJ instability through dorsal stress radiography in distal radius fractures.
Certain type of injury of the triangular fibrocartilage complex associated with distal radius fracture can result in distal radioulnar joint instability (DRUJ). Untreated DRUJ instability may lead to poor result in the treatment of acute distal radius fractures. The aim of this study was to evaluate DRUJ instability in distal radius fractures through dorsal stress radiography comparing the affected and unaffected wrists intraoperatively. 49 patients with a distal radius fracture who were operatively treated with a volar locking plate were included. Dorsal stress radiography was used to evaluate both affected and unaffected wrists peri-operatively to detect DRUJ instability. Under general anesthesia, a dorsal stress test was performed on the unaffected wrist. Additionally, after fixation of the affected wrist, a dorsal stress test was performed. The ulnar translation ratio (UTR) was measured through the dorsal stress radiograph. Arthroscopic examination was performed on all affected wrists according to Palmer's and Atzei classification. The UTR of the affected wrist and the TFCC injury Palmer-type IB tendency were positively correlated (odds ratio: 1.18, p-value: 0.002). Additionally, as the UTR difference between the affected and unaffected wrists enlarged, it revealed a significant DRUJ instability tendency due to Palmer-type IB TFCC injury (p-value: 0.000006, Wilcoxon rank-sum test). Dorsal stress radiography is a reliable, simple procedure to evaluate DRUJ instability intraoperatively. UTR value from dorsal stress radiography could be useful for evaluating DRUJ instability associated with distal radius fracture.


Noninvasive visualization of molecular events in the mammalian zygote.
Following fertilization, a number of molecular events are triggered in the mammalian zygote. As biochemical studies using mammalian gametes and zygotes have inherent difficulties, the molecular nature of these processes is currently unclear. We have developed a method to visualize these events. In vitro transcribed mRNAs encoding for proteins fused with green fluorescent protein were microinjected into oocytes or embryos and fluorescence signals were observed. Using this technique we succeeded in obtaining images of the DNA methylation status in living mouse and rabbit embryos. Moreover, time-lapse images were acquired of spindle and nuclear formation during second meiosis and first mitosis. Importantly, the microinjected embryos developed to the normal offspring even after observation, suggesting that the technique is relatively noninvasive. Thus, our method may help elucidate the molecular aspects of fertilization and preimplantation development and, based on the real-time genetic and epigenetic status, could become a tool to select "good quality" embryos before implantation.


First-pass and equilibrium-MRA of the aortoiliac region with a superparamagnetic iron oxide blood pool MR contrast agent (SH U 555 C): results of a human pilot study.
The purpose of this study was to study different doses for first-pass and equilibrium phase MRA of aortoiliac vessels with a superparamagnetic iron oxide (SPIO) intravascular MR contrast agent (SH U 555 C) after single i.v. bolus injection. Sixteen healthy volunteers were prospectively enrolled into this single-blind, placebo-controlled clinical trial. SHU 555 C was injected as an i.v. bolus at stepwise increased dose levels of 5, 10, 20 and 40 micromol Fe/kg bodyweight (b.w.) corresponding to injection volumes of 0.01, 0.02, 0.04 and 0.08 ml/kg b.w. Serial high-resolution three-dimensional MRA of the aortoiliac vessels was acquired during first-pass and equilibrium, at 6 min intervals up to 42 min after contrast application using a breath-hold three-dimensional FLASH sequence on a 1.5 T scanner. Intravascular enhancement was calculated within the abdominal aorta and the inferior vena cava and a statistical analysis for significant differences in vessel enhancement was performed during the bolus and equilibrium phases. The visibility of vessels was ranked and effects of potential artifacts on image quality were graded for each time point and dose group. SH U 555 C showed a dose-dependent intravascular enhancement during the observation period (42 min). The highest dose of 40 micromol Fe/kg b.w. revealed the highest image quality during first-pass and equilibrium phases. The intravascular enhancement in the aorta increased dose-dependently from 5 to 40 micromol kg b.w. during first-pass and equilibrium phases (p<0.05). Intravascular signal inhomogeneities were observed at lower doses and decreased with increasing doses. First-pass MRA was diagnostic at doses of 10, 20 and 40 micromol Fe/kg b.w. For equilibrium MRA, a dose of 40 micromol Fe/kg b.w. was considered to be diagnostic. SH U 555 C proved to be a contrast agent with a high T1-effect suitable for both first-pass MRA comparable to gadolinium-enhanced MRA and high resolution equilibrium MRA up to 42 min post-injection (p.i.).


A Review of In-Office Dynamic Image Navigation for Extraction of Complex Mandibular Third Molars.
We performed a retrospective review of in-office removal of complex mandibular third molars with a dynamic image navigation system (DINS). A retrospective review was conducted of cases completed from 2010 to 2014 by a single oral and maxillofacial surgeon. The average age of the patients was 47 years (range, 27 to 72 years). Extraction complexity was classified with Juodzbalys and Daugela's classification system. The included study cases had complexity scores of 9 or greater. Each patient received custom intraoral splints to secure the tracking array and underwent cone beam computed tomography image acquisition. All surgical procedures were performed with a precalibrated tracking straight handpiece under dynamic navigation. All 25 cases were treated successfully with the use of the DINS. Twelve of these cases were associated with pathologic lesions. Three patients were noted to have inferior alveolar nerve paresthesia. One patient sustained a pathologic fracture at week 2. Postoperative infections were noted in 7 cases, 2 of which had a pre-existing infection. One patient reported temporary limitation of mouth opening. A coronectomy was performed in 1 case. We present results using a new technology, the DINS, for removal of complex mandibular third molars. Potential advantages are 1) improved visualization and localization of anatomic structures such as the inferior alveolar nerve, lingual cortical plate, and adjacent roots; 2) improved control during osteotomy; 3) decreased surgical access requirements and reduction in overall bone removal; 4) ability to perform complex procedures successfully in an in-office setting; 5) decreased surgical time resulting from improved visualization; and 6) potential use as a teaching tool. Possible limitations of the use of an in-office DINS include increased cost, increased time attributed to presurgical planning, initial learning curve, and optical array interference by the surgeon or assistants during surgery.


Occurrence of recurrent aphthous stomatitis only on lining mucosa and its relationship to smoking--a possible hypothesis.
Recurrent aphthous stomatitis (RAS) is one of the most common ulcers affecting the oral cavity. Though it is known that RAS affects only the lining (non-keratinized) mucosa sparing the masticatory (keratinized) mucosa and is unlikely to be seen in smokers, no concrete explanations have been put forward. A hypothesis is proposed that the keratin layer blocks the ingress of antigens and prevents the occurrence of RAS on masticatory mucosa. Similarly, combustible products of smoking are known to cause keratinization and therefore have a similar effect on the lining mucosa and inhibit its occurrence. In addition, nicotine or its metabolites can result in decrease of pro-inflammatory cytokines like tumor necrosis factor-α, interleukins 1 and 6, and increase of anti-inflammatory cytokine interleukin-10. Consequently, there is reduced susceptibility to RAS due to immunosuppression and/or reduction in inflammatory response.


The DIAB-HYCAR Study.
Microalbuminuria and proteinuria are strong independent predictors for increased cardiovascular mortality in non-insulin-dependent diabetic (NIDDM) patients. In such patients, angiotensin converting enzyme (ACE) inhibition improves the evolution of diabetic nephropathy; however, no data are currently available on the effects of such intervention on cardiovascular morbidity and mortality. The aim of the Diab-Hycar study is to test the hypothesis that ACE inhibition with a low daily dose of 1.25 mg ramipril, which has no significant effect on blood pressure, may reduce cardiovascular morbidity and/or mortality in normotensive or hypertensive NIDDM patients with persistent albuminuria. Selected and followed by general practitioners, 4000 patients will receive their usual oral antidiabetic treatment and if necessary antihypertensive treatment (ACE inhibitors excluded). In addition in a randomized, double-blind trial they will be given either a placebo or 1.25 mg ramipril daily. The follow-up is currently scheduled to last 3 years. The efficacy of ACE-inhibition will be assessed by the following major end-points: cardiovascular death, sudden death, myocardial infarction, stroke, renal replacement therapy. The Diab-Hycar study started on 3 February 1995. By 1 September 1995, 11,000 urine samples were tested. The prevalence of persistent albuminuria was 23%, 964 patients were initially included in the study, with 619 eligible patients included soon after. Different strategies have been developed to record cardiovascular events correctly and to minimize the number of patients lost to follow-up.


Supervised Obesity Reduction Trial for AF ablation patients: results from the SORT-AF trial.
Weight management seems to be beneficial for obese atrial fibrillation (AF) patients; however, randomized data are sparse. Thus, this study aimed to investigate the influence of weight reduction on AF ablation outcomes. SORT-AF is an investigator-sponsored, prospective, randomized, multicentre, and clinical trial. Patients with symptomatic AF (paroxysmal or persistent) and body mass index (BMI) 30-40 kg/m2 underwent AF ablation and were randomized to either weight-reduction (group 1) or usual care (group 2), after sleep-apnoea-screening and loop recorder (ILR) implantation. The primary endpoint was defined as AF burden between 3 and 12 months after AF ablation. Overall, 133 patients (60 ± 10 years, 57% persistent AF) were randomized to group 1 (n = 67) and group 2 (n = 66), respectively. Complications after AF-ablation were rare (one stroke and no tamponade). The intervention led to a significant reduction of BMI (34.9 ± 2.6-33.4 ± 3.6) in group 1 compared to a stable BMI in group 2 (P < 0.001). Atrial fibrillation burden after ablation decreased significantly (P < 0.001), with no significant difference regarding the primary endpoint between the groups (P = 0.815, odds ratio: 1.143, confidence interval: 0.369-3.613). Further analyses showed a significant correlation between BMI and AF recurrence for patients with persistent AF compared with paroxysmal AF patients (P = 0.032). The SORT-AF study shows that AF ablation is safe and successful in obese patients using continuous monitoring via ILR. Although the primary endpoint of AF burden after ablation did not differ between the two groups, the effects of weight loss and improvement of exercise activity were beneficial for obese patients with persistent AF demonstrating the relevance of life-style management as an important adjunct to AF ablation in this setting. NCT02064114.


Children with congenital colorectal malformations during the UK Sars-CoV-2 pandemic lockdown: an assessment of telemedicine and impact on health.
This pilot study was designed to assess bowel function and quality of life (QoL) in children and adolescents with congenital colorectal malformations (CCM) during the first UK COVID lockdown period. Changes in health were assessed through semi-structured interviews, gastrointestinal functional outcomes using Krickenbeck scoring and QoL by the modified disease-specific HAQL (Hirschsprung's disease anorectal malformation quality of life questionnaire). The State-Trait Anxiety Inventory (STAI)™ for adults was used to assess parental anxiety. Thirty-two families were interviewed; 19 (59%) reported no change in their child's health during the lockdown, 5 (16%) a deterioration and 8 (25%) an improvement. Neither the severity of the CCM, nor the degree of bowel dysfunction, correlated with any deterioration. The HAQL score was not correlated to a change in health. Anxiety scores ranged from no anxiety to clinical concerns. Telemedicine was well accepted by 28/32 parents (88%); however, in-person appointments were preferred if there were clinical concerns. In the follow-up of children and adolescents with CCM during the first UK lockdown using telemedicine we found that over half had stable health conditions. Patients needing additional care could not be predicted by the severity of their disease or their bowel function alone.


Functions of cell surface galectin-glycoprotein lattices.
Programmed remodeling of cell surface glycans by the sequential action of specific glycosyltransferases can control biological processes by generating or masking ligands for endogenous lectins. Galectins, a family of animal lectins with affinity for beta-galactosides, can form multivalent complexes with cell surface glycoconjugates and deliver a variety of intracellular signals to modulate cell activation, differentiation, and survival. Recent efforts involving genetic or biochemical manipulation of O-glycosylation and N-glycosylation pathways, as well as blockade of the synthesis of endogenous galectins, have illuminated essential roles for galectin-glycoprotein lattices in the control of biological processes including receptor turnover and endocytosis, host-pathogen interactions, and immune cell activation and homeostasis.


Thiamine protects against paraquat-induced damage: scavenging activity of reactive oxygen species.
To demonstrate the superoxide anion (O(2)(-)) scavenging activity of thiamine, we comparatively investigated the inhibition of cell growth reduction and repression of the oxidative stress-inducible gene expression (soxS, sodA, zwf and soi-19::lacZ) triggered by paraquat, intracellular O(2)(-) generator, using an Escherichia coli system. When thiamine (>1 μM) was added to the culture, a decrease of growth rate caused by paraquat was significantly recovered. Paraquat treatment (1 μM) to aerobically grown E. coli highly increased the expression of soxS and its regulons sodA and zwf, genes for manganese-containing superoxide dismutase (Mn-SOD) and glucose-6-phosphate dehydrogenase (G6PDH) to cope with the oxidative stress. However, the induction of Mn-SOD and G6PDH was suppressed by the thiamine supplement. The induction of the soi-19::lacZ gene, whose expression was dependent on paraquat, was also repressed by more than 10 μM of the thiamine addition to the culture. To characterize the role of thiamine, which challenges the paraquat toxicity, an in vitro experiment of nitroblue tetrazolium (NBT) reduction was performed. The NBT reduction by O(2)(-) generated in the xanthine/hypoxanthine system was inhibited by the thiamine supplement in a dose-dependent manner. Moreover, it competed with the 2-deoxy-d-ribose in absorbing the hydroxyl radical (OH) generated by γ-irradiation (800 Gy) and thus inhibited the formation of malondialdehyde in vitro. In conclusion, this evidence suggests that thiamine may partly act as an antioxidant to scavenge O(2)(-) (or OH) directly and thus affect the cellular response to oxidative stress induced by reactive oxygen species.


Surface modification of crosslinked poly(styrene-divinyl benzene) micrometer-sized particles of narrow size distribution by ozonolysis.
Micrometer-sized polystyrene template particles of narrow size distribution were prepared by dispersion polymerization of styrene in 2-methoxyethanol. Uniform micrometer-sized polystyrene/crosslinked poly(styrene-divinyl benzene) composite particles were formed by a single-step swelling process of the template particles with styrene, divinyl benzene and benzoyl peroxide, followed by polymerization at 70 degrees C. Uniform micrometer-sized crosslinked poly(styrene-divinyl benzene) particles of higher surface area were produced by dissolution of the template polystyrene part of the former composite particles with N,N-dimethylformamide. Hydroperoxide conjugated crosslinked poly(styrene-divinyl benzene) particles were produced by ozonolysis of these particles. The effect of ozonolysis conditions, such as exposure time and flow rate of the ozone, on the hydroperoxide conjugation to the crosslinked particles was also studied. Functionalization of the crosslinked poly(styrene-divinyl benzene) particles was performed by graft polymerization of vinylic monomers such as acrylonitrile and chloromethylstyrene on the hydroperoxide conjugated crosslinked particles. This was accomplished by raising the temperature (e.g., 70 degrees C) of deairated acetonitrile dispersions containing the hydroperoxide conjugated particles and the vinylic monomers. The influence of various polymerization parameters on the grafting yield, e.g., monomer concentration, conjugated hydroperoxide concentration, and temperature, was also elucidated.


The conformation of a tetratritylated alpha-cyclodextrin with unusual proton NMR.
Tetratritylation of alpha-cyclodextrin (CD) and subsequent peracetylation of the partially tritylated mixture allowed the preparation and isolation of the symmetrical 6(A),6(B),6(D),6(E)-tetratritylated alpha-CD in pure form. The (1)H NMR spectra of the compound showed abnormal behaviour with the anomeric proton of one of the glycopyranosyl systems resonating below 3.0 ppm, which is exceptionally unusual. To understand this anomaly in the (1)H NMR data, we performed a complete NMR analysis and using molecular modelling as a tool, we were able to obtain a conformation that can explain the observed NMR phenomenon.


Using the electrically-evoked compound action potential (ECAP) interphase gap effect to select electrode stimulation sites in cochlear implant users.
Studies in cochlear implanted animals show that the IPG Effect for ECAP growth functions (i.e., the magnitude of the change in ECAP amplitude growth function (AGF) slope or peak amplitude when the interphase gap (IPG) is increased) can be used to estimate the densities of spiral ganglion neurons (SGNs) near the electrode stimulation and recording sites. In humans, the same ECAP IPG Effect measures correlate with speech recognition performance. The present study examined the efficacy of selecting electrode sites for stimulation based on the IPG Effect, in order to improve performance of CI users on speech recognition tasks. We measured the ECAP IPG Effect for peak amplitude in adult (>18 years old) CI users (N= 18 ears), and created experimental programs to stimulate electrodes with either the highest or lowest ECAP IPG Effect for peak amplitude. Subjects also listened to a program without any electrodes deactivated. In a subset of subject ears (11/18), we compared performance differences between the experimental programs to post-operative computerized tomography (CT) scans to examine underlying factors that might contribute to the efficacy of an electrode site-selection approach. For sentences-in-noise, average performance was better when subjects listened to the experimental program that stimulated electrodes with the highest rather than the lowest IPG Effect for ECAP peak amplitude. A similar pattern was noted for transmission and perception of consonant place cues in a consonant recognition task. However, on average, performance when listening to a program with higher IPG Effect values was equal to that when listening with all electrodes activated. Results also suggest that scalar location (scala tympani or vestibuli) should be considered when using an ECAP-based electrode site-selection procedure to optimize CI performance.


Development of the Adjusted Wind Chill Equivalent Temperature (AWCET) for cold mortality assessment across a subtropical city: validation and comparison with a spatially-controlled time-stratified approach.
Global warming has reduced the adaptability of the people living in subtropical regions to cope up with cold stress due to lengthening of hot days and shortening of transition period from hot to cold weather. However, existing studies on measuring cold stress are based on biometeorological indices designed for temperate regions. This may overestimate the impact of wind chill on mortality risk in subtropical cities. This study developed an Adjusted Wind Chill Equivalent Temperature (AWCET) index. A spatially-controlled time-stratified approach was applied to evaluate the ability of AWCET for estimating cold mortality in subtropical cities, based on a mortality dataset (2008-2012) in Hong Kong. The use of AWCET could indicate increase in all-cause, cardiovascular, respiratory, and cancer-related mortality risk during the days with average temperature < = 1st [11.0 °C], <= 3rd [12.6 °C] and < = 5th [13.4 °C] percentiles. The results were stable and consistent based on both log-linear and curve-linear relationships between AWCET and mortality risk. AWCET was also compared with the New Wind Chill Equivalent Temperature (NWCET) designed for temperate regions, and has found that higher magnitude of mortality risk would be found when using AWCET for assessing all-cause and cause-specific mortality in Hong Kong, for days with average temperature < = 1st, <= 3rd and < = 5th percentiles. AWCET is validated to be effective to access cold mortality in the context of subtropical cities. The use of AWCET may enhance the cold weather warning system in subtropical cities, as a supplementary tool to help demonstrating small administrative-level perceived temperature with volunteered geographic information.


Theories that narrate the world: Ronald A. Fisher's mass selection and Sewall Wright's shifting balance.
Theories are composed of multiple interacting components. I argue that some theories have narratives as essential components, and that narratives function as integrative devices of the mathematical components of theories. Narratives represent complex processes unfolding in time as a sequence of stages, and hold the mathematical elements together as pieces in the investigation of a given process. I present two case studies from population genetics: R. A. Fisher's "mas selection" theory, and Sewall Wright's shifting balance theory. I apply my analysis to an early episode of the "R. A. Fisher - Sewall Wright controversy."


The correlation of serum long non-coding RNA ANRIL with risk factors, functional outcome, and prognosis in atrial fibrillation patients with ischemic stroke.
This study aimed to evaluate the predictive value of long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) for atrial fibrillation (AF) patients with ischemic stroke and investigate its correlation with risk factors, functional outcome, and prognosis. A total of 386 consecutive AF patients were recruited. AF patients were followed up for 24-48 months by outpatient follow-up, telephone follow-up, and medical record. The time of ischemic stroke in patients with AF was recorded, and follow-up was continued for 6 months. LncRNA ANRIL expression from serum was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Compared with the AF with ischemic stroke group (14.3 ± 2.3), patients in the AF without ischemic stroke group (11.9 ± 1.8) had significantly lower serum lncRNA ANRIL levels (P < .05). The sensitivity and specificity of lncRNA ANRIL for identifying AF with ischemic stroke were 76.6% and 81.4%, respectively. Spearman correlation analysis results shown that lncRNA ANRIL was significantly correlated with the NIHSS score (rSpearman = .490, P < .001) and the mRS score (rSpearman = .466, P < .001). Compared with the lncRNA ANRIL high-expression group, the recurrence-free survival (RFS) of the lncRNA ANRIL low-expression group was significantly higher (χ2 = 11.009, log-rank P < .001). Cox proportional regression model analysis indicated that the serum lncRNA ANRIL level (P = .004), NIHSS score (P = .001), infarct volume (P = .035), and smoking (P < .001) were the risk factors for AF with ischemic stroke. Serum lncRNA ANRIL exerts a good predictive value for AF with ischemic stroke, and its increased expression is correlated with worse RFS for patients.


Correlation between vitiligo antibodies and extent of depigmentation in vitiligo.
We correlated the level of vitiligo antibodies to the extent of depigmentation in thirty-two patients with vitiligo. Vitiligo antibodies were assayed by protein A-sepharose immunoprecipitation method. Antibodies were present in four of eight (50%) patients with minimal vitiligo (less than 2% body surface involved), in nine of ten (90%) patients with moderate vitiligo (2 to 5% surface involved), and in thirteen of fourteen (93%) patients with more extensive disease (greater than 5% surface involved). The level of vitiligo antibodies in the three groups expressed as a binding index was 2.9% +/- 2.03, 5.6% +/- 2.92, and 8.0% +/- 3.03 SD, respectively. These results suggest that there is a relation between the incidence and level of vitiligo antibodies and the extent of depigmentation in vitiligo.


Effect of glucose of growth hormone, prolactin and thyroid-stimulating hormone response to diazepam in normal subjects.
The effect of hyperglycemia on growth hormone, thyroid-stimulating hormone, and prolactin response to oral diazepam (10 mg) was assessed in 7 normal subjects. A peak growth hormone response of 13.5 +/- 0.3 ng/ml (mean +/- SEM) significantly above the base line (p less than 0.001) was achieved when diazepam was given alone. Hyperglycemia after glucose load abolished this response. There was no significant response of thyroid-stimulating hormone or prolactin after the administration of oral diazepam with and without glucose.


Sequence of mouse CDC47, a member of the minichromosome maintenance (Mcm) family involved in the DNA replication licensing system.
The cDNA encoding a mouse protein, mCDC47, belonging to the minichromosome maintenance (Mcm) family possibly involved in the DNA replication licensing system, was cloned and sequenced. Its deduced amino acid (aa) sequence contained a putative DNA-dependent ATPase motif commonly observed in the family, and a zinc-finger-like domain found in some members of the family.


Bicarbonate secretion in rabbit ileum: electrogenicity, ion dependence, and effects of cyclic nucleotides.
Ileal HCO3- secretion is not well understood. The aim of this study was to examine its Na+ and Cl- dependencies, electrogenicity, and responses to amiloride, 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonate (SITS), and cyclic nucleotides. The serosa to mucosa HCO3- flux (Jsm) across rabbit ileal mucosa mounted between HCO(3-)-free mucosal solution and HCO(3-)-containing serosal solutions was determined by titration. In SO4(2-)-containing Ringer's solution, Jsm varied with [Na+] in two phases, one with a high and one with a low affinity for Na+; amiloride inhibited the high- and SITS inhibited the low-affinity phase. Switching from SO4(2-)- to Cl(-)-containing Ringer's solution caused a SITS-inhibitable 42% increase in Jsm. Changes in Jsm were coupled 3:2 with changes in short-circuit current. Cyclic nucleotide effects on Jsm were as follows. In SO4(2-)-containing Ringer's solution at 141 (but not 80) mmol/L Na+, theophylline caused equal increases in Jsm and short-circuit current that equaled the combined effects of 8-Br-5'-cyclic guanosine monophosphate (cGMP) and 8-Br-5'-cyclic adenosine monophosphate (cAMP). Serosal SITS blocked these effects, but amiloride did not. In Cl(-)-containing Ringer's solution, theophylline and bumetanide together (but not separately) increased Jsm. (1) Basolateral HCO3- entry occurs via Na+/H exchange and a SITS-inhibitable process (Na(+)-HCO3- cotransport?). (2) Most HCO3- exit across the brush border occurs by a Cl(-)-independent process and some by Cl-/HCO3- exchange. (3) At low cellular [Cl-], HCO3- can be secreted via anion channels activated by cAMP and cGMP. (4) Ileal HCO3- secretion is electrogenic.


Laparoscopic appendicostomy for management of fecal incontinence.
Fecal incontinence from any cause is a socially unacceptable condition and a major detriment to educational and psychosocial development in young people with certain disabilities. Recently several procedures have been described that allow antegrade colonic enemas in the treatment of this problem. We report here an additional method of establishing this proximal colon access, namely laparoscopic appendicostomy. Although not applicable to all patients, this procedure has been successful in a select group with excellent results, and we recommend its consideration when open surgery is not otherwise required.


Toxicity, ultrastructural effects, and metabolic studies with 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane(o,p'-DDD) and its methyl analog in the guinea pig and rat.
Effects of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p'-DDD) (Lysodren; Mitotane) (I) and 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2, 2-dichloropropane (Mitometh) (II) were investigated. Ultrastructural and toxicity studies were conducted with male Hartley outbred guinea pigs given 300 mg/kg/day ip for 14 days. Profound mitochondrial damage in the guinea pig adrenal cortex, an index of Lysodren's action as a cancer chemotherapeutic, reversible necrosis of the zona fasciculata and zona reticularis with swelling, disrupted cristae, and organelles destroyed in the mitochondria from these areas. Yet guinea pigs given Mitometh tolerated the drug better than those given an equivalent amount of Lysodren. In general the animals treated with Mitometh showed less alopecia, diarrhea, and weakness. The only deaths recorded in our study were in the Lysodren group. In addition po administration of these two drugs to male Sprague-Dawley rats and male Hartley guinea pigs for 4 days allowed for a direct comparison of urinary metabolites. Metabolites were identified from urine extracts by computerized mass spectrometry interfaced with capillary gas chromatography. Both compounds were shown to undergo dehydrohalogenation and side-chain cleavage to a limited extent; however, only Lysodren afforded side-chain oxidation metabolites. In fact, the dominant metabolite from Lysodren biotransformation was the corresponding carboxylic acid o,p'-DDA (III). On the other hand, Mitometh resisted side-chain oxidative metabolism and was less toxic than Lysodren. Therefore, when given to guinea pigs and rats, Mitometh had Lysodren-like biologic activity, did not undergo rapid inactivation, and was less toxic than Lysodren. Mitometh represents a potential alternative to Lysodren which should be investigated further for its possible use in the treatment of adrenal cortical carcinoma and Cushing's syndrome.


A vaccine is still a long way off.
Trials are under way but we can't count on a vaccine to get us out of the crisis.


A Randomized Trial to Improve Adherence to Follow-up Eye Examinations Among People With Glaucoma.
Appointment nonadherence is common among people with glaucoma, making it difficult for eye care providers to monitor glaucoma progression. Our objective was to determine whether the use of patient navigators, in conjunction with social worker support, could increase adherence to recommended follow-up eye appointments. A randomized, controlled trial evaluated the effectiveness of an intervention that used patient navigators and social workers to improve patient adherence to follow-up eye care compared with usual care. Participants with glaucoma and other eye diseases (N = 344) were identified at primary care clinics in community settings through telemedicine screening of imaging and then randomized to enhanced intervention (EI) or usual care (UC). Data on participants' visits with local ophthalmologists were collected for up to 3 years from randomization. Groups were compared for timely attendance at the first visit with the local ophthalmologist and adherence to recommended follow-up visits. Timely attendance at the first visit was higher for EI than UC (74.4% vs 39.0%; average relative risk [aRR] = 1.85; 95% CI, 1.51-2.28; P < .001). Rates of adherence to recommended annual follow-up during year 1 were 18.6% in the EI group and 8.1% in the usual care group (aRR = 2.08; 95% CI, 1.14-3.76; P = .02). The aRR across years 2 and 3 was 3.92 (95% CI, 1.24-12.43; P = .02). An intervention using patient navigators and social workers doubled the rate of adherence to annual recommended follow-up eye care compared with usual care in community settings, and was effective at increasing connections with local ophthalmologists. Interventions to further improve long-term adherence are needed.


A conditional feedback loop regulates Ras activity through EphA2.
The EphA2 receptor tyrosine kinase is frequently overexpressed in many cancers, including 40% of breast cancers. Here, we show that EphA2 is a direct transcriptional target of the Ras-Raf-MAPK pathway and that ligand-stimulated EphA2 attenuates the growth factor-induced activation of Ras. Thus, a negative feedback loop is created that regulates Ras activity. Interestingly, the expression of EphA2 and ephrin-A1 is mutually exclusive in a panel of 28 breast cancer cell lines. We show that the MAPK pathway inhibits ephrin-A1 expression, and the ligand expression inhibits EphA2 levels contributing to the receptor-ligand reciprocal expression pattern in these cell lines. Our results suggest that an escape from the negative effects of this interaction may be important in the development of cancer.


Two β-glucuronosyltransferases involved in the biosynthesis of type II arabinogalactans function in mucilage polysaccharide matrix organization in Arabidopsis thaliana.
Arabinogalactan-proteins (AGPs) are heavily glycosylated with type II arabinogalactan (AG) polysaccharides attached to hydroxyproline residues in their protein backbone. Type II AGs are necessary for plant growth and critically important for the establishment of normal cellular functions. Despite the importance of type II AGs in plant development, our understanding of the underlying role of these glycans/sugar residues in mucilage formation and seed coat epidermal cell development is poorly understood and far from complete. One such sugar residue is the glucuronic acid residues of AGPs that are transferred onto AGP glycans by the action of β-glucuronosyltransferase genes/enzymes. Here, we have characterized two β-glucuronosyltransferase genes, GLCAT14A and GLCAT14C, that are involved in the transfer of β-glucuronic acid (GlcA) to type II AGs. Using a reverse genetics approach, we observed that glcat14a-1 mutants displayed subtle alterations in mucilage pectin homogalacturonan (HG) compared to wild type (WT), while glcat14a-1glcat14c-1 mutants displayed much more severe mucilage phenotypes, including loss of adherent mucilage and significant alterations in cellulose ray formation and seed coat morphology. Monosaccharide composition analysis showed significant alterations in the sugar amounts of glcat14a-1glcat14c-1 mutants relative to WT in the adherent and non-adherent seed mucilage. Also, a reduction in total mucilage content was observed in glcat14a-1glcat14c-1 mutants relative to WT. In addition, glcat14a-1glcat14c-1 mutants showed defects in pectin formation, calcium content and the degree of pectin methyl-esterification (DM) as well as reductions in crystalline cellulose content and seed size. These results raise important questions regarding cell wall polymer interactions and organization during mucilage formation. We propose that the enzymatic activities of GLCAT14A and GLCAT14C play partially redundant roles and are required for the organization of the mucilage matrix and seed size in Arabidopsis thaliana. This work brings us a step closer towards identifying potential gene targets for engineering plant cell walls for industrial applications.


Crystal structure of the carnitine transporter and insights into the antiport mechanism.
CaiT is a membrane antiporter that catalyzes the exchange of L-carnitine with gamma-butyrobetaine across the Escherichia coli membrane. To obtain structural insights into the antiport mechanism, we solved the crystal structure of CaiT at a resolution of 3.15 A. We crystallized CaiT as a homotrimer complex, in which each protomer contained 12 transmembrane helices and 4 l-carnitine molecules outlining the transport pathway across the membrane. Mutagenesis studies revealed a primary binding site at the center of the protein and a secondary substrate-binding site at the bottom of the intracellular vestibule. These results, together with the insights obtained from structural comparison with structurally homologous transporters, provide mechanistic insights into the association between substrate translocation and the conformational changes of CaiT.


Characterization of an Artificial Liver Support System-Related Vasovagal Reaction.
An artificial liver support system (ALSS) is an effective therapy for patients with severe liver injury. A vasovagal reaction (VVR) is a common complication in various treatment settings but has not been reported previously in ALSS. This study retrospectively evaluated patients who suffered an ALSS-related VRR between January 2018 and June 2019. We collected data from VVR episodes including onset time, duration, changes in heart rate (HR) and blood pressure (BP), and drug treatment. Among 637 patients who underwent ALSS treatment, 18 were included in the study. The incidence of VVR was approximately 2.82%. These patients were characterized by a rapid decrease in BP or HR with associated symptoms such as chest distress, nausea, and vomiting. The majority of patients (78%) suffered a VVR during their first ALSS treatment. Sixteen patients (89%) had associated symptoms after treatment began. Sixteen patients (89%) received human albumin or Ringer's solution. Atropine was used in 11 patients (61%). The symptoms were relieved within 20 min in 15 patients and over 20 min in 3 patients. A VVR is a rare complication in patients with severe liver injury undergoing ALSS treatment. Low BP and HR are the main characteristics of a VVR.


Vernal keratoconjunctivitis activity induces decrease of ocular surface CD14, TLR-4 and TLR-9 expression.
CD14 is involved in the modulation of immune reaction via toll-like receptors (TLR) and may influence the development of allergic diseases. The role of CD14 in vernal keratoconjunctivitis (VKC) has not yet been investigated. The aim of this study is to evaluate changes of tear soluble sCD14 and conjunctival CD14, TLR-4 and 9 expression in patients with VKC in the active and quiescent phases. Eighteen patients with VKC during active inflammation (group A, N = 9), in the quiescent phase (group Q, N = 5) and after recovery (group R, N = 4) and 10 healthy subjects were included. Expression of sCD14 in tears and of CD14, TLR-4, and TLR-9 by conjunctival epithelium were evaluated by Western Blot in all groups. Expression of tear sCD14 and of conjunctival CD14, TLR-4, and TLR-9 was significantly decreased in group A when compared with healthy subjects and with VKC group Q and R. Lower expression of sCD14, CD14, TLR-4, and TLR-9 were significantly correlated with the severity of papillary reaction, while the lower sCD14 was correlated with severity of conjunctival hyperemia. Tear sCD14, and conjunctival CD14, TLR4, and TLR-9 decreased during ocular surface inflammatory reaction in patients with VKC. CD14 and TLRs ocular surface evaluation may represent biomarkers of VKC activity and novel therapeutic target.


Photodynamic therapy of brain tumours.
Photodynamic therapy is a binary treatment combining the selective uptake of a photosensitizer into a tumour followed by irradiation of the tumour with light of the appropriate wavelength to cause activation of the sensitizer as selective tumour kill. Photodynamic therapy has been extensively investigated in laboratory studies in the treatment of cerebral tumours and has been utilised in clinical trials to treat a variety of tumours including cerebral glioma. The clinical trials have usually used PDT as an adjuvant therapy following tumour resection but studies are being undertaken to use the treatment in combination with stereotactic techniques. The photosensitizer haematoporphyrin derivative (HpD) has been shown to be selectively localised into all grades of glioma with a direct correlation between the grade of glioma and HpD level in the tumour. The levels were highest in the glioblastoma multiforme (mean uptake of 5.9 micrograms HpD/g tumour wet weight) and lower in the intermediate grade anaplastic astrocytoma (2.4 micrograms/g) and low grade astrocytoma (1.6 micrograms/g). Uptake into normal brain tissue taken from HpD sensitized patients was 0.2 microgram/g. HpD was also localised into the brain adjacent to the tumour region.