Identification of the soluble EphA7-interacting protein Nicalin as a regulator of EphA7 expression.
A soluble form of EphA7 (sEphA7) has been found to antagonize the role of full-length EphA7 (EphA7-FL) to stabilize the membrane level of the tight junction protein Claudin6 (CLDN6) during Xenopus pronephros development. However, the mechanism underlying this antagonistic effect remains unclear. In this study, we identified Nicalin, a Nicastrin-like protein, as a novel sEphA7-interacting protein using immunoprecipitation (IP)/mass spectrometry (MS). In HEK293 cells, Nicalin interacted with sEphA7 and they predominantly co-localized in the endoplasmic reticulum (ER). Interestingly, Nicalin diminished the protein level of sEphA7 in the membranous fraction but increased that in the insoluble cytoplasmic fraction with a reduced molecular weight, suggesting that Nicalin restricts the entry of sEphA7 into the ER for further modification. sEphA7 probably acted as a chaperone and enhanced the membrane level of EphA7-FL and the formation of EphA7 complex, however, this effect was reversed by Nicalin. Our work suggested that Nicalin limits sEphA7 secretion, thereby preventing the formation of EphA7 complex. These results demonstrated the potential role of Nicalin in regulating EphA7 expression and revealed a potential mechanism underlying the antagonistic effect between sEphA7 and EphA7-FL.


Long-term effects of submandibular gland excision on drooling in children with neurodevelopmental disorders: A cross-sectional study.
Submandibular gland excision (SMGE) is suitable for the management of drooling in patients with non-progressive neurodisabilities. We aimed to investigate the long-term effects of SMGE. Patients who had SMGE between 2007 and 2018 were included. Main outcomes were a Visual Analogue Scale (VAS), Drooling Severity (DS), and Drooling Frequency (DF) collected at baseline, 8 weeks, 32 weeks and with a median of 313 weeks after SMGE (long-term). Secondary outcomes were satisfaction with the procedure, Drooling Quotient (DQ) and adverse events (AEs). We included thirty-five patients in the long-term analysis with a mean age of 14.5 years. A baseline VAS score of 80.4 was found, which improved on the long-term (mean difference -21.8, t(26) = 4.636, p < 0.0005)). DS and DF decreased significantly at the long-term compared to baseline (Z = -4.361, p < 0.0001 for DS, Z = -3.065, p = 0.002 for DF). Twenty-three out of 35 (66%) patients would recommend the procedure to peers. This study indicates a long-term stable effect on drooling after SMGE in patients with anterior drooling. Recurrence of drooling occurs due to unknown reasons, nevertheless most caregivers and/or patients are still satisfied and would recommend the procedure to others.


The effect of coagulation protection with combination of epsilon aminocaproic acid and plasma saver in open-heart surgery.
Bleeding remains a major complication and a major determinant in the prognosis of open-heart surgery. Coagulopathy related to cardiopulmonary bypass (CPB) seems to be the culprit. Since homologous blood transfusion in many occasions is not only responsible for mobidity and mortality but also increases medical costs. Therefore, the application of autologous blood transfusion including components such as PRBC, FFP and platelets concentrate is inevitable and comes in its stead. To reduce the use of homologous plasma and platelets transfusion in open-heart surgery, we designed a study to utilize the combination of autologous platelet rich plasma (PRP) and epsilon aminocaproic acid (EACA) to evaluate its effects on blood loss and blood component transfusion in open-heart patients. Sixty patients who received elective cardiac surgery were randomly divided into 3 groups: 1. Control group; 2. EACA group (150 mg/kg, i.v. before CPB); 3. PRP-EACA group (PRP 10 ml/kg harvested with a plasma saver followed by i.v. EACA 150 mg/kg). Anesthesia was uniform in all patients. Coagulation profile was evaluated by thromboelastography (TEG) during the operation. Blood loss during operation and the amount of drainage from the chest tubes in the postoperative period were recorded and compared between groups. Patients who were given EACA injection before CPB saw less blood loss perioperatively and received less transfusion of blood components. TEG analysis showed that patients who received EACA injection had a better coagulation profile and the platelet function was also better after CPB. However, no additive effect can be attained from combination of autologous PRP transfusion and EACA injection. With Pre-CPB EACA as protection, reduction of both blood loss and blood transfusion could be realized in open-heart surgery.


An evaluation of the impact of advanced nurse practitioner triage and clinical intervention for medically expected patients referred to an acute National Health Service hospital.
To evaluate the impact of advanced nurse practitioner triage on the management of medically expected patients referred to an acute National Health Service hospital. The objectives of the study were to determine whether advanced nurse practitioner triage reduced waiting times and hospital admissions and expedited essential investigations and treatments. The effectiveness of employing advanced nurse practitioners to meet service demands has been widely studied in emergency departments and critical care units. However, no studies have evaluated the impact advanced nurse practitioners can have on the management of medically expected patients, who have been referred to hospital because they are acutely unwell and require immediate medical intervention. A pre- and postimplementation evaluation. The Revised Standards for Quality Improvement Reporting Excellence guidelines were used as a framework to guide the triaging role of advanced nurse practitioners. The charts of patients attending before and after the implementation of the advanced nurse practitioner triage role were retrospectively analysed. The implementation of advanced nurse practitioner triage for medically expected patients saw a statistically significant reduction in the length of time patients have to wait to be seen. There were also significant improvements in timings to diagnosis and treatment of patients presenting with conditions such as sepsis or community-acquired pneumonia. Additionally, patient admissions to hospital were reduced, as advanced nurse practitioners instead streamed a number of patients to ambulatory care for same day treatment and/or medical follow-up. Advanced nurse practitioner triage has made significant improvements to the efficiency and effectiveness of care and management of medically expected patients who were referred to acute hospital settings. Utilisation of advanced nurse practitioner triage in the ambulatory care setting is an effective method by which to streamline and improve the management of medically expected patients.


Changes in students' sociopolitical attitudes during medical school: socialization or maturation effect?
This study examined medical students' attitudes toward the issue of universal access to medical care in order to determine whether students become more conservative with increased training and, if this is the case, whether changes in students' sociopolitical attitudes can be mostly attributed to the influence of professional education (socialization effect) or to the fact that students change their way of thinking as a result of getting older (maturation effect). Data were obtained from a survey of 586 freshmen, juniors and recent graduates trained in three differently-oriented schools, one being more socially-oriented in its approach to medical education than the other two. The findings documented a conservative trend in more advanced students, not only in the two traditional schools but in the socially-oriented school as well. However, based on the authors' conceptual model, this conservative trend could not be attributed to a pure socialization effect nor to a pure maturation effect. Rather, both types of effect seemed simultaneously at play. In general, students' sociopolitical attitudes were more related to their personal background characteristics than to the characteristics of their professional medical training. These results suggest that selection more than medical training per se is the crucial determinant in influencing medical graduates' sociopolitical outlook.


Risk factors associated with drug resistant focal epilepsy in adults: A case control study.
Using an adult cohort of patients with focal epilepsy, we aimed to identify risk factors for development of drug-resistant epilepsy, which if identifiable would allow patients to receive appropriate counsel and earlier surgical treatment. This is a case-control study nested within a cohort, 146 adult patients with focal epilepsy were included. Definitions were used in accordance with ILAE criteria. The odds ratio and its confidence interval were calculated. We performed a logistic regression analysis. Seventy-one [48.6%] patients met the criteria for drug-resistant epilepsy [cases] and 75 [51.4%] patients were controls. The mean age of patients was 44.5 ± 16.4 years. The most significant variables associated with developing drug-resistant epilepsy include younger age at diagnosis [18.75 vs. 32.2, p < 0.001], years of evolution of epilepsy [22.54 vs. 16.05, p < 0.001], number of AED [4.8 vs. 2.87, p < 0.001], complex partial seizures [51 vs. 35 OR 2.9, p = 0.002], having more than one seizure per month [51 vs. 38, p = 0.009], bi-temporal focus [14 vs. 4 p = 0.008] and mesial temporal sclerosis [23 vs. 11 p = 0.01]. Good response to first AED [7 vs. 29 OR 0.2, p = 0.001] and epilepsy secondary to encephalomalacia [8 vs. 20 OR 0.35, p = 0.018] might be protective factors against drug resistant epilepsy. Longer time of epilepsy evolution, high frequency of seizures, complex partial seizure presentation, higher number of antiepileptic drugs, mesial temporal sclerosis and bitemporal epilepsy are predictive factors of subsequent pharmacoresistance.


Correction to: Evaluation of Generic Methods to Predict Human Pharmacokinetics Using Physiologically Based Pharmacokinetic Model for Early Drug Discovery of Tyrosine Kinase Inhibitors.
The original version of this article unfortunately contained a mistake. Conflict of interest statement was incorrect. The corrected COI statement is given below.


Factors influencing uptake and retention of amino-containing drugs in large unilamellar vesicles exhibiting transmembrane pH gradients.
The level of uptake and retention of amino-containing drugs in large unilamellar vesicles (LUVs) following uptake in response to a transmembrane pH gradient (DeltapH) can vary dramatically depending on the drug. For example, the anticancer drugs doxorubicin and epirubicin can be readily retained, whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly. In this investigation, we examine the influence of the hydrophobicity of the entrapped amines (that induce the DeltapH) and the anionic lipid content of the LUV on drug retention. It is shown that entrapment of increasingly hydrophobic monoamines (methylamine to amylamine) all lead to an induced DeltapH of 3 units and essentially complete drug uptake under the conditions employed, but do not lead to improved retention of vincristine and ciprofloxacin. However, significantly improved retention could be achieved by substitution of the anionic lipid distearoylphosphatidylglycerol (DSPG) for distearoylphosphatidylcholine (DSPC) in the LUV bilayer. Further, it is shown that if the induced DeltapH is reduced to 1.4 units (driven by entrapped diamine) nearly 100% accumulation of doxorubicin and epirubicin could be achieved, whereas only 25% loading for vincristine and ciprofloxacin was observed. Taken together these results provide methodology for improving (weak base) drug retention in liposomes and indicate that drugs that can partition into the lipid bilayer exhibit improved uptake and retention characteristics.


Buschke-Löwenstein tumor in childhood: a case report.
Buschke-Löwenstein tumor or giant condyloma is a warty verrucous lesion, characterized by slow growth, locally infiltrating and disfiguring lesions. Despite its benign histological appearance and low risk of metastasis, Buschke-Löwenstein tumor is an intermediate lesion between condyloma acuminatum and verrucous carcinoma. It has been linked to human papilloma virus, mainly subtypes 6 and 11. Other factors implicated in this disease include poor hygiene, chronic irritation, promiscuity, and cellular immunocompromised states. It rarely occurs in children. The first line of treatment is radical surgical excision with or without adjuvant chemotherapy. We report the case of a 12-year-old girl with a giant perianal condyloma that was treated with surgical excision and a 6-week course of 5-fluorouracil beginning 6 weeks after surgery, with excellent functional and cosmetic results.


"Tardus and parvus" phenomenon in upper limb arteries for identifying subclavian arterial stenosis.
The detection of subclavian artery (SCA) stenosis or occlusion is important, and an easy and accurate noninvasive screening method is needed. Pulsed Doppler spectra of bilateral SCA, vertebral arteries, axillary arteries, and brachial arteries were recorded and analyzed both in patients with SCA stenosis and healthy subjects. Thirty-five patients showed SCA stenosis less than 80% (mean: 72 +/- 14%; Vmax: 450.1 +/- 101.5 cm/sec) and seven patients demonstrated one-side SCA occlusion. The Vmax, systolic acceleration (SA) and resistance index (RI) were much lower (parvus) while the acceleration time (AT) was much longer (tardus) in axillary and brachial arteries on the ipsilateral than those both on the contralateral and the control group (Axillary artery: Vmax: 31.3 +/- 11.8 vs. 62.0 +/- 24.1 and 85.8 +/- 14.3 cm/sec, P < 0.01; SA: 2.0 +/- 1.0 vs. 6.8 +/- 4.9 and 9.6 +/- 2.0 m/sec(2), P < 0.05; RI: 0.8 +/- 0.1 vs. 1.1 +/- 0.4 and 1.1 +/- 0.3, P < 0.01; AT: 141 +/- 34 vs. 86 +/- 26 and 76 +/- 9 ms, P < 0.01. Brachial artery: Vmax: 47.5 +/- 25.2 vs. 76.7 +/- 37.6 and 84.6 +/- 14.2 cm/sec, P < 0.05; SA: 3.1 +/- 2.1 vs. 9.1 +/- 5.2 and 10.1 +/- 3.5 m/sec(2), P < 0.01; RI: 1.0 +/- 0.1 vs. 1.2 +/- 0.1 and 1.2 +/- 0.1, P < 0.01; AT: 155 +/- 31 vs. 86 +/- 19 and 78 +/- 12ms, P < 0.01). The "tardus and parvus" phenomenon in ipsilateral axillary and brachial arteries could be employed as an alternative method and a shortcut for detection of the SCA stenosis or occlusion.


[Ataxic hemiparesis caused by a thalamic lacuna].
A 64 year old man was admitted for an ataxic hemiparesis. Magnetic resonance imaging (MRI) suggested a lacunar infarct. The lesion was located in the postero-lateral part of the contralateral thalamus, sparing the internal capsule.


Simulation of sensory neuronal discharge characteristics: the effects of multiple receptor sites and sources of variability.
There is conflict in the literature concerning the effect of multiple receptive endings on sensory afferent discharge. We simulated the discharge of intrapulmonary chemoreceptors of ducks and studied the effect of numbers of receptive endings, membrane 'noise' and changes in receptor threshold and gain. We found increasing membrane noise could not account for variability in spontaneously discharging intrapulmonary chemoreceptors and that, over a wide range of amplitude of various sources of noise, increasing the number of receptive endings increased discharge frequency and precision of transduction of the stimulus by reducing variability.


Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data From Malaria Volunteer Infection Studies.
Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines. We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hours (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n = 66), sporozoites via mosquito bite (n = 336), or injection (n = 51). The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% confidence interval [CI], .73-.77/day), PMR48 was 31.9 (95% CI, 28.7-35.4), PMRLC was 16.4 (95% CI, 15.1-17.8), and parasite life-cycle was 38.8 hours (95% CI, 38.3-39.2 hours). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI, .67-.75/day; PMR48 26.6, 95% CI, 22.2-31.8) but significantly higher (P < .001) than in sporozoite studies (0.47/day, 95% CI, .43-.50/day; PMR48 8.6, 95% CI, 7.3-10.1). Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.


Testosterone causes pleiotropic effects on cleanerfish behaviour.
Mathematical modelling regarding evolutionary theory typically assumes that optimal strategies are not constrained through mechanistic processes. In contrast, recent studies on brain anatomy and neurobiology suggest that flexibility in social behaviour is rather constrained by the physiological state of the social decision-making network. Changing its state may yield selective advantages in some social contexts but neutral or even detrimental effects in others. Here we provide field evidence for such physiological trade-offs. We subjected wild female cleaner wrasse to injections of testosterone or of saline solution (control) and then observed both intraspecific interactions and interspecific cleaning behaviour with other reef fish, referred to as clients. Testosterone-treated females intensified intraspecific social interactions, showing more aggression towards smaller females and tendencies of increased aggressive and affiliative contacts with dominant males. Such testosterone-mediated changes fit the hypothesis that an increase in testosterone mediates female's focus on status in this protogynous hermaphrodite species, where females eventually change sex to become males. Moreover, we also identified other effects on interspecific social interactions: testosterone-treated females interacted less with client reef fishes and hence obtained less food. Most importantly, they selectively reduced service quality for species that were less likely to punish after being cheated. Overall, our findings suggest that testosterone causes pleiotropic effects on intra and interspecific social behaviour by broadly influencing female cleaners' decision-making.


Social cognitive factors associated with physical activity in elementary school girls.
To examine social cognitive factors associated with physical activity (PA) among preadolescent girls. Social cognitive theory was used to examine PA in girls (N=90; 71% African American) participating in Girls on the Run. Multiple regressions explored factors associated with PA at posttesting and 3-month follow-up. Significant increases in PA, social influences, and self-efficacy were found, which were sustained at 3-month follow-up. Self-efficacy and social influences had the strongest relations to PA at posttest; self-efficacy remained the strongest predictor of PA at 3-month follow-up. Social support and self-efficacy are important targets of PA interventions in preadolescent girls.


[Vascular endothelial growth factor--fundamental research and experimental study in plastic surgery].
To review the fundamental research and the experimental study of vascular endothelial growth factor (VEGF). The laboratory information and experimental study of VEGF were extensively reviewed. VEGF, as a mitogen specifically for endothelial cells, could strongly stimulate angiogenesis as well as vascular permeability, especially in hypoxia state. Experimentally, survival area and viability of flaps could be increased significantly when exogenous VEGF was applied in the form of protein or cDNA. VEGF provides a new way for therapeutic angiogenesis in reparative and reconstructive surgery.


Fc-specific and covalent conjugation of a fluorescent protein to a native antibody through a photoconjugation strategy for fabrication of a novel photostable fluorescent antibody.
Fluorophore-antibody conjugates with high photobleaching resistance, high chemical stability, and Fc-specific attachment is a great advantage for immunofluorescence imaging. Here, an Fc-binding protein (Z-domain) carrying a photo-cross-linker (p-benzoylphenylalanine, Bpa) fused with enhanced green fluorescent protein (EGFP), namely photoactivatable ZBpa-EGFP recombinant, was directly generated using the aminoacyl-tRNA synthetase/suppressor tRNA technique without any further modification. By employing the photoactivatable ZBpa-EGFP, an optimal approach was successfully developed which enabled EGFP to site-selectively and covalently attach to native antibody (IgG) with approximately 90% conjugation efficiency. After characterizing the Fc-specific and covalent manner of the EGFP-photoconjugated antibody, its excellent photobleaching resistance for immunofluorescence imaging was demonstrated in a model study by monitoring the toll-like receptor 4 (TLR4) expression in HepG2 cells. The proposed approach here for the preparation of a novel fluorescent antibody is available and reliable, which would play an important role in fluorescence immunoassay, and is expected to be extended to the generation of other biomolecule-photoconjugated antibodies, such as other fluorescent proteins for multiplex immunofluorescence imaging or reporter enzymes for highly sensitive enzyme immunoassays.Graphical abstract.


De-coupled phytoplankton growth and microzooplankton grazing in a simulated oil spill event in mesocosms.
Microzooplankton (<200 μm) are essential intermediates between primary production and organisms at the higher trophic levels. Their ecological functions could be substantially affected by crude oil pollution. A natural plankton community was exposed to 10 μL L-1 of chemically dispersed crude oil (DOil) in outdoor mesocosms for 7 days, with control (Ctrl) mesocosms set up for comparison. Dilution experiments were conducted to estimate the grazing rates of microzooplankton on the 2nd and 6th days of the pollutants exposure. Results showed 0.36-2.28 d-1 microzooplankton grazing rates in the Ctrl mesocosms on both days but negative rates in the DOil mesocosms. A significant linear relationship between in situ phytoplankton growth and microzooplankton grazing rates was found in the Ctrl treatment but not in the DOil treatment. This suggests a de-coupling between phytoplankton growth and microzooplankton and the potential for the formation of phytoplankton blooms in seawater after an oil spill event.


Association between the interleukin (IL)-17A rs2275913 polymorphism and rheumatoid arthritis susceptibility: a meta-analysis and trial sequential analysis.
This meta-analysis was conducted to investigate the relationship between the interleukin (IL)-17A rs2275913 polymorphism and rheumatoid arthritis (RA) susceptibility. Eligible studies were retrieved from PubMed, Embase, and Web of Science. The fixed- or random-effects model was used to calculate the pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) on the basis of heterogeneity. Overall, 11 studies containing 4019 RA patients and 4137 controls were included in this meta-analysis. The results suggested a significant association between the IL-17A rs2275913 polymorphism and RA susceptibility in the overall population (allelic model A vs. G: OR = 0.89, 95%CI: 0.83-0.95; heterozygote model GA vs. GG: OR = 0.87, 95%CI: 0.78-0.96; homozygote model AA vs. GG: OR = 0.82, 95%CI: 0.71-0.96; dominant model GA + AA vs. GG: OR = 0.86, 95%CI: 0.78-0.94). In the subgroup analyses, the IL-17A rs2275913 polymorphism was significantly associated with RA risk in Europeans (allelic model A vs. G: OR = 0.87, 95%CI: 0.78-0.97; heterozygote model GA vs. GG: OR = 0.79, 95%CI: 0.68-0.93; dominant model GA + AA vs. GG: OR = 0.79, 95%CI: 0.68-0.92), but not in Africans or Americans. This study suggests that the IL-17A rs2275913 polymorphism is significantly associated with RA susceptibility in Europeans.INPLASY registration number: INPLASY202170056.


Surgical repair and reconstruction of aortic arch in debakey type I aortic dissection: recent advances and single-center experience in the application of branched stent graft.
Aortic dissection (AD) represents a clinically uncommon aortic pathology which predicts a dismal prognosis if not promptly treated. In acute Debakey type I AD (ADIAD), aortic lesion extends from aortic root to even distal abdominal aorta among which aortic arch and its three main branches still remain a great surgical challenge for repair and reconstruction. Several decades have witnessed the painstaking efforts of cardiovascular surgeons across the globe for optimizing the surgical procedures, from total or hemi-arch replacement, "elephant trunk" technique to branched stent graft. However, operative mortality and morbidity still remain to be reduced and surgical strategy is to be advanced and simplified, particularly the repair and reconstruction of aortic arch and supra-aortic vessels. In this paper, we reviewed the relevant literature concerning recent advances in surgical intervention of aortic arch and summarized our opinions in the application of branched stent graft in ADIAD. The operative strategy for acute Debakey type I aortic dissection still remain to be advanced and simplified, especially the repair and reconstruction of aortic arch and supra-aortic vessels. For selection of branched stent grafts, the anatomic features and pathological changes of diseased arch are the crucial factors for clinical decision making. Branched stent graft is potentially an effective alternative for the treatment of type I AD with diseased aortic arch and supra-aortic vessels. The selection of branched stent grafts still remains to be further discussed in large-scale studies in the future.


A novel molecular index for secondary oil migration distance.
Determining oil migration distances from source rocks to reservoirs can greatly help in the search for new petroleum accumulations. Concentrations and ratios of polar organic compounds are known to change due to preferential sorption of these compounds in migrating oils onto immobile mineral surfaces. However, these compounds cannot be directly used as proxies for oil migration distances because of the influence of source variability. Here we show that for each source facies, the ratio of the concentration of a select polar organic compound to its initial concentration at a reference point is independent of source variability and correlates solely with migration distance from source rock to reservoir. Case studies serve to demonstrate that this new index provides a valid solution for determining source-reservoir distance and could lead to many applications in fundamental and applied petroleum geoscience studies.


Electronically Mismatched Cycloaddition Reactions via First-Row Transition Metal, Iron(III)-Polypyridyl Complex.
The iron(III)-polypyridyl complex and its derivatives showed sufficient oxidizing potential to act as a one-electron oxidant, producing radical cations from olefins and promoting the efficient radical cation [2 + 2] and [2 + 4] cycloaddition reactions. Subsequent chain propagation afforded trisubstituted cyclobutane or cyclohexene derivatives, and this facile route enables the replacement of rare metals with sustainable, green, and inexpensive iron in radical cation cycloadditions.


Lipid segregation and IgE receptor signaling: a decade of progress.
Recent work to characterize the roles of lipid segregation in IgE receptor signaling has revealed a mechanism by which segregation of liquid ordered regions from disordered regions of the plasma membrane results in protection of the Src family kinase Lyn from inactivating dephosphorylation by a transmembrane tyrosine phosphatase. Antigen-mediated crosslinking of IgE receptors drives their association with the liquid ordered regions, commonly called lipid rafts, and this facilitates receptor phosphorylation by active Lyn in the raft environment. Previous work showed that the membrane skeleton coupled to F-actin regulates stimulated receptor phosphorylation and downstream signaling processes, and more recent work implicates cytoskeletal interactions with ordered lipid rafts in this regulation. These and other results provide an emerging view of the complex role of membrane structure in orchestrating signal transduction mediated by immune and other cell surface receptors.


Effect of Bifidobacterium animalis subsp. lactis SF on enhancing the tumor suppression of irinotecan by regulating the intestinal flora.
The gut microbiota plays a role in tumor therapy by participating in immune regulation. Here, we demonstrated through 8-day probiotic supplementation experiments and fecal microbiota transplantation experiments that Bifidobacterium animalis subsp. lactis SF enhanced the antitumor effect of irinotecan and prevented the occurrence of intestinal damage by modulating the gut microbiota and reducing the relative abundance of pro-inflammatory microbiota. Therefore, the intestinal inflammation was inhibited, the TGF-β leakage was reduced, and the PI3K/AKT pathway activation was inhibited. Thus, the tumor apoptotic autophagy was finally promoted. Simultaneously, the reduction of TGF-β relieved the immunosuppression caused by CPT-11, promoted the differentiation of CD4+ and CD8+ T cells in tumor tissue, and consequently inhibited tumor growth and invasion. This study disclosed the mechanism of B. lactis SF assisting CPT-11 in antitumor activity and suggested that B. lactis SF plays a new role in anticancer effects as a nutritional intervention.


The effect of gamma-interferon on HLA class II antigen expression on isolated human nasal chondrocytes.
HLA class II antigens play an important role in the immunological response. In this study, we report on HLA class II antigen expression in vitro by human nasal cartilage cells as detected with an immunoperoxidase staining and immunofluorescence flow cytometric analysis using monoclonal antibodies. Their expression was induced during a 7-day incubation period with gamma-interferon. These findings suggest that a possible mode of action of the preservation methods of cartilage allografts for inducing a prolonged acceptance time is based on the prevention of HLA class II antigen expression by the cartilage cells.


Model-P: a basecalling method for resequencing microarrays of diploid samples.
Basecalling is a critical step of the analysis of DNA resequencing microarray data for single nucleotide polymorphism discovery and genotyping. For microarrays hybridized with DNA derived from diploid organisms, basecalling with high accuracy at high call rates is a challenging task. Current methods sometimes do not produce satisfactory results. We explored using physical models based on the sequences of the probe and the target to predict feature intensities in resequencing microarrays. Based on these intensity-predicting models, a new basecalling method (Model-P), which takes into consideration the expected feature intensities for different potential genotypes, was developed. Model-P is shown to have better performance at high call rates compared with ABACUS, the current state-of-the-art method, on a test dataset and on relatively AT-rich regions. Model-P is available upon request.


Effects of agomelatine on electrocorticogram activity on penicillin-induced seizure model of rats.
Agomelatine is a new antidepressant drug acting as an antagonist of 5-hydroxytryptamine receptor 2C (5-HTR2C) and agonist of melatonergic receptors 1 and 2 (MT1 and MT2). Because of this dual action, it is an atypical antidepressant. The aim of this study was to investigate chronic anticonvulsant effects of agomelatine on penicillin-induced epilepsy model. Adult male Sprague-Dawley rats divided into four groups and were administered with tap water (vehicle), and agomelatine doses of 10 mg/kg, 50 mg/kg and 100 mg/kg for 14 days via oral gavage. After the last doses were given, epileptic seizures were induced by intracortical penicillin (500 IU/2.5 μl) application in rats under urethane (1.25 g/kg intraperitoneal) anesthesia. Electrocorticogram (ECoG) recordings were obtained from the somatomotor cortex through 90 min, and spike frequencies and amplitudes were analyzed. The spike frequency analyses revealed that only 50 mg/kg agomelatine administration decreased the spike frequencies of hypersynchronous discharge of neurons caused by penicillin (p < 0.05). No significant differences in amplitudes between experimental groups were observed. In addition, mRNA expressions of vesicular glutamate transporter 1 (VGLUT1) and vesicular gamma-aminobutyric acid transporter (VGAT) in response to the agomelatine active dose, 50 mg/kg, showed no significant effect of agomelatine on the mRNA expression. Our results indicate that chronic treatment with agomelatine may have potential anticonvulsant effects. Agomelatine may be a promising drug for epilepsy patients having depression due to its antiepileptic and antidepressant effects.


Temporal trends of multiple sclerosis disease activity: Electronic health records indicators.
Long-term data on multiple sclerosis (MS) inflammatory disease activity are limited. We examined electronic health records (EHR) indicators of disease activity in people with MS. We analyzed prospectively collected research registry data and linked EHR data in a clinic-based cohort from 2000 to 2016. We used the trend of the yearly incident relapse rate from the registry data as benchmark. We then calculated the temporal trends of potentially relevant EHR measures, including mean count of the MS diagnostic code, mentions of MS-related concepts, MS-related health utilizations and selected prescriptions. 1,555 MS patients had both registry and EHR data. Between 2000 and 2016, the registry data showed a declining trend in the yearly incident relapse rate, parallel to an increasing trend of DMT usage. Among the EHR measures, covariate-adjusted frequency of diagnostic code of MS, procedure codes of MS-related imaging studies and emergency room visits, and electronic prescription for steroids declined over time, mirroring the temporal trend of the benchmark yearly incident relapse rate. This study highlights EHR indicators of MS relapse that could enable large-scale examination of long-term disease activities or inform individual patient monitoring in clinical settings where EHR data are available.


Postoperative Intratumoral or Peritumoral Hematomas After Vestibular Schwannoma Resection.
Surgical removal of a vestibular schwannoma is a complex and challenging procedure, which may be complicated by development of postoperative hematomas, particularly after incomplete resection of the tumor. To investigate the occurrence of postoperative intra- or peritumoral hematomas after surgery for a vestibular schwannoma. This retrospective study evaluated 49 patients (age range 17-78 years) with a vestibular schwannoma, who were treated surgically via the lateral suboccipital approach between 2011 and 2016. The tumors ranged in size from 0 mm (in a case of an intracanalicular lesion) to 56 mm. In 30 cases (61%), total or near-total resection was accomplished, and in 19 cases (39%), subtotal or partial resection was done. On the basis of their bleeding tendency during tumor removal, the patients were divided into a "less-bleeding" (38 cases; 78%) and a "more-bleeding" (11 cases; 22%) subgroups. A maximal vestibular schwannoma diameter >30 mm, patient age >60 years, and more bleeding during tumor removal were significantly associated with incomplete (subtotal or partial) resection. In six cases (12%), serial computed tomography after surgery demonstrated a postoperative hematoma, which was caused by insufficient irrigation of the surgical field (in two cases) or resulted from peritumoral hemorrhage (in two cases), intratumoral hemorrhage (in one case), or both intra- and peritumoral hemorrhage (in one case). The latter patient required urgent reoperation. In all cases, postoperative hematomas occurred after incomplete (subtotal or partial) resection of a vestibular schwannoma, and their development was significantly associated with more bleeding during tumor removal. For avoidance of postoperative hematomas, careful hemostasis is required after completion of vestibular schwannoma removal, especially in cases with incomplete resection and an excessive bleeding tendency of the tumor tissue.


Familial hypercholesterolemia.
Abnormalities in the lipid profile though uncommon in pediatric practice pose an increased risk for developing heart disease. Studies suggest that adult cardiovascular disease has its roots in children and young adults. A significant correlation between atherosclerotic changes in children and young adults and total and LDL cholesterol levels also exists. The association is particularly true for Familial Hypercholesterolemia. We report a young boy aged 14 years who presented with all the features of Familial Hypercholesterolemia.


Characterization and clinical relevance of ALDHbright populations in prostate cancer.
High aldehyde dehydrogenase (ALDH) has been suggested to selectively mark cells with high tumorigenic potential in established prostate cancer cell lines. However, the existence of cells with high ALDH activity (ALDH(bright)) in primary prostate cancer specimens has not been shown so far. We investigated the presence, phenotype, and clinical significance of ALDH(bright) populations in clinical prostate cancer specimens. We used ALDEFLUOR technology and fluorescence-activated cell-sorting (FACS) staining to identify and characterize ALDH(bright) populations in cells freshly isolated from clinical prostate cancer specimens. Expression of genes encoding ALDH-specific isoforms was evaluated by quantitative real-time PCR in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer tissues. ALDH1A1-specific expression and prognostic significance were assessed by staining two tissue microarrays that included more than 500 samples of BPH, prostatic intraepithelial neoplasia (PIN), and multistage prostate cancer. ALDH(bright) cells were detectable in freshly excised prostate cancer specimens (n = 39) and were mainly included within the EpCAM((+)) and Trop2((+)) cell populations. Although several ALDH isoforms were expressed to high extents in prostate cancer, only ALDH1A1 gene expression significantly correlated with ALDH activity (P < 0.01) and was increased in cancers with high Gleason scores (P = 0.03). Most importantly, ALDH1A1 protein was expressed significantly more frequently and at higher levels in advanced-stage than in low-stage prostate cancer and BPH. Notably, ALDH1A1 positivity was associated with poor survival (P = 0.02) in hormone-naïve patients. Our data indicate that ALDH contributes to the identification of subsets of prostate cancer cells of potentially high clinical relevance.


Genome-wide analyses of Glutathione S-transferase gene family and expression profiling under deltamethrin exposure in non-biting midge Propsilocerus akamusi.
Glutathione S-transferases (GSTs) are major enzymes in detoxification phase II, and have been functioned in resistance to various insecticides or oxidative stress. Herein, we selected the non-biting midge, Propsilocerus akamusi, widespread in Asian aquatic ecosystems, to uncover the gene location, structure, and phylogenetics relationship of GSTs at genome scale first time. Thirty-three cytosolic and four microsomal GST genes were identified and located on the four chromosomes. The cytosolic GSTs involved in the eight subclasses and five GST genes were unclassified. The expansion of GST genes in P. akamusi experienced duplication events on the delta, theta, xi, iota, and unclassified subclasses. The RNA-Seq analyses and RT-qPCR validation showed that the expression of PaGSTt2 gene is significantly elevated, with deltamethrin concentration increasing. The tertiary structure of PaGSTt2 enzyme was reconstructed, which was different from the other theta gene in the active site. In addition, the GST genes of six chironomids were first described based on the assembled genomes to explore the difference of those in the adaptation to kinds of environments. The GST frame for P. akmusi and its expression profiles provide valuable resources to understand their role in insecticide resistance of this species, as well as those of other biting midges.


Identifying identity and attributing value to attributes: reconsidering mechanisms of preference decisions.
Although the orbitofrontal cortex (OFC) robustly encodes value during preference decisions, it also encodes multiple non-value features of choice options. The role of this information, and its relationship to the options' overall value remain open questions. In this opinion, we attempt to disentangle oft-studied categories of option information - identity and attributes - in the context of both classic theories of economic choice and contradicting evidence of choice biases in multi-attribute decisions. In doing so, we aim to set forth considerations for understanding the wide variety of decision-relevant information encoded by the OFC during preference decisions.


Received anti-VEGF therapy in a patient with CRAO sparing the CLRA with subretinal fluid: A case report.
Central retinal artery occlusion (CRAO) sparing the cilioretinal artery (CLRA) with severe subretinal fluid and non-characteristic cherry-red spot is uncommon. In the present case, the patient received an intravitreal injection of anti- vascular endothelial growth factor, which is very rare. A 59-year-old man underwent vitrectomy of the left eye for diabetic retinopathy and vitreous hemorrhage. Six months after the operation, the patient presented with sudden painless visual-acuity decline in his left eye and was diagnosed with CRAO; his best corrected visual acuity was weak light perception. Whole retinal edema was seen on the fundus, and macular gray retinal opacification was present without a characteristic cherry-red spot. Optical coherence tomography revealed subretinal fluid (SRF) in the papillomacular bundle and inner retinal thickening. Fundus fluorescein angiography confirmed that the central retinal artery was not filled at 40 seconds and that the CLRA supplied a part of the macular area. Eight months after the second intravitreal injection of ranibizumab, Optical coherence tomography showed a significant reduction in inner retinal hyperreflectivity and the thickness of the nasal macular retina. The SRF was clearly absorbed, and the visual acuity improved to 1.1 logMAR units. Atypical CRAO. The patient was treated with intravitreal injection of anti-VEGF in his left eye. The thickness of the nasal macular retina decreased. The SRF was clearly absorbed, and the patient's visual acuity significantly improved. When CRAO occurs in patients with diabetic retinopathy sparing the CLRA, the non-characteristic cherry-red spot may be due to macular inner retinal edema, SRF and other factors. According to the patient's condition, anti-vascular endothelial growth factor can be administered as appropriate to inhibit choroidal neovascularization, reduce SRF in the macular retina, and save some vision.


Intron-mediated enhancement of heterologous gene expression in maize.
Chimeric genes containing the coding sequence for bacterial chloramphenicol acetyl transferase (CAT) have been introduced by electroporation into maize protoplasts (Black Mexican Sweet) and transient expression monitored by enzyme assays. Levels of CAT expression were enhanced 12-fold and 20-fold respectively by the inclusion of maize alcohol dehydrogenase-1 introns 2 and 6 in the chimeric construct. This enhancement was seen when the intron was placed within the 5' translated region but not when it was located upstream of the promoter or within the 3' untranslated region. Deletion of exon sequences adjacent to intron 2 abolished its ability to mediate enhancement of CAT gene expression. Northern analysis of protoplasts electroporated with intron constructs revealed elevated levels of CAT mRNA. However, this elevation was insufficient to account for the increased enzyme activity. One explanation of these results is that splicing affects both the quantity and quality of mRNA.


Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury.
Much attention is currently focused on the role of perivascular adipose tissue in development of cardiovascular disease (CVD). Some researchers view it as promoting CVD through secretion of cytokines and growth factors called adipokines, while recent reports reveal that perivascular adipose tissue can exert a protective effect on CVD development. Furthermore, adiponectin, an anti-inflammatory adipokine, reportedly suppresses neointimal hyperplasia after endovascular injury, whereas such vascular remodeling is enhanced by pro-inflammatory adipokines secreted by perivascular adipose, such as tumor necrosis factor-α (TNF-α). These findings suggest that extent of vascular remodeling, a pathological process associated with CVD development, depends on the balance between pro- and anti-inflammatory adipokines secreted from perivascular adipose tissue. We previously demonstrated that angiopoietin-like protein 2 (Angptl2), a pro-inflammatory factor secreted by adipose tissue, promotes adipose tissue inflammation and subsequent systemic insulin resistance in obesity. Here, we examined whether Angptl2 secreted by perivascular adipose tissue contributes to vascular remodeling after endovascular injury in studies of transgenic mice expressing Angptl2 in adipose tissue (aP2-Angptl2 transgenic mice) and Angptl2 knockout mice (Angptl2(-/-) mice). To assess the role of Angptl2 secreted by perivascular adipose tissue on vascular remodeling after endovascular injury, we performed adipose tissue transplantation experiments using these mice. Wild-type mice with perivascular adipose tissue derived from aP2-Angptl2 mice exhibited accelerated neointimal hyperplasia after endovascular injury compared to wild-type mice transplanted with wild-type tissue. Conversely, vascular inflammation and neointimal hyperplasia after endovascular injury were significantly attenuated in wild-type mice transplanted with Angptl2(-/-) mouse-derived perivascular adipose tissue compared to wild-type mice transplanted with wild-type tissue. RT-PCR analysis revealed that mouse Angptl2 expression in perivascular adipose tissue was significantly increased by aging, hypercholesterolemia, and endovascular injury, all risk factors for coronary heart disease (CHD). Immunohistochemical and RT-PCR analysis of tissues from patients with CHD and from non-CHD patients indicated that ANGPTL2 expression in epicardial adipose tissue was unchanged. Interestingly, that analysis also revealed a positive correlation in ANGPTL2 and ADIPONECTIN expression in epicardial adipose tissue of non-CHD patients, a correlation not seen in CHD patients. However, in epicardial adipose tissue from CHD patients, ANGPTL2 expression was positively correlated with that of TNF-α, a correlation was not seen in non-CHD patients. These findings suggest that pro-inflammatory adipokines cooperatively accelerate CHD development and that maintaining a balance between pro- and anti-inflammatory adipokines likely protects non-CHD patients from developing CHD. Overall, our studies demonstrate that perivascular adipose tissue-secreted Angptl2 accelerates vascular inflammation and the subsequent CVD development.


Influence of recasting different types of dental alloys on gingival fibroblast cytotoxicity.
Surplus alloy from the initial casting is commonly reused with the addition of new alloy. This recasting procedure could affect the cytotoxicity of dental alloys. The purpose of this in vitro study was to evaluate the effect of repeated casting of high-noble and base metal alloys on gingival fibroblast cytotoxicity. Disk-shaped specimens (5 × 2 mm, n=60) of a high-noble (Au-Pt) and 2 base metal (Ni-Cr and Cr-Co, n=20) alloys were prepared with 100% new alloy and 50%, 65%, and 100% once recast alloy. The elemental composition of specimens was analyzed with X-ray energy-dispersive spectroscopy. Five specimens from each group were conditioned in saline with 3% fetal bovine serum albumin. The conditioning media were analyzed for elemental release with atomic absorption spectroscopy. Cytotoxic effects were assessed on human gingival fibroblast with a 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyl tetrazolium bromide (MTT) colorimetric assay. The data were analyzed with 1-way and 2-way ANOVA and Tukey's HSD multiple comparison test (α-=.05). Elemental compositions of Co-Cr and Au-Pt alloys were significantly different among casting protocols. Elemental release of Co-Cr and Ni-Cr alloys was significantly different between new and recast specimens (P<.001). Nickel release increased with recast alloy addition. The 2-way ANOVA showed a significant effect of the casting procedure (P<.001) alloy group (P<.001) and their interaction for cytotoxicity (P<.001). The Ni-Cr alloy groups with 65% and 100% recast alloy had lower cellular activity than all other specimens (P<.001). The results of this study indicated that alloys containing nickel have increased cytotoxic effects and that composition of the alloys affected the cytotoxicity. Furthermore, recasting nickel-containing alloys with 65% surplus metal addition significantly increased the cytotoxic activity.


alpha B-crystallin is a cytoplasmic interaction partner of the kidney-specific cadherin-16.
The Ca(2+)-dependent membrane-spanning classical cadherins bind directly to cytosolic catenins. This cadherin-catenin interaction is known to be critical for the fundamental role of cadherins in cell-cell adhesion. The small subfamily of the 7D-cadherins, however, cannot interact with catenins due to their highly truncated cytoplasmic tail. Thus far, no cytoplasmic interaction partner for the 7D-cadherins has been described. With the use of the cytoplasmic domain of the Ksp (kidney-specific)-cadherin, which belongs to the family of 7D-cadherins, as bait in affinity chromatography with human kidney lysates, the small heat-shock protein alpha B-crystallin was identified by matrix-assisted laser desorption/ionization-time-of-flight analysis as a cytosolic binding partner of Ksp-cadherin. This interaction was verified by co-immunoprecipitation analysis. With the use of overlapping peptides representing the entire alpha B-crystallin molecule, the N-terminal part of alpha B-crystallin, which does not possess chaperone activity, was identified as responsible for the binding to Ksp-cadherin. This interaction was found to be specific since only the cytoplasmic domain of Ksp-cadherin, but not LI (liver-intestine)-cadherin (another member of the 7D-cadherin family), interacted with alpha B-crystallin. In the human kidney, both alpha B-crystallin and Ksp-cadherin co-localize to cells of the collecting duct. They also co-localize with the actin cytoskeleton and co-precipitate with the latter. These findings suggest that the interaction of Ksp-cadherin with alpha B-crystallin is important for the connection of Ksp-cadherin to the cytoskeleton and thus for maintaining tissue integrity in the kidney.


Optimising preoperative risk stratification tools for prostate cancer using mpMRI.
To improve preoperative risk stratification for prostate cancer (PCa) by incorporating multiparametric MRI (mpMRI) features into risk stratification tools for PCa, CAPRA and D'Amico. 807 consecutive patients operated on by robot-assisted radical prostatectomy at our institution during the period 2010-2015 were followed to identify biochemical recurrence (BCR). 591 patients were eligible for final analysis. We employed stepwise backward likelihood methodology and penalised Cox cross-validation to identify the most significant predictors of BCR including mpMRI features. mpMRI features were then integrated into image-adjusted (IA) risk prediction models and the two risk prediction tools were then evaluated both with and without image adjustment using receiver operating characteristics, survival and decision curve analyses. 37 patients suffered BCR. Apparent diffusion coefficient (ADC) and radiological extraprostatic extension (rEPE) from mpMRI were both significant predictors of BCR. Both IA prediction models reallocated more than 20% of intermediate-risk patients to the low-risk group, reducing their estimated cumulative BCR risk from approximately 5% to 1.1%. Both IA models showed improved prognostic performance with a better separation of the survival curves. Integrating ADC and rEPE from mpMRI of the prostate into risk stratification tools improves preoperative risk estimation for BCR. • MRI-derived features, ADC and EPE, improve risk stratification of biochemical recurrence. • Using mpMRI to stratify prostate cancer patients improves the differentiation between risk groups. • Using preoperative mpMRI will help urologists in selecting the most appropriate treatment.


Reducing Postoperative Call Volume Through Verbal Preoperative Education.
To improve patient satisfaction and understanding of what to expect after chronic ear surgery and reduce call volume to an otology clinic at an academic tertiary referral center. Quality improvement initiative. A single-academic tertiary referral center. One hundred and ten patients who underwent chronic ear surgery in March to May 2018. Preoperative counseling over the phone 1 week before surgery. Patient call volume to the clinic within a 2-week postoperative window, patient understanding, and satisfaction of perioperative course. There was a significant increase in patient satisfaction (10.1% increase, 9.8 intervention vs. 8.9 no intervention, p = 0.0032) and in patient understanding of what to expect after surgery (6.7% increase, 9.5 intervention vs. 8.9 no intervention, p = 0.0275). There was a significant decrease in mean number of calls per patient to the clinic (57.6% decrease, 0.31 intervention vs. 0.72 no intervention, p = 0.0105) and in percentage of patients who made any number of calls to the clinic (20% intervention vs. 46%, no intervention, p = 0.00438). Verbal preoperative counseling over the phone was effective in significantly reducing unnecessary call volume to the clinic and in improving patient satisfaction and overall understanding of what to expect after surgery.


Decorated Oxidation-resistive deficient Titanium oxide nanotube supported NiFe-nanosheets as high-efficiency electrocatalysts for overall water splitting.
In this study, oxidation-resistive deficient TiO2-x supported NiFe-based electrocatalysts were developed towards efficient and durable water splitting performance. The oxidation-resistive deficient TiO2-x support with oxygen vacancies ensures good stability and electrical conductivity of the catalyst. The decorated NiFe and NiFeP nanosheets serve as efficient catalysts for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), respectively. In 1 M KOH, the NiFe@TiO2-x and NiFeP@TiO2-x electrodes show low overpotential for OER (300 mV) and HER (273 mV) at 100 mA cm-2, respectively, and excellent stability performance in overall water splitting as well. In-situ Raman and theoretical analysis reveals that the in-situ formed Fe3+-doped NiOOH species are essential in catalyzing OER on NiFe@TiO2-x, particularly the electron localization of surface Fe-O bonds offers lower energy barriers for OER elemental reactions and thus enhance its catalytic activity. This work provides an oxide-based catalyst support strategy for the development of stable and active overall water splitting catalysts, and advances the insights on catalytic origin of NiFe-based catalysts as well.


Patients' understanding of pelvic floor disorders: what women want to know.
To assess the effect of initial visit with a specialist on disease understanding in women with pelvic floor disorders. Women with referrals or chief complaints suggestive of urinary incontinence or pelvic organ prolapse were recruited from an academic urology clinic. The patients completed a Test of Functional Health Literacy in Adults and scripted interview sessions before and after a physician encounter. Physician's treatment plans were standardized based on diagnosis and were explained using models. Interview transcripts were analyzed using qualitative grounded theory methodology. Twenty women with pelvic floor disorders (urinary incontinence or pelvic organ prolapse) were recruited and enrolled in this pilot study. The mean age was 60.5 years (range, 31-87 years) and most of the women were white, with a college degree or beyond. Test of Functional Health Literacy in Adults scores indicated adequate to high levels of health literacy. Preliminary themes before and after the physician encounter were extracted from interviews, and 2 main concepts emerged. First, after the initial physician's visit, knowledge of their diagnosis and the ability to treat their symptoms relieved the patients' concerns related to misunderstandings of the severity of their disease, Second, the patients tended to focus on treatment and had difficulty grasping certain diagnostic terms. This resulted in good understanding of treatment plans despite an inconsistent understanding of diagnosis. Our findings demonstrated a significant effect of the initial physician's visit on the patients' understanding of their pelvic floor disorder. Despite the variation in diagnostic recall after the physician encounter, the patients had a good understanding of treatment plans. This served to increase perceived control and adequately relieve patients' fears.


Bio-technologies for a glandular stem cell cardiomyopexy.
The glandular stem cell cardiomyopexy should become a treatment option for end-stage heart failure. It combines an expected regenerative potential of transformed adult glandular stem cells into cardiomyocytes within the myocardium or onto the myocardium of the recipient and the potential of a hypercapillarized latissimus dorsi muscle (LDM) wrapped around the heart for stem cell nutrition and girdling.


Implementation and Evaluation of a Transformational Leadership Education Session for Nurse Leaders and Nurse Educators.
Transformational leadership is one of the most utilized models of leadership across the disciplines. It can positively impact the leader-follower relationship, performance of the leader, and productivity of the organization. The purpose of the project was to assess the impact of an educational session on the recognition and execution of transformational leadership characteristics for nurse leaders and nurse educators. An interactive transformational leadership education session aimed to affect the recognition and execution of nurse leaders' and nurse educators' transformational leadership characteristics. A Wilcoxon Signed Rank Test yielded a statistically significant increase in idealized influence (behavior), and an increase in intellectual stimulation and inspirational motivation. This project creates the infrastructure for future ongoing initiatives focusing on the beneficial impact of transformational leadership development for nurse leaders and educators. A supportive environment for transformational leadership development may take the institution to the next level regarding engagement, productivity, and performance, all of which are vital to organizational success.


Trends in the Use of Gabapentinoids and Opioids in the Postoperative Period Among Older Adults.
In response to the opioid epidemic, recommendations from some pain societies have encouraged surgeons to embrace multimodal pain regimens with the intent of reducing opioid use in the postoperative period, including by prescribing gabapentinoids. To describe trends in postoperative prescribing of both gabapentinoids and opioids after a variety of surgical procedures by examining nationally representative Medicare data and further understand variation by procedure. This serial cross-sectional study of gabapentinoid prescribing from January 1, 2013, through December 31, 2018, used a 20% US Medicare sample. Gabapentinoid-naive patients 66 years or older undergoing 1 of 14 common noncataract surgical procedures performed in older adults were included. Data were analyzed from April 2022 to April 2023. One of 14 common surgical procedures in older adults. Rate of postoperative prescribing of gabapentinoids and opioids, defined as a prescription filled between 7 days before the procedure and 7 days after discharge from surgery. Additionally, concomitant prescribing of gabapentinoids and opioids in the postoperative period was assessed. The total study cohort included 494 922 patients with a mean (SD) age of 73.7 (5.9) years, 53.9% of whom were women and 86.0% of whom were White. A total of 18 095 patients (3.7%) received a new gabapentinoid prescription in the postoperative period. Of those receiving a new gabapentinoid prescription, 10 956 (60.5%) were women and 15 529 (85.8%) were White. After adjusting for age, sex, race and ethnicity, and procedure type in each year, the rate of new postoperative gabapentinoid prescribing increased from 2.3% (95% CI, 2.2%-2.4%) in 2014 to 5.2% (95% CI, 5.0%-5.4%) in 2018 (P < .001). While there was variation between procedure types, almost all procedures saw an increase in both gabapentinoid and opioid prescribing. In this same period, opioid prescribing increased from 56% (95% CI, 55%-56%) to 59% (95% CI, 58%-60%) (P < .001). Concomitant prescribing also increased from 1.6% (95% CI, 1.5%-1.7%) in 2014 to 4.1% (95% CI, 4.0%-4.3%) in 2018 (P < .001). The findings of this cross-sectional study of Medicare beneficiaries suggest that new postoperative gabapentinoid prescribing increased without a subsequent downward trend in the proportion of patients receiving postoperative opioids and a near tripling of concurrent prescribing. Closer attention needs to be paid to postoperative prescribing for older adults, especially when using multiple types of medications, which can have adverse drug events.


Oral vs intravenous ciprofloxacin in the initial empirical management of severe pyelonephritis or complicated urinary tract infections: a prospective randomized clinical trial.
There are few data on the efficacy of oral antibiotics in the initial empirical management of severe forms of urinary tract infection (UTI). In a multicenter, prospective, randomized trial we compared oral (500 mg twice daily) vs intravenous ciprofloxacin (200 mg twice daily) in the initial empirical management of hospitalized patients with serious forms of UTI. Exclusion criteria were severe sepsis, inability to take oral medication, or the presence of obstruction or renal foci of suppuration. The study population included 66 women with pyelonephritis, 43 patients with community-acquired UTIs, and 32 patients with hospital-acquired UTIs. The frequency of bacteremia was 28 (42%) of 66 in the patients with pyelonephritis and 25 (33%) of 75 in those with complicated UTIs. Seventy-two patients were randomized to treatment with oral and 69 to intravenous ciprofloxacin. There were no infection-related deaths and no patients required an early change of antibiotics because of worsening clinical status during the initial empirical phase of treatment. The mean duration of fever was 1.7 days in patients treated by the oral vs 1.9 days in patients treated by the intravenous route (P = .15). The rates of microbiological failure (3% in the oral vs 2% in the intravenous treatment group) and of unsatisfactory clinical response (4% oral vs 3% intravenous) were low. A treatment change was eventually required in 14% of the patients assigned to the oral and 7% of the patients assigned to the intravenous regimen, mainly because of the isolation of enterococci or ciprofloxacin-resistant organisms in pretherapy urine specimens. In the hospital setting, oral ciprofloxacin is as effective as the intravenous regimen in the initial empirical management of serious UTIs, including bacteremic forms, in patients without severe sepsis, obstruction, or renal foci of suppuration. The efficacy of the oral regimen indicates a potential use for ciprofloxacin in outpatient treatment of a subset of patients currently hospitalized on account of disease severity.


ENACT (ENvironmental enrichment for infants; parenting with Acceptance and Commitment Therapy): a randomised controlled trial of an innovative intervention for infants at risk of autism spectrum disorder.
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with impacts on behaviour, cognition, communication, social interaction and family mental health. This paper reports the protocol of a randomised controlled trial (RCT) of a very early intervention, ENACT (ENvironmental enrichment for infants; parenting with Acceptance and Commitment Therapy), for families of infants at risk of ASD. We aim to recruit 66 mothers of infants at risk of ASD (ie, infants with a sibling or parent diagnosed with ASD) to this RCT. Families will be randomly assigned to care-as-usual or ENACT. ENACT is a very early intervention, leveraging parent-child interactions to improve early social reciprocity, while supporting parental mental health and the parent-child relationship through Acceptance and Commitment Therapy. Intervention content is delivered online (approximately 8 hours) and supported by more than 7 consultations with a clinician. Parents will perform the social reciprocity intervention with their child (30 min per day). Assessments at four time points (baseline, 3 months, 6 months, and 12 months corrected age) will assess parent-infant interaction, parental mental health, infant development and early ASD markers. Analysis will be by intention to treat using general linear models for RCTs. This protocol has been approved by the Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/19/QCHQ/50131) and the University of Queensland Human Research Ethics Committee (2019000558). If efficacy is demonstrated, the intervention has the potential for wide and accessible dissemination. Australian New Zealand Clinical Trials Registry (ACTRN12618002046280).


Survival of renal cell carcinoma metastatic to nonthyroid head and neck region: A systematic review.
Metastasis of renal cell carcinoma to nonthyroid head and neck region is rare. Survival benefit for complete metastasectomy of more common renal cell foci has been reported in the literature. It is uncertain whether metastasectomy in nonthyroid head and neck region would provide a similar benefit. We conducted a retrospective review of all renal cell metastases to the head and neck region treated in the past 15 years at an academic hospital, and a systematic review of all relevant reports with survival data in the literature between 1960 and 2016. An analysis of pooled data was performed to estimate overall survival. Six cases from our institution and 260 independent cases reported in the literature were included in the survival analyses (n = 266). The median follow-up time was 12 months (range 0-180 months). The overall median survival was 36 months (95% confidence interval [CI] 23.7-48.3). The median survival for those who underwent complete metastasectomy in the head and neck was significantly higher at 60 months (95% CI 41.1-78.9) than those who had incomplete or no metastasectomy (12 months, 95% CI 9.5-14.5). Multivariable Cox proportional hazards model estimated that, after controlling for potential confounders, complete metastasectomy remained associated with reduced risk of death (hazard ratio 0.44, 95% CI 0.29-0.69). Complete metastasectomy was associated with 4-year longer median overall survival than incomplete metastasectomy or no metastasectomy. Laryngoscope, 128:889-895, 2018.


Effects of diazepam on behaviour suppressed by extinction in pigs.
Diazepam injected to pigs previously trained to perform an operant response for food according to a continuous reinforcement schedule significantly increased resistance to extinction compared to control pigs. In pigs submitted to a time-out procedure diazepam increased the number of nonreinforced responses at the beginning of the acquisition but was unable to disinhibit suppressed behaviour in the later stages of acquisition when the extinguished behaviour was well acquired. The results are discussed with respect to antiaversive or disinhibitory effects of benzodiazepines and an alternative interpretation, the strengthening of the prevailing behavioural tendency in the animal's repertoire at the time of test, is put forward.


Treatment of human pulmonary paragonimiasis with triclabendazole: clinical tolerance and drug efficacy.
An open clinical trial to determine the efficacy and tolerability of postprandial doses of triclabendazole against Paragonimus mexicanus in 62 patients with pulmonary paragonimiasis from the Ecuadorian Amazon region was performed. Praziquantel was used as therapeutic control. Patients were allocated at random to the following 4 therapeutic regimens: triclabendazole, 5 mg/kg once daily for 3 d (16 patients), 10 mg/kg twice on one day (15 patients), and 10 mg/kg in a single dose (16 patients), and praziquantel, 25 mg/kg thrice daily for 3 d (15 patients). Clinical tolerance, based on the frequency and severity of adverse reactions, was superior in all 3 triclabendazole regimens to that of praziquantel. No alteration was observed in hepato-renal functions or haematological values. The clinical symptoms resolved at a comparable rate in all 4 treatment groups. A more rapid parasitological response to treatment, as determined by the reduction in the average number of parasite eggs found in sputum, was seen in patients treated with triclabendazole than with praziquantel. By day 90, 60 patients had no egg detected in their sputum; 2 patients, treated with a single dose of 10 mg/kg, had a few and were re-treated with triclabendazole (5 mg daily for 3 d). On day 365, none of the patients had eggs in their sputum. Triclabendazole can be recommended as an alternative drug of choice for the treatment of pulmonary paragonimiasis; it is as effective as praziquantel in clearing infections and better tolerated.


Late enterocutaneous fistula as a complication after umbilical hernioplasty.
Umbilical hernia is a high-prevalence problem in adults. Traditional herniorrhaphy is marked by high recurrence rates, but nowadays, the use of prosthetic materials has improved results and has even brought about lower morbidity rates, making the enterocutaneous fistula an exceptional complication of umbilical hernioplasty. We report on a case of a 54-year-old male who developed a high-debt enterocutaneous fistula 1 year after undergoing an operation for an umbilical hernia by means of a plug-technique hernioplasty. We discuss the case, treatment, and preventable aspects of this complication.


A longitudinal study of seroreactivities to Plasmodium falciparum antigens in Nigerian infants during their first year of life.
The kinetics of passively transferred maternal antibodies to antigens of Plasmodium falciparum and the dynamics of acquisition of these antibodies during the first year of life was investigated in infants born in a malaria endemic area of south-western Nigeria. Blood samples were collected from the infants at bi-monthly follow-up visits for the analysis of total serum immunoglobulin G, IgM, IgA and antibodies to the antigen Pf155/RESA and against synthetic peptides representing antigenic sequences of the blood stage antigen Pf155/RESA and Ag332 or the circumsporozoite protein (CSP). IgG levels fell from birth till 4 months and a steady rise was observed thereafter till ten months of life. On the contrary mean IgM and IgA levels increased throughout the first year of life. Generally the number of infants positive for antibodies to the antigens under investigation fell from birth and between 4-6 months of age was either low or absent. None of the infants were positive for antibodies to the peptide representing Ag332 during the first year of life. The earliest seroconversion was detected at 6 months of age involving the Pf155/RESA and (NANP)6 antigens. The results indicate a high level of exposure in this study area to malaria infection early in life. The finding of an active antibody response to malarial antigens in infancy encourages the hope that a malaria vaccine administered early in life may accelerate the development of naturally acquired immunity and thus protect the population most at risk.


Does surgical intervention significantly prolong the patency of failed angioaccess grafts previously treated with percutaneous techniques?
In the last decade, percutaneous techniques have been increasingly used to treat angioaccess graft thrombosis. Often when catheter-based treatment fails, surgeons are called upon to treat these occluded bridge fistulas. It has been our impression that operative intervention has not significantly increased the longevity of angioaccess grafts that have failed percutaneous intervention. During a 2-year period, 101 operative procedures were performed on failed bridge fistulas. All had previously been treated with percutaneous thrombolysis and dilatation. The number of previous interventions ranged from one to five. Primary patency rates of the angioaccess grafts following surgical revision were 43%, 24%, and 12% at 30, 60, and 90 days, respectively. We conclude that surgical intervention does not significantly prolong the patency of angioaccess grafts that have previously failed percutaneous interventions and that its routine use cannot be recommended.


Codon usage in muscle genes and liver genes.
Synonymous codon usage frequencies, derived from cDNA clone sequences, were compared for several sets of vertebrate genes. Gene sets as diverse as those expressed in avian skeletal muscle and in mammalian liver showed similar patterns of synonymous codon usage. There were no significant differences suggesting tissue-specific co-adaptation of codon usage patterns and tRNA anticodon profiles. The results indicate a consensus codon usage pattern for vertebrate genes which is largely independent of taxonomic class, tissue of expression, and the cellular fate and rate of evolution of the encoded proteins. Certain elements of the consensus codon usage pattern indicate that it is the product of natural selection and not simply a mutational equilibrium among phenotypically equivalent synonyms.


Usefulness of noninvasive estimate of pulmonary vascular resistance to predict mortality, heart failure, and adverse cardiovascular events in Patients With stable coronary artery disease (from the Heart and Soul Study).
Pulmonary vascular resistance (PVR) is an important hemodynamic variable that affects prognosis and therapy in a wide range of cardiovascular and pulmonary conditions. We sought to determine whether a noninvasive estimate of PVR predicts adverse outcomes in patients with stable coronary artery disease. Using Doppler echocardiography we measured the estimated PVR (defined as the ratio of the tricuspid regurgitant velocity [TRV] to the velocity-time integral [VTI] of the right ventricular outflow tract [RVOT]) in 795 ambulatory patients with stable coronary artery disease. Participants were categorized by quartiles of the TRV/VTI RVOT ratio. Hazard ratios (HRs) and 95% confidence intervals were calculated for all-cause mortality, heart failure hospitalization, and adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or stroke). After 4.3 years of follow-up there were 161 deaths, 44 deaths from cardiovascular causes, 103 heart failure hospitalizations, and 120 adverse cardiovascular events. Compared with patients in the lowest TRV/VTI RVOT quartile, those in the highest quartile were at increased risk of all-cause mortality (unadjusted HR 1.8, 95% confidence interval 1.3 to 2.5), heart failure hospitalization (unadjusted HR 2.9, 95% confidence interval 2.0 to 4.3), and adverse cardiovascular events (unadjusted HR 2.0, 95% confidence interval 1.4 to 2.9). After multivariate adjustment, patients in the highest quartile were at increased risk of heart failure hospitalizations (adjusted HR 2.5, 95% confidence interval 1.3 to 4.7). In conclusion, a noninvasive estimate of PVR (TRV/VTI RVOT ratio) predicts mortality, heart failure hospitalization, and adverse cardiovascular events in patients with stable coronary artery disease.


Phosphatidylinositol kinase enzymes regulate the retrograde axonal transport of NT-3 and NT-4 in sympathetic and sensory neurons.
Phosphatidylinositol 3-kinase (PI3-kinase) and phosphatidylinositol 4-kinase (PI4-kinase) enzymes are an important family of signaling molecules that have been implicated in the regulation of intracellular vesicle trafficking. It has previously been shown that PI3-kinase and PI4-kinase enzymes regulate neuronal survival and the retrograde axonal transport of nerve growth factor in sympathetic and sensory neurons. We have extended these studies to examine the role these enzymes play in the regulation of the retrograde axonal transport of neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in sympathetic and sensory neurons in vivo. Wortmannin (0.1 nmol/eye), a PI3-kinase and PI4-kinase antagonist, reduced the amount of (125)I-NT-3 retrograde transport in sympathetic neurons by approximately 50% and (125)I-NT-4 in sympathetic neurons by approximately 40% and sensory neurons by approximately 20%. The PI3-kinase antagonist LY294002 (100 nmol/eye) reduced the retrograde axonal transport of (125)I-NT-4 in sympathetic and sensory neurons, and (125)I-NT-3 in sympathetic neurons. Phenylarsine oxide (PAO), a PI4-kinase antagonist, significantly inhibited (125)I-NT-4 retrograde axonal transport in sympathetic and sensory neurons. These results show that wortmannin-sensitive PI3-kinases and PI4-kinases may be involved in NT-3 and NT-4 retrograde axonal transport. The retrograde axonal transport of neurotrophic factors in sympathetic and sensory neurons in vivo appears to depend upon the activation of different receptors and second messenger cascades at the nerve terminal.


Reducing Pediatric Intraoral Radiography Radiation Dose Using Reduced-Power Dental X-Ray Units: A Randomized Trial.
Purpose: To assess the diagnostic confidence of intraoral radiographic image quality while reducing the pediatric patient's radiation exposure using a longer position indicating device (PID), additional X-ray beam filtration and rectangular collimation while using modern, lower-power intraoral dental X-ray units.
Methods: A randomized prospective study scored bitewing intraoral dental images based on relevant clinical features. Observer studies with pediatric dentists and dental residents were conducted to verify whether diagnostic confidence remained unchanged after dose reduction modifications. The study involved a two-phase investigation to determine: (1) the best thickness of aluminum (Al) 2024-T3 alloy filter and (2) required increased exposure time to maintain intraoral radiographic image quality. A 30 cm PID with a rectangular collimator was used to further manage patient dose. For each phase, images from 125 patients were collected from February 2017 to September 2018 and analyzed.
Results: The results from the observer study using a 30 cm PID, 1.02 mm thick Al alloy filter, and a rectangular collimator resulted in a patient dose reduction between 64 percent (exposure time of 400 msec) to 77 percent (250 msec), without any statis- tically significant effect to the diagnostic confidence of the observers in evaluating the reduced radiation images.
Conclusion: Long recognized dose reduction methods, when implemented on a modern, low-power intraoral dental X-ray unit, do not impact confidence in bite- wing diagnostic images, but substantially reduce patient dose and should be adopted to increase patient safety, especially for children.


[Evolution of transfusionnal requirements in hematology].
Predicting transfusion requirements relies both on epidemiology and therapeutic changes in hematology. The incidence rate of B-cell neoplasias especially non-Hodgkin lymphoma and myelodysplasia is increasing. Chemotherapy related myelodysplasia will reflect the improvement of solid tumor prognostic in the future. For myelodysplasias, therapeutic changes including oral iron chelators and more intensive transfusion policies will likely result in an increase of PRC requirements, a situation shared by sickle-cell disease.


Awareness of intratumoral bacteria and their potential application in cancer treatment.
Hitherto, the recognition of the microbiota role in tumorigenesis and clinical studies mostly focused on the intestinal flora. In contrast to the gut microbiome, microorganisms resident in tumor tissue are in close contact with cancer cells and therefore have the potential to have similar or even different functional patterns to the gut flora. Some investigations have shown intratumoral bacteria, which might come from commensal microbiota in mucosal areas including the gastrointestinal tract and oral cavity, or from nearby normal tissues. The existence, origin, and interactions of intratumoral bacteria with the tumor microenvironment all contribute to intratumoral microorganism heterogeneity. Intratumoral bacteria have a significant role in tumor formation. They can contribute to cancer at the genetic level by secreting poisons that directly damage DNA and also intimately related to immune system response at the systemic level. Intratumoral bacteria have an impact on chemotherapy and immunotherapy in cancer. Importantly, various properties of bacteria such as targeting and ease of modification make them powerful candidates for precision therapy, and combining microbial therapies with other therapies is expected to improve the effectiveness of cancer treatment. In this review, we mainly described the heterogeneity and potential sources of intratumoral bacteria, overviewed the important mechanisms by which they were involved in tumor progression, and summarized their potential value in oncology therapy. At last, we highlight the problems of research in this field, and look forward to a new wave of studies using the various applications of intratumoral microorganisms in cancer therapy.


Different formats of imprinted polymers for determining organotin compounds in environmental samples.
Organotin compounds and their degradation products enter the environment mainly as a result of their use as biocides and antifouling paints. Analysis of these compounds in environmental samples has to be very sensitive and selective so that their concentrations corresponding to the low environmental target values can also be detected. Generally, analysis of a complex matrix leads to high interferences during the different process steps; clean-up procedures are recommended to overcome this problem. For the past many years, solid phase extraction by employing imprinted materials has been extensively used for many organic substances that are used for pre-concentration and clean-up purposes with excellent results. Here, we present three different imprinted polymers prepared via bulk, precipitation, and emulsion polymerization methods that use similar compositions. The synthesized polymer particles were characterized morphologically by employing scanning electron microscopy and Brunauer-Emmett-Teller analysis. Binding properties were calculated using the Langmuir-Freundlich isotherm. Depending on the properties of the materials, different analytical applications for complex matrices are proposed. These applications are mainly used on tributyltin and its degradation products for environmental analysis.


17-Hydroxy-jolkinolide A inhibits osteoclast differentiation through suppressing the activation of NF-κB and MAPKs.
Osteoclasts (OC) are bone-specific multinucleated giant cells (MNCs) derived from the monocyte/macrophage hematopoietic lineage cells. Inhibiting osteoclast formation is considered as an effective therapeutic approach for the treatment of the pathological bone loss. In this study, we investigated effects of 17-hydroxy-jolkinolide A (HJA), an ent-abietane diterpenoid isolated from the dried root of Euphorbia fischeriana, on osteoclastogenesis induced by RANKL. The results showed that HJA significantly inhibited RANKL-induced osteoclast formation from primary bone marrow macrophages (BMMs). HJA also prevented bone resorption by mature osteoclasts in a dose-dependent manner. In addition, the expression of osteoclastic marker genes, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (Cts K) and MMP-9, was significantly inhibited by HJA. Furthermore, HJA also significantly inhibited RANKL-induced activation of NF-κB and phosphorylation of MAPK. Our results indicate that HJA has an inhibitory role in the bone loss by preventing osteoclast formation as well as its bone resorptive activity. Therefore, HJA may be useful as a therapeutic reagent for bone loss-associated diseases.


KPNA3-knockdown eliminates the second heat shock protein peak associated with the heat shock response of male silkworm pupae (Bombyx mori) by reducing heat shock factor transport into the nucleus.
In this study, we investigated the role of karyopherin alpha 3 in the heat shock response in male silkworm pupae. Karyopherin alpha recognizes the classical nuclear location sequence on proteins and transports them into the nucleus by forming a trimetric complex with karyopherin beta. Three predicted karyopherin alphas (KPNA1, KPNA2 and KPNA3) have been identified from the silkworm Bombyx mori. Pull-down assay result showed that KPNA3 can pull down heat shock transcription factor (HSF) from proteins extracted from tissues using non-denature lysis buffer. After 45 °C heat shock on male B. mori pupae for 30 min, we identified two heat shock protein (HSP) mRNA expression peaks correlating with HSP19.9, HSP20.4 and HSP25.4 at 4 h (peak 1) and 24 h (peak 2). The second peak was eliminated after knockdown of KPNA3. Similar results were obtained following knockdown of HSF, which is the trans-activating factor of heat shock. However, KPNA3 knockdown was not accompanied by the decreased HSF protein levels at 24 h after heat shock which were observed following HSF knockdown. We also expressed recombinant protein GST-KPNA3 and His-HSF in Escherichia coli to perform GST pull-down assay and the result confirmed the interaction between KPNA3 and HSF. We concluded that KPNA3 knockdown eliminates the second heat shock protein peak in the heat shock response of male silkworm pupae by reducing HSF transport into the nucleus.


Terbium as a luminescent probe of metal-binding sites in protein kinase C.
In the present report, we demonstrate that Tb3+ binds to protein kinase C and serves as a luminescent reporter of certain cationic metal-binding sites. Tb3+ titration of 50 nM protein kinase C results in a 20-fold enhancement of Tb3+ luminescence which is half-maximal at 12 microM Tb3+. A Kd of approximately 145 nM was determined for Tb3+ binding to the enzyme. The excitation spectrum of bound Tb3+ exhibits a peak at 280 nm characteristic of energy transfer from protein tryptophan or tyrosine residues. The luminescence of this complex can be markedly decreased by other metals, including Pb2+ (IC50 = 25 microM), La3+ (IC50 = 50 microM), Hg2+ (IC50 = 300 microM), Ca2+ (IC50 = 6 mM), and Zn2+ (IC50 greater than 10 mM), and chelation of Tb3+ by 2 mM EGTA. Tb3+ binding to protein kinase C is correlated with its inhibition of protein kinase activity (IC50 = 8 microM), r = 0.99) and phorbol ester binding (IC50 = 15 microM, r = 0.98). Tb3+ inhibition of protein kinase C activity cannot be overcome by excess Ca2+, but can be partially overcome with excess phosphatidylserine or by chelation of Tb3+ with EGTA. Tb3+ noncompetitively inhibits phorbol ester binding by decreasing the maximal extent of binding without significantly altering binding affinity. The results suggest that the Tb3(+)-binding site is at or allosterically related to the enzyme's phosphatidylserine-binding site, but is distinct from the phorbol ester-binding domain and the Ca2(+)-binding site that regulates enzyme activity.


Identification of VPS35 p.D620N mutation-related Parkinson's disease in a Taiwanese family with successful bilateral subthalamic nucleus deep brain stimulation: a case report and literature review.
Vacuolar protein sorting 35 (VPS35) was recently reported to be a genetic cause for late-onset autosomal dominant Parkinson's disease (PD). However, VPS35 mutations are rarely reported in Asian populations. Herein, we report the first Taiwanese family with the pathogenic VPS35 p.D620N mutation, including one patient treated successfully with subthalamic nucleus deep brain stimulation (STN-DBS). A 61-year-old woman presented with progressive left hand resting tremor at the age of 42. Neurological examinations revealed mask face and akinetic-rigidity over left extremities. She showed a good response to levodopa treatment, and her unified Parkinson's disease rating scale (UPDRS) motor scores improved from 42 to 15 under the levodopa equivalent dose of 1435 mg/day. She developed peak-dose dyskinesia and motor fluctuation seven years after the onset of symptoms, and received bilateral STN-DBS at the age of 55. Stimulation led to a marked improvement in her motor symptoms with a 37% improvement in the UPDRS motor score during the OFF period five years after surgery. The patient's mother and three siblings were also diagnosed with PD in their forties, following an autosomal-dominant inheritance pattern. We performed genetic analysis of the proband using a targeted next generation sequencing (NGS) panel covering 17 known PD-causative genes. We identified a pathogenic missense mutation in VPS35 gene, c.1858G > A (p.D620N), in this patient. This is the first report of the VPS35 p.D620N mutation in a Taiwanese family. Additionally, our report contributes to the current understanding of genetically defined PD patients treated successfully with STN-DBS.


Preclinical Immersion Experiences Improve Medical Student Perceptions of Surgery.
Medical students historically receive little to no preclinical exposure to surgery and surgical subspecialties. As a result, by the time they reach their clinical clerkship time, students often have already found interest in other specialties. The goal of this study is to utilize the knowledge to action (KTA) implementation framework to design and refine a clinical immersion experience during the second year of medical school. A total of 94 second-year Harvard Medical School students underwent the surgical immersion experience between 2019 and 2022 (the program was postponed in 2020 due to COVID). The development and refinement of the curriculum were nicely modeled by the KTA implementation framework. We identified a gap in medical student preclinical education, adapted a curriculum for preclinical medical students at Massachusetts General Hospital , selected the curriculum components to provide a high-level overview of surgery, monitored the student experience, and evaluated outcomes using the student surveys. Based on the survey results, inductive thematic analysis was utilized to identify prominent positive and negative themes. The feedback was then used to tailor subsequent iterations of the immersion experience. Eighty-eight medical students completed the survey (RR = 93.6%), and 85% rated the immersion experience as "excellent", 11% "very good", 4% "good", and 0% "fair" or "poor". There was no significant difference in ratings between sessions. Several key themes were identified, including changed perceptions, diversity of surgical fields, teamwork, surgery clerkship preparedness, and the need for more preclinical exposure. Preclinical medical students gave overwhelmingly positive reviews of the surgical immersion experience. A half-day intervention is sufficient to begin changing students' views toward surgery, disproving stereotypes, and even inspiring some to consider a surgical field themselves. In addition, the KTA implementation framework is a useful model for the development and refinement of medical education curricula.


Feeling the Burn: Phototoxicity and Photoallergy.
An interaction between light's radiation and certain exogenous and endogenous substances can lead to the development of photoallergic and/or phototoxic dermatoses. Clinically, reactions may range from acute and self-limited to chronic and recurrent. Delays in diagnosis are not uncommon due to complex clinical presentations, broad differentials, and limited number of specialists who perform phototesting. Therefore, a critical understanding of these dermatoses is essential for accurate diagnosis and appropriate management. The epidemiology, light sources, mechanisms, clinical presentations, evaluation protocols, common culprits, treatments, key challenges, and future directions related to photoallergy and phototoxicity are reviewed herein.


Ureteral Complications Requiring Intervention After Kidney Transplant: A Single-Center Experience.
The surgical aspect of kidney transplant can be the surgical technique itself or the use of reconstruction techniques in the case of a complication requiring reoperation. In our study, we examined particularly surgical techniques and reconstruction options for ureteral anastomoses. Data from patients who underwent kidney transplant from 2010 to 2020 (N = 433) were examined retrospectively at follow-up of at least 1 year. We sought an association between the type of ureteral anastomoses and parameters considered to be risk factors based on literature data. We did not note the complicated cases that solved spontaneously and only selected cases where the ureteral anastomosis complication (UAcomp) needed urologic, radiological, or surgical intervention. In a smaller group, we examined the correlation between BK polyomavirus and ureteral stenosis. A total of 9.2% (n = 40) of patients developed UAcomp, 67.5% (n = 27) of whom required reoperation. In complicated cases, the rate of primary ureteral anastomosis type was 60.0% (n = 24) ureteroneocystostomy (UNS) and 40.0% (n = 16) ureteroureterostomy (UU) (P = .184). After UNS, 7.7% (n = 17) of cases required reoperation, and this rate was 4.7% (n = 10) after UU (P = .164). After treatment of the UAcomp, 95.0% (n = 38) of the patients were discharged with a functioning graft, and 5.0% (n = 2) required graftectomy. Complications of ureteral anastomosis with appropriate interventions results in good graft function. The type of ureteral anastomosis is not significantly associated with UAcomp. It is important that the operating surgeon is well versed in UNS and UU techniques to be able to adapt to any situation, be it primary surgery or reoperation.


Regression of liver stiffness after sustained hepatitis C virus (HCV) virological responses among HIV/HCV-coinfected patients.
We assessed the impact of a sustained virological response (SVR) on liver stiffness among HIV/hepatitis C virus (HCV)-coinfected patients enrolled in the ANRS CO13 HEPAVIH cohort. We studied HIV/HCV-coinfected patients who received at least one dose of any anti-HCV treatment and who had documented SVR status, a pretreatment FibroScan value of at least 7.1 kPa, and at least one posttreatment FibroScan value. The time required to achieve at least a 30% decrease in liver stiffness was analyzed by constructing Kaplan-Meier curves and using Cox proportional hazards models. Among 98 patients treated for HCV infection with either pegylated interferon along with ribavirin (n = 89) or protease inhibitor-based triple therapy (n = 9), 53 patients (54%) had an SVR. Median follow-up was 44.6 (interquartile range: 28.8-58.9) months. The probability of achieving a 30% decrease in FibroScan values was 51% [95% confidence interval (CI): 39-66] in patients with an SVR and 21% in nonresponders (95% CI: 11-36) at 1 year, and 74% (61-86) and 28% (17-44) at 2 years, respectively. In the subgroup of 35 cirrhotic patients (pretreatment liver stiffness ≥12.5 kPa), 14 of 18 patients with an SVR and three of 17 nonresponders had a fibrosis score below 12.5 kPa at the last follow-up examination. Multivariable analysis showed that SVR was independently associated with a ≥30% reduction in liver stiffness, both in the overall study group (hazard ratio: 5.77; 95% CI: 2.00-16.62; P = 0.0012) and in cirrhotic patients (hazard ratio: 8.21; 95% CI: 2.15-31.34; P = 0.0021). Robustness analyses using FIB4 values showed similar results. SVR is significantly associated with improvement in liver stiffness in HIV/HCV-coinfected patients, including those with cirrhosis.


Structure of an inhibitor complex of the proteinase from feline immunodeficiency virus.
The crystal structure of a recombinant form of the proteinase encoded by the feline immunodeficiency virus (FIV PR) has been solved at 2 A resolution and refined to an R-factor of 0.148. The refined structure includes a peptidomimetic, statine-based inhibitor, LP-149, which is an even more potent inhibitor of HIV PR. Kinetic parameters were obtained for the cleavage of five substrates by FIV PR, and inhibition constants were measured for four inhibitors. The structure of FIV PR resembles other related retroviral enzymes although few inhibitors of HIV PR are capable of inhibiting FIV PR. The structure of FIV PR will enhance our knowledge of this class of enzymes, and will direct testing of new proteinase inhibitors in a feline animal model.