Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies.
EphB3 is a major key player in a variety of cellular activities, including cell migration, proliferation, and apoptosis. However, the exact role of EphB3 in cancer remains ambiguous. Accordingly, new EphB3 inhibitors can increase the understanding of the exact roles of the receptor and may act as promising therapeutic candidates. Herein, a hybrid approach of structure-based design and virtual combinatorial library generated 34 quinazoline sulfonamides as potential selective EphB3 inhibitors. A molecular docking study over EphB3 predicted the binding affinities of the generated library, and the top seven hit compounds (3a and 4a-f), with GlideScore ≥ -6.20 Kcal/mol, were chosen for further MM-GBSA calculations. Out of the seven top hits, compound 4c showed the highest MM-GBSA binding free energy (-74.13 Kcal/mol). To validate these predicted results, compounds 3a and 4a-f were synthesized and characterized using NMR, HRMS, and HPLC. The biological evaluation revealed compound 4c as a potent EphB3 inhibitory lead (IC50 = 1.04 µM). The screening of 4c over a mini-panel of kinases consisting of EGFR, Aurora A, Aurora B, CDK2/cyclin A, EphB1, EphB2, EphB4, ERBB2/HER2, and KDR/VEGFR2, showed a promising selective profile against EphB3 isoform. A dose-dependent assay of compound 4c and a molecular docking study over the different forms of EphB provided insights into the elicited biological activities and highlighted reasonable explanations of the selectivity.


Inhibition of the phospholipase C-linked metabotropic glutamate receptor by 2-amino-3-phosphonopropionate is dependent on extracellular calcium.
D,L-2-Amino-3-phosphonopropionate (AP-3), a proposed metabotropic receptor antagonist, produced a concentration-dependent increase in the formation of inositol 1,4,5-trisphosphate in rat hippocampal slices. The response was maximal at 1 mM and completely due to the L-isomer. D,L-AP-3 was half as efficacious as (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a selective agonist of this receptor. The response produced by maximally effective concentrations of L-AP-3 and 1S,3R-ACPD together for 5 min was not significantly different from that produced by 1S,3R-ACPD alone. However, pretreatment for 40 min with either 1 mM L-AP-3 or D,L-AP-3 completely inhibited the response to 1S,3R-ACPD. This inhibition was long-lasting (wash-resistant) and was reversed by reduction of the extracellular Ca2+ concentration. Also, pretreatment for 40 min with 1S,3R-ACPD reduced, but did not completely block, the response to readdition of 1S,3R-ACPD. L-AP-3 (1 mM) also produced a stereoselective 2.3-fold increase in the efflux of glutamate from the hippocampal slices. These data suggest that incubation of hippocampal slices with AP-3 induces a time-dependent desensitization of the metabotropic response by a mechanism that is dependent on extracellular Ca2+. The possible roles of receptor occupancy and inhibition of glutamate uptake by AP-3 are also discussed.


The role of fentanyl in the treatment of breakthrough cancer pain: Different biotechnologies, different results and different drug costs.
The aim of this paper was to assess the drug costs of the different biotechnologies (intranasal fentanyl spray (INFS), oral transmucosal fentanyl citrate (OTFC) and fentanyl buccal tablet (FBT)) in the treatment of breakthrough cancer pain (BTCP). We have calculated the mean drug costs (expressed in euros (€)) for patients treated for BTCP. INFS resulted the less expensive towards OTFC and FBT, with 697 440 €versus (vs.) 809 552 €vs. 779 662 €every 100 patients treated for BTCP, respectively. In conclusion, combining drug costs of different biotechnologies (INFS, OTFC and FBT) with the measure of efficacy represented by the reduction of BTCP avoided (incremental cost-effectiveness ratio, ICER), INFS resulted in better cost-effectiveness.


Neuroinflammation as a possible link between attention-deficit/hyperactivity disorder (ADHD) and pain.
Attention-deficit/hyperactivity disorder (ADHD) and pathological pain are two complex syndromes of multifactorial origin. Despite their prevalence and broad impacts, these conditions are seldom recognized and managed simultaneously. The co-existence of neuropsychiatric conditions (such as ADHD) and altered pain perception and chronic pain has been noted in children, and the comorbidity of ADHD and chronic pain is well documented in adults. Pathophysiological studies have suggested dysfunction of the dopaminergic system as a common neurochemical basis for comorbid ADHD and pain. Considerable evidence supports the role of neuroinflammation in the pathophysiology of both. We suggest that central neuroinflammation underlies altered pain perception and pain sensitization in persons with ADHD. Based on our hypothesis, targeting neuroinflammation may serve as a potential new therapeutic intervention to treat ADHD and comorbid pain in children and adolescents and a preventive strategy for the development of chronic pain in adults with ADHD.


Novel approach to synthesis of silver nanoparticles in interpolyelectrolyte complexes based on pectin, chitosan, starch and their derivatives.
The effect of the chemical structure of interpolyelectrolyte complexes (IPEC) based on polymers of natural origin (pectin--chitosan+, pectin--cationic starch (starch+), carboxymethylcellulose (CMC-)-cationic β-cyclodextrin (β-CD+), anionic starch (starch-)-cationic starch (starch+) on the structure, morphology, thermomechanical and antimicrobial properties of silver-containing nanocomposites obtained by thermochemical reduction of Ag+ ions in interpolyelectrolyte-metal complexes (IMC) was studied. Thermochemical reduction of Ag+ ions in the IMC bulk for 30 min at 150 °C led to formation of silver-containing nanocomposites and this fact was confirmed by wide-angle X-ray scattering method. Transmission electron microscopy showed that different sized of silver nanoparticles were formed depending on the chemical structure of IPEC. The average size of silver nanoparticles was found to be 4.7 nm for pectin--Ag-chitosan+; 5.3 nm for pectin--Ag-starch+; 6.3 for CMC--Ag-β-CD+ and 9 nm for starch--Ag-starch+, correspondingly. The nanocomposites having smaller average nanoparticle size exhibited higher antimicrobial activity against S. aureus and E. coli strains. Pectin--Ag-chitosan+ nanocomposites formed by thermochemical reduction of Ag+ ions showed that the diameter of the inhibition zone against S. aureus and E. coli strains was 19.7 and 32.6 mm, respectively, whereas these values were 15.6 and 14 mm, respectively, for the same nanocomposites obtained by chemical reduction using ascorbic acid.


Reversal of female sterilisation: a comparative study.
In 80 women who had reversal of sterilisation, a study was made of their clinical features at the time of sterilisation and of the factors related to successful outcome. Compared with controls at the time of sterilisation, the women requesting reversal were younger, of lower social class and of higher parity; in addition they were more likely to have an unstable relationship and to have been sterilised following a recent pregnancy. After reversal, intrauterine pregnancy occurred in 26/80 (32.5%) and ectopic pregnancy in 6/80 (7.5%), the majority of successful pregnancies occurring in younger women within one year of reversal following a non-destructive method of tubal occlusion. There was no evidence that techniques of management, including the use of an operating microscope, significantly influenced outcome, and controlled trials will be required to establish their efficacy.


Extracting cervical spine popping sound during neck movement and analyzing its frequency using wavelet transform.
With the excessive use of smartphones, cervical spine pain is becoming increasingly prevalent. A denoised cervical spine popping sound can aid in monitoring and estimating the state of the cervical spine. However, cervical spine popping sounds that are collected when a subject performs neck movements is contaminated by constant noise. Therefore, a denoising algorithm called Wavelet Transform-Based Stationary-Nonstationary (WTST-NST) is adopted to remove the noise. The input signal is decomposed using wavelet transform to obtain the wavelet coefficients. The wavelet coefficients are then separated into two parts, the nonstationary part and the stationary part, using stationary-nonstationary filtering technology. Finally, the wavelet coefficients of the nonstationary part are reconstructed to obtain the denoised cervical spine popping sound. In addition, the frequency components of the sound are analyzed using the multiresolution analysis of the wavelet transform. The experimental results demonstrate that the implementation of the WTST-NST algorithm in the sound analysis of cervical spine facet joints efficiently reduces the overlapped noise, producing an almost pure cervical spine popping sound. Furthermore, the frequency components of cervical spine popping sounds during the smartphone use period are significantly higher than that in the non-use period and are significantly associated with self-reported neck and upper back pain during the smartphone use period. Therefore, the WTST-NST algorithm preserved almost all the features of the sampled input signal. The denoised cervical spine popping sound can be used to quickly and conveniently monitor the status of the cervical spine during the smartphone use period.


Enhanced aging of polystyrene microplastics in sediments under alternating anoxic-oxic conditions.
Aging of microplastics (MPs) (i.e., degradation and weathering) is ubiquitous in the environment. The MP aging process is thought to be limited to light and static areas, while aging in dark and fluctuating anoxic-oxic areas is poorly understood. Here, we provide initial evidence for aging of polystyrene microplastics (PS-MPs) under different anoxic/oxic conditions in sediments, and we further explored these mechanisms using sediment column experiments and pure-culture experiments. The results showed that PS-MPs in alternating anoxic-oxic sediments displayed the highest degree of aging. In the in-situ experiment, both the weight losses and O/C ratios of PS-MPs aged under alternating anoxic-oxic conditions were ∼2 times higher than those aged under static oxic and static anoxic conditions during 2-month experiments. In a 2-month column experiment, the PS-MPs in the alternating anoxic-oxic group showed weight losses and O/C ratios that were, respectively, triple and double the corresponding values for the static oxic and static anoxic groups. Column and pure-culture experiments demonstrated that dark production of ·OH which showed a positive correlation with a Fe redox process could explain enhanced MP aging under the alternating anoxic-oxic conditions. These findings provide a basis for risk assessment and management of MPs in the natural environment, such as in intertidal zones and paddy fields, and also have implications for engineering of optimized MP degradation processes.


Induction of synchronized relapses in SJL/J mice with chronic relapsing experimental allergic encephalomyelitis.
Chronic relapsing experimental allergic encephalomyelitis (CR-EAE) was induced in SJL/J mice by two injections of encephalitogenic emulsion. The majority of mice developed multiple relapses from day 22 to day 367 post injection. To induce synchronized relapses a third injection of the encephalitogenic emulsion was given. Almost all mice that received the third injection developed an acute, synchronized relapse with severe clinical signs within 7 to 11 days. Histologically, there was no difference between the lesions in the spontaneous versus the precipitated relapse. CR-EAE in SJL/J mice modified with the third injection offers an advantage of a reproducible and well-timed acute relapse, which allows precise dissection of the immunological events governing spontaneous relapses in chronic EAE.


Fuzzy fractional-order model of the novel coronavirus.
In this paper, a novel coronavirus infection system with a fuzzy fractional differential equation defined in Caputo's sense is developed. By using the fuzzy Laplace method coupled with Adomian decomposition transform, numerical results are obtained for better understanding of the dynamical structures of the physical behavior of COVID-19. Such behavior on the general properties of RNA in COVID-19 is also investigated for the governing model. The results demonstrate the efficiency of the proposed approach to address the uncertainty condition in the pandemic situation.


Conceptualization of Success in Young Adulthood.
Successful transition from childhood to adulthood is context and culture dependent. This article reviews concepts of mental health and theoretic constructs of successful adulthood that suggest intentional policies and practices are developed with a specific vision of success. Parents, educators, mental health professionals, and policymakers need to be cognizant of their assumptions and essential roles in these processes. The early development of illness may disrupt and alter the timelines of different developmental milestones and trajectories. It is important to discuss what "success" looks like with transitional age youth and their family members, because treatment approaches may adapt accordingly.


Obstructive sleep apnoea/hypopnoea as the initial presentation of relapsing polychondritis.
Relapsing polychondritis (RP) is a relatively rare rheumatological condition, which can affect the upper airway and prove potentially life threatening. We report the first case of RP presenting initially as the obstructive sleep apnoea/hypopnoea syndrome, discuss management and review the extant literature.


Binding of ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by HIV-1.
APJ, a G protein-coupled seven-transmembrane receptor, has been shown to serve as a co-receptor for the entry of human immunodeficiency virus type 1 (HIV-1), and it is dramatically expressed in central nervous system (CNS)-based cells. ALX40-4C was identified as a small-molecule antagonist of the chemokine receptor CXCR4, which can specifically inhibit HIV-1 entry via this co-receptor. In this study, we demonstrated that ALX40-4C inhibited both APJ- and CXCR4/APJ-mediated cell membrane fusion in a dose-dependent manner. In competitive binding assays, (125)I-Apelin13 was replaced by ALX40-4C with an IC(50) of 2.9 microM, as compared with an IC(50) of 0.2 nM for Apelin13. Furthermore, ALX40-4C could block ligand-induced APJ internalization and signaling. ALX40-4C, as an antagonist to APJ, directly binds to and prevents use of APJ as a HIV-1 co-receptor. Thus, ALX-4C has potential utility for further elucidation of HIV-1 neuropathogenesis and therapy of HIV-1-induced encephalopathy.


The histologic presentation of hepatitis E reflects patients' immune status and pre-existing liver condition.
Infection with the hepatitis E virus (HEV) is one of the main causes of acute hepatitis worldwide. Given that, the histopathology of hepatitis E is relatively poorly characterized, and it is unclear what exactly determines its remarkable variability. The aim of our study was a systematic analysis of hepatitis E histology, especially with regard to the clinical setting. Fifty-two liver samples (48 biopsies, 1 liver explant, 3 autopsy livers) from 41 patients with molecularly proven hepatitis E (28 HEV genotype (gt) 3, three gt 1, one gt 4 and 9 undetermined gt) were systematically evaluated for 33 histopathologic features. Following one approach, the biopsies were assigned to one of five generic histologic patterns. In another approach, they were subjected to hierarchical clustering. We found that 23/41 (56%) patients were immunocompromised, whereas 18 (44%) had no known immunosuppression. Five patients (12%) had pre-existing liver disease (LD). The histopathologic spectrum ranged from almost normal to acute, chronic, and steato-hepatitis to subtotal necrosis, and was thus distributed across all five generic patterns. Hierarchical clustering, however, identified three histopathologic clusters (C1-C3), which segregated along the immune status and pre-existing LD: C1 comprised mostly patients with pre-existing LD; histology mainly reflected the respective LD without pointing to the additional hepatitis E. C2 comprised mostly immunocompetent patients; histology mainly displayed florid hepatitis. C3 comprised mostly immunocompromised patients; histology mainly displayed smoldering hepatitis. Accordingly, C1-C3 differed markedly with respect to their clinical and histopathologic differential diagnoses. Hierarchical clustering suggests three groups with distinct histopathologies, indicating biologically different manifestations of hepatitis E. The association of histopathologic changes with the patient's immune status and pre-existing LD plausibly explains the diversity of hepatitis E histopathology, and suggests that these factors are the crucial underlying determinants. We expect our results to improve patient management by guiding the clinico-pathologic diagnosis of hepatitis E.


Specific and nonspecific reactions of mouse immune system under the effect of short-term exposure in warm and/or cold water.
Transient changes in environmental temperature produce a short-term, but significant effect on the immune system reactions in laboratory mice. Activities of nonspecific resistance factors (peritoneal macrophages) in mice exposed in warm or cold water were characterized by similar reactions, while the reactions of cellular and humoral immunity were opposite. Exposure to cold water activated cellular immunity, while warm water activated humoral immune system. The most significant changes in the immune system reactions were observed during the first 3 days of thermal exposure. Temperature alteration from cold to warm leads to activation of cellular and suppression of humoral components of the immune system. Alteration of water temperature from warm to cold leads to activation of nonspecific resistance factors, cellular and humoral immunity.


The broken dental needle--a hazard.
A case of a disposable needle broken during an inferior alveolar injection and its successful removal is reported. Methods of locating the needle and preventing this occurrence are discussed.


The use of intrastent peripheral stent in large coronary arteries: report of three cases.
We report three cases of coronary angioplasty using the IntraTherapeutics Intrastent biliary stent. We describe a technique utilizing routine coronary angioplasty equipment including 8 Fr guiding catheters and 0.014" guidewires. This technique can be easily performed in large-diameter coronary arteries.


Efficacy of Alendronate for the Prevention of Bone Loss in Calcar Region Following Total Hip Arthroplasty.
Bone mineral density (BMD) loss around femoral implants, particularly in the proximal femur, is a common outcome after total hip arthroplasty. Previous studies reported the prevention of postsurgical decrease in BMD with the use of osteoporosis drug therapy. This randomized study evaluated the efficacy of alendronate and alfacalcidol for preserving BMD over a long-term follow-up. Sixty consecutive patients with hip osteoarthritis who had undergone primary cementless total hip arthroplasty were randomly assigned to an alendronate (n = 20), alfacalcidol (n = 18), or control (n = 22) group. Periprosthetic BMD was measured using dual-energy X-ray absorptiometry at 1 week, 1 year, and the current follow-up (minimum 9 years after surgery). Changes in BMD are reported as mean percentages relative to the values at 1 week (baseline reference). All groups showed a significant decrease in the BMD of the calcar at the current follow-up compared to the values at both 1 week and 1 year postoperatively (P < .001). The BMD values were significantly higher in the alendronate group than in the alfacalcidol and control groups (P < .05). The BMD values at the current follow-up were 76% ± 30% (alendronate group), 64% ± 22% (alfacalcidol group), and 59% ± 22% (control group) of the baseline values. Our findings demonstrate the efficacy of early administration of alendronate for the prevention of bone loss in the calcar region.


Respiratory function and cognitive profile in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder with 30%-50% of patients exhibiting cognitive impairment. The pathophysiological mechanisms of cognitive dysfunction are probably multifactorial although hypoventilation secondary to respiratory dysfunction may contribute to cognitive decline. The current study aimed to identify the relationship between respiratory function in ALS patients and the presence and degree of cognitive impairment. Amyotrophic lateral sclerosis patients were prospectively recruited from a multidisciplinary ALS clinic. Baseline clinical assessments including respiratory function as assessed by spirometry were recorded with forced vital capacity (FVC) ≤ 75% considered to be reduced respiratory function. Cognitive testing was performed utilizing the Addenbrooke's Cognitive Examination (ACE) and the Mini-Mental State Examination (MMSE). From a cohort of 100 ALS patients, 48% were categorized as having impaired respiratory function (FVC = 58.24% ± 2.15%) whilst 52% had normal function (88.65% ± 1.27%). Compared to the group with normal respiratory function (ACE 90.68 ± 0.89, MMSE 28.22 ± 0.21), patients with respiratory dysfunction had significantly reduced cognitive function (ACE 86.83 ± 1.5, P = 0.025; MMSE 26.29 ± 0.45, P = 0.029). Furthermore, subscores demonstrated significant differences between the groups with respect to domains in memory (P = 0.003) and attention (P = 0.05) with a trend observed in fluency (P = 0.082). There was a significant correlation between patient baseline FVC and ACE scores as well as between FVC and memory and fluency subscores (P < 0.01). Amyotrophic lateral sclerosis patients with respiratory compromise were more likely to develop reduced cognitive function. In addition to improving physical function, it remains plausible that non-invasive ventilation may alter the progression of cognitive impairment in ALS patients and potentially improve overall quality of life and carer burden.


Caveat fluorophore: an insiders' guide to small-molecule fluorescent labels.
The last three decades have brought a revolution in fluorescence microscopy. The development of new microscopes, fluorescent labels and analysis techniques has pushed the frontiers of biological imaging forward, moving from fixed to live cells, from diffraction-limited to super-resolution imaging and from simple cell culture systems to experiments in vivo. The large and ever-evolving collection of tools can be daunting for biologists, who must invest substantial time and effort in adopting new technologies to answer their specific questions. This is particularly relevant when working with small-molecule fluorescent labels, where users must navigate the jargon, idiosyncrasies and caveats of chemistry. Here, we present an overview of chemical dyes used in biology and provide frank advice from a chemist's perspective.


Stimulation of wound bursting strength during protein malnutrition.
Nutrition is one of the most important factors affecting wound healing. Patients who have significant protein malnutrition and require emergency surgery are frequently encountered. Conventional nutritional preparation for surgery, with intravenous hyperalimentation, requires 10 to 14 days to demonstrate advantageous reversal of catabolism. Growth hormone is known to have an anabolic effect in malnourished animals. The purpose of this investigation was to study the ability of growth hormone, administered from the time of celiotomy, to improve wound strength in protein-malnourished animals and compare its efficacy with preoperative nutritional repletion. Rats were divided into four groups: Group I--normal control rats, group II--malnourished rats, group III--malnourished rats treated with growth hormone for 5 postoperative days, and group IV--malnourished rats refed normal chow for 3 days before operation. Controlled laparotomy wounds were closed with monofilament nylon which was removed at the time wound bursting strength was tested. Bursting strengths at the sixth day postoperative were as follows (means +/- SD): (table; see text) Wound strength of malnourished animals was significantly less than that of controls, (P less than 0.001). Wound bursting strength of groups III and IV was significantly improved over that of malnourished animals (group II), P less than 0.001. The bursting strength of group IV was significantly higher than that of group III. Growth hormone administration following celiotomy is nearly as effective in improving wound healing as preoperative nutritional repletion. These results suggest that growth hormone may be clinically applicable in preventing wound complications in malnourished patients requiring urgent or emergency laparotomy.


Development of metal radioactive liquid reference material for proficiency test.
This study developed liquid reference materials containing various metals, to be used for quality assurance of radiation measurements of the most common metallic wastes generated during the operation or decommissioning of nuclear power plants. The liquid reference materials were prepared by assuming the dissolution of stainless-steel using acid and melting of the major metals present in the stainless steel, namely Fe, Ni, Cr, and Mn, along with the standard sources (134Cs, 137Cs, 60Co, 90Sr). The theoretical massic activity of the standard sources added to the samples and the measured reference values of the gamma and beta emitters in the samples were compared, and they showed good agreement within a one-sigma confidence interval (k = 1). Using the developed reference materials, a proficiency test was conducted on three domestic labs, and the results were evaluated using Z-score. While the evaluation results showed good agreement between the reference values and the reported values for 137Cs and 60Co, all participating labs reported lower values than the reference value for 134Cs. For 90Sr, two out of the three labs reported significantly higher values than the reference value. Based on the results of this study, the developed metal radioactive liquid reference material is expected to be registered as certified reference material (CRM) in the future. They will be used as the CRM for measuring and ensuring the quality of radioactive metal waste.


Analysis of the clinicopathological features and prognostic factors in 734 cases of Chinese Hui and Han patients with adenocarcinoma of the esophagogastric junction.
To explore the clinicopathological features and prognostic factors of 734 cases of Chinese Hui and Han patients with adenocarcinoma of the esophagogastric junction (AEG). In total, 734 patients were confirmed to have AEG by gastroscopy and pathology at the General Hospital of Ningxia Medical University between January 2002 and December 2012. Univariate and multivariate analyses of demographic, clinicopathological, and prognostic data were performed. In total, 734 AEG patients underwent surgical intervention, including 169 Hui patients and 565 Han patients. The male to female ratio was 9.5:1 in Hui patients and 6.4:1 in Han patients, and the average age in both groups was approximately 61 years. The Han patients were more likely to have a cigarette smoking history and an alcohol consumption history than the Hui patients (58.8% vs. 29.4%, p = 0.000; 45.8% vs. 14.6%, p = 0.000). The 5-year survival rate in the Hui and Han patients was 54.3% and 39.9%, respectively (p = 0.024). Age (p = 0.005), sex (p = 0.015), pathologic T stage (p = 0.056), pathologic N stage (p = 0.000), pathologic M stage (p = 0.001), number of resected lymph nodes (p = 0.001) and adjuvant chemoradiotherapy (p = 0.002) were significant independent prognostic factors. The AEG patients were primarily male and elderly in both Hui and Han groups with the prognosis of Hui patients better than Han patients. Age, sex, pathologic T3-4 stage, pathologic N stage, pathologic M stage, number of resected lymph nodes, and adjuvant chemoradiotherapy were significant independent factors predictive of the prognosis of AEG in both groups.


Interleukin-1 and tumor necrosis factor synthesis by mouse peritoneal macrophages is enhanced by dietary n-3 polyunsaturated fatty acids.
The peritoneal macrophages from mice maintained for 16 days on a diet containing (10%) menhaden oil contained less arachidonic acid and more n-3 polyunsaturated fatty acids (n-3 PUFA) than those maintained on diets containing an equivalent amount of corn oil. Following stimulation with lipopolysaccharide, the production of PGE2, interleukin-1 (IL-1) and tumor necrosis factor (TNF) was 2.1 vs. 5.3 ng PGE2/micrograms DNA; 685 vs. 30 units IL-1/micrograms DNA and 14 vs. less than 4 units TNF by macrophages from mice consuming menhaden and corn oil, respectively. Macrophages from animals on diets containing olive oil generated intermediate amounts of PGE2 and equivalent amounts of IL-1 and TNF to those on corn oil. The data indicate that dietary n-3 PUFA at specific intake levels relative to n-6 PUFA may enhance cytokine generation by reducing PGE2 synthesis.


Insulin resistance increases loss of antibody to hepatitis B surface antigen in nondiabetic healthy adults.
The aim of this study was to evaluate the impact of insulin resistance on the persistence of a protective level of anti-HBs (hepatitis B surface antigen) in a nondiabetic general population. A cohort study was designed comprising of 38 473 Korean men and women with anti-HBs at concentrations ≥10 mIU/mL, who underwent a health examination. Insulin resistance was assessed with a homoeostasis model assessment of insulin resistance (HOMA-IR). A decline in anti-HBs to <10 mIU/L during the follow-up was considered to be a loss of protective anti-HBs. Cox-proportional hazard models were used to estimate the adjusted hazard ratios and 95% confidence intervals for anti-HBs loss across quintiles of HOMA-IR and insulin. We identified 20 826 incidents of loss of anti-HBs antibody during 180 522 person-years of follow-up (incident rate 11.5 per 100 person-years). Increasing HOMA-IR was positively associated with incident loss of anti-HBs. The multivariable-adjusted hazard ratios (95% confidence intervals) for incident loss of anti-HBs comparing quintiles 2-5 vs quintile 1 of HOMA-IR were 1.09 (1.04-1.14), 1.14 (1.09-1.19), 1.14 (1.09-1.19) and 1.21 (1.16-1.27), respectively. These associations were stronger in younger individuals under the age of 35 than in people 35 years of age or older (P for interaction = 0.004). The association was also more evident in subjects with higher titres (≥100 mIU/mL) of anti-HBs than in those with low titres (P for interaction < 0.001). Insulin resistance was associated with an increased risk for loss of vaccine-acquired anti-HBs in a large sample of a nondiabetic, general population, indicating a possible role of insulin resistance in vaccine-induced immunity.


Methanotrophic oxidation of organic micropollutants and nitrogen upcycling in a hybrid membrane biofilm reactor (hMBfR) for simultaneous O2 and CH4 supply.
Pharmaceuticals and other organic micropollutants (OMPs) present in wastewater effluents are of growing concern, as they threaten environmental and human health. Conventional biological treatments lead to limited removal of OMPs. Methanotrophic bacteria can degrade a variety of OMPs. By employing a novel bubble-free hybrid membrane biofilm bioreactor (hMBfR), we grew methanotrophic bacteria at three CH4 loading rates. Biomass productivity and CH4 loading showed a linear correlation, with a maximum productivity of 372 mg-VSS·L-1·d-1, with corresponding biomass concentration of 1117.6 ± 56.4 mg-VSS·L-1. Furthermore, the biodegradation of sulfamethoxazole and 1H-benzotriazole positively correlated with CH4 oxidation rates, with highest biodegradation kinetic constants of 3.58 L·g-1·d-1 and 5.42 L·g-1·d-1, respectively. Additionally, the hMBfR recovered nutrients as microbial proteins, with an average content 39% DW. The biofilm community was dominated by Methylomonas, while the bulk was dominated by aerobic heterotrophic bacteria. The hMBfR removed OMPs, allowing for safer water reuse while valorising CH4 and nutrients.


Influence of pig age on virus titer and bactericidal activity of porcine reproductive and respiratory syndrome virus (PRRSV)-infected pulmonary intravascular macrophages (PIMs).
Twelve pigs (six 4-week-old and six 4-month-old cross-bred, specific pathogen free pigs) were used as donors for both pulmonary intravascular macrophages (PIMs) and pulmonary alveolar macrophages (PAMs). The PIMs and PAMs were infected in vitro with low (ISU-55) or high (VR-2385) virulence strains of PRRSV at 1 multiplicity of infection (m.o.i.) for comparisons of virus titers at 48 h post infection (PI). PIMs were as permissive as PAMs to infection with both PRRSV isolates yielding similar progeny titers (10(4.81) vs. 10(5.22) TCID50/ml, respectively). Both ISU-55 and VR-2385 were able to infect PIMs and no significant difference in virus replication as measured by virus titers between isolates was found (10(5.33) vs. 10(4.69) TCID50/ml, respectively). PIMs from 4-weak-old pigs yielded a higher virus titer following PRRSV infection than PIMs from 4-month-old pigs (10(5.43) vs. 10(4.59) TCID50/ml, respectively; p < 0.02). VR-2385-infected PIMs had significantly decreased bactericidal (Staphylococcus aureus) activity compared with uninfected PIMS at 48 h PI (p < 0.05). There was no difference in bactericidal activity between ISU-55 (low virulence)-infected PIMs and VR-2385 (high virulence)-infected PIMs. Both ISU-55 and VR-2385 infection significantly decreased the production of superoxide anion (SOA) at 24 and 48 h PI (p < 0.01). In conclusion, (1) PRRSV had a detrimental effect on bactericidal activity and SOA production of PIMs, (2) PIMs from younger pigs were more permissive to PRRSV infection, and (3) the selected PRRSV strains, which differ in their abilities to induce pneumonia in vivo were not different when tested in vitro by measuring virus titer and bactericidal functions.


The effect of bearing tumours on the ability of mice to reject bone marrow transplants.
To examine the possible relationship between the cells mediating resistance to tumour cells and those mediating rejection of foreign bone marrow transplants (BMT), the effect of tumour-bearing on BMT rejection has been measured by means of the spleen colony assay. Moderate doses (less than 5.0 X 10(6] of bone marrow cells from DBA/2 strain mice, which normally produce few haemopoietic spleen colonies in gamma-irradiated (950R) CBA/J strain mice, gave numerous (confluent) colonies when given soon after injection of Ehrlich ascites tumour (EAT) cells. Transfusion of [3H]UdR-labelled DBA/2 bone marrow cells demonstrated that the increased spleen colony formation in tumour-bearing mice was not due simply to changes in the total number of injected cells homing to the spleen. Injection of EAT ascites fluid alone, given to CBA/J mice before 950R + BMT, transiently reduced spleen colony development, the effect being more marked when fluid from older tumors was used. Supernatant fluid from EAT cells grown in vitro also depressed growth of BMT in vivo. The results reveal two processes in progress in mice bearing an ascites tumour: (1) an early reduction in the natural resistance to BMT allowing successful grafting and spleen colony formation, and (2) a progressive production by the tumour cells of short-acting soluble factors tending to suppress the proliferation of colony forming bone marrow cells in the transplant. The effect of the tumour-bearing state in weakening the natural resistance to foreign BMT strongly suggests that both tumour and foreign marrow graft resistance are mediated by the same or closely related effector cells.


In vitro ultraviolet A irradiation decreases both release ability and gene-expression of vascular endothelial growth factor-A from mast cells.
Ultraviolet A (UVA) rays penetrate the dermis, influencing the function of different cells, including mast cells, able to produce angiogenic factors. We investigated vascular endothelial growth factor (VEGF) release and gene-expression from mast cells (MCs), after UVA irradiation in vitro. The release of VEGF-A by Human MCs-1 (HMC-1) was induced by calcium ionophore A23187 and phorbol 12 myristate 13 acetate (PMA). Half of the cells received increasing doses of UVA (5, 25 and 50 J/cm(2)), the unirradiated HMC-1 served as controls. VEGF release and VEGF's messenger ribonucleic acid (mRNA) were detected respectively by enzyme-linked immunoabsorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Results showed a UVA dose-dependent inhibitory effect on VEGF-A release from HMC-1. In particular, the release ability was reduced by 71.2% with 5 J/cm(2); 85% with 25 J/cm(2) and 86.3% with 50 J/cm(2). The VEGF-A RNA expression was reduced after UVA irradiation with 5 J/cm(2). We speculated that, at least in vitro and at our experimental conditions, UVA irradiation decreases mast cells-VEGF release and gene-expression.


Is there really sphincter spasm in anal fissure?
To assess sphincter function in patients with anal fissure, anal manometry has been performed in ten patients. Anal resting pressure was increased, but both sphincters functioned normally. The increased anal resting pressure was neither due to internal nor to external sphincter spasm.


Sarcomatoid carcinoma of the lung: a predictor of poor prognosis.
Sarcomatoid cancer (SARC) of the lung is a rare histologic type of non-small cell lung cancer (NSCLC). Although believed to be associated with poor prognosis, its effect on survival and recurrence has not been well defined. Our goal was to determine the prognostic significance of SARC histology in patients undergoing pulmonary resection. We retrospectively evaluated all patients who underwent pulmonary resection for NSCLC during a 20-year period at the University of Texas MD Anderson Cancer Center and compared recurrence and survival rates of patients with SARC with a cohort of patients with typical NSCLC. To account for known prognostic factors such as smoking status, age, gender, pathologic stage, and adjuvant therapy, we used one-to-one matching based on propensity scores. The study included 63 SARC patients and 1133 NSCLC patients with complete data. Propensity score matching identified 63 NSCLC patients that were similar to the 63 SARC patients from known clinical factors. The 5-year survival for SARC patients was 24.5% compared with 46.3% for NSCLC patients (p = 0.01); median time to recurrence was 11.3 months and 61.4 months, respectively (p = 0.001). Compared with other histologic subtypes, SARC behaves in an aggressive fashion. These tumors are frequently symptomatic, are locally advanced, and have higher rates of recurrence. Future investigation of novel treatment approaches is warranted. Nonsurgical treatment modalities may be appropriate for patients with clinically advanced disease.


Tislelizumab in combination with gemcitabine plus cisplatin chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer: a retrospective study.
Combining immune checkpoint inhibitors with chemotherapy can synergistically improve antitumor activity and are generally well tolerated. Recently, the efficacy and safety of combination therapy has been demonstrated for many cancers, including urothelial carcinomas. The aim of this retrospective pilot study was to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer. We conducted a retrospective analysis of 31 patients with locally advanced or metastatic bladder cancer from December 2020 to January 2022 with an Eastern Cooperative Oncology Group performance status of 0/1. Of the 31 patients, 14 patients received tislelizumab (200 mg i.v. every 3 weeks, Q3W) plus 21 days cycles of chemotherapy (gemcitabine, 1000 mg/m2 i.v. on days 1 and 8 of each cycle + cisplatin, 70 mg/m2 i.v. on day 2 of each cycle) (TGC) treatment and 17 patients received gemcitabine plus cisplatin chemotherapy (GC) treatment. All patients treated with bladder cytoreductive surgery and were treated for four 21 days cycles until disease progression or intolerable treatment-related adverse events (TRAEs). The objective progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and TRAEs were recorded and reviewed. As of the cut-off date (March 25, 2022), PFS, OS, ORR, DCR, CBR and TRAEs were evaluated in 14 patients receiving combination therapy and 17 patients in the chemotherapy alone group. The median PFS was 36.0 [95% confidence interval (CI) 33.1-38.9] weeks in the TGC group and 29.0 (95% CI 25.4-32.6) weeks in the GC group [hazard ratio (HR) 0.15 (95% CI 0.04-0.55)]. In the GC group, the median OS was 48.0 (95% CI 39.7-56.3) weeks; the median OS was not yet mature for the TGC group [HR 0.26 (95% CI 0.07-0.94)]. Treatment with TGC resulted in improved DCR (TGC 71.4%; GC 65.0%) and CBR (TGC 64.3%; GC 52.9%) compared with GC. However, although higher incidences of grade ≥ 3 TRAEs were observed with TGC compared with GC (35.7% vs 23.5%), the difference was not statistically significant (p = 0.47). This study suggested that TGC provided survivors of locally advanced or metastatic bladder cancer with encouraging antitumor activity and was generally well tolerated.


Procedural Headache Medicine in Neurology Residency Training: A Survey of US Program Directors.
To survey neurology residency program directors (PDs) on trainee exposure, supervision, and credentialing in procedures widely utilized in headache medicine. Clinic-based procedures have assumed a prominent role in headache therapy. Headache fellows obtain procedural competence, but reliance on fellowship-trained neurologists cannot match the population eligible for treatments. The inclusion of educational modules and mechanisms for credentialing trainees pursuing procedural competence in residency curricula at individual programs is not known. A web-based survey of US neurology residency PDs was designed by the American Headache Society (AHS) procedural special interest section in collaboration with AHS and American Academy of Neurology's Headache and Facial Pain section leadership. The survey addressed exposure, training, and credentialing in: (1) onabotulinumtoxinA (onabotA) injections, (2) extracranial peripheral nerve blocks (PNBs), and (3) trigger point injections (TPIs). Fifty-five PDs (42.6%) completed the survey. Compared to noncompleters, survey completers were more likely to feature headache fellowships at their institutions (38.2% vs 10.8%, P=0.0002). High exposure (onabotA=90.9%, PNBs=80.0%, TPIs=70.9%) usually featured hands-on patient instruction (66.2%) and lectures (55.7%). Supervised performance rates were high (onabotA=65.5%, PNBs=60.0%, TPIs=52.7%), usually in continuity clinic (60.0%) or headache elective (50.9%). Headache specialists (69.1%) or general neurology (32.7%) faculty most commonly trained residents. Formal credentialing was uncommon (16.4-18.2%), mostly by documenting supervised procedures (25.5%). Only 27.3% of programs permitted trainees to perform procedures independently. Most PDs felt procedural exposure (80.0-90.9%) and competence (50.9-56.4%) by all trainees was important. Resident exposure to procedures for headache is high, but credentialing mechanisms, while desired by most PDs, are not generally in place. Implementation of a credentialing process may ensure trainees enter practice with the ability to perform procedures safely and effectively.


Maximum predictive power of the microarray-based models for clinical outcomes is limited by correlation between endpoint and gene expression profile.
Microarray data have been used for gene signature selection to predict clinical outcomes. Many studies have attempted to identify factors that affect models' performance with only little success. Fine-tuning of model parameters and optimizing each step of the modeling process often results in over-fitting problems without improving performance. We propose a quantitative measurement, termed consistency degree, to detect the correlation between disease endpoint and gene expression profile. Different endpoints were shown to have different consistency degrees to gene expression profiles. The validity of this measurement to estimate the consistency was tested with significance at a p-value less than 2.2e-16 for all of the studied endpoints. According to the consistency degree score, overall survival milestone outcome of multiple myeloma was proposed to extend from 730 days to 1561 days, which is more consistent with gene expression profile. For various clinical endpoints, the maximum predictive powers of different microarray-based models are limited by the correlation between endpoint and gene expression profile of disease samples as indicated by the consistency degree score. In addition, previous defined clinical outcomes can also be reassessed and refined more coherent according to related disease gene expression profile. Our findings point to an entirely new direction for assessing the microarray-based predictive models and provide important information to gene signature based clinical applications.


Supportive Care in Patients with Critical Coronavirus Disease 2019.
Specific therapies for the treatment of coronavirus disease 2019 (COVID-19) have limited efficacy in the event a patient worsens clinically and requires admission to the intensive care unit (ICU). Thus, providing quality supportive care is essential to the overall management of patients with critical COVID-19. Patients with respiratory failure not requiring intubation should be supported with noninvasive positive pressure ventilation, continuous positive airway pressure, or high flow oxygenation. Use of these respiratory modalities may prevent patients from subsequently requiring intubation. Basic components of supportive care for the critically ill should be applied equally to patients with COVID-19 in the ICU.


Assessing Graves' ophthalmopathy-specific quality of life in Korean patients.
To investigate the clinical significance of Grave's ophthalmopathy-specific quality of life (GO-QOL) in Korean patients. A cross-sectional study was conducted at the Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea, on 98 consecutive Grave's ophthalmopathy (GO) patients. The GO-QOL survey provided by Terwee and colleagues and suggested by the European group on Graves' orbitopathy (EUGOGO) was translated into Korean language and distributed to study participants. Clinical severity was judged by scores of the modified NOSPECS classification, and inflammatory activity was measured by a seven-point scale of clinical activity score (CAS). The mean GO-QOL scores were 73.7 (standard deviation (SD), 26) for visual functioning, 61.9 (SD 26) for appearance, and 67.8 for total quality of life (QOL; SD 22). The worse QOL scores for each part were significantly associated with the higher modified NOSPECS score and CAS after adjusting for confounders such as age and sex (P<0.05, respectively). In particular, decreased QOL scores for visual function were significantly correlated with a higher grade of extraocular muscle involvement (P<0.05). Lower QOL scores for appearance were associated with more severe soft-tissue involvement and proptosis (P<0.05, respectively). GO-QOL suggested by EUGOGO showed correlation with objective clinical parameters. GO-QOL can be a simple and effective tool in the evaluation of the clinical and psychological illness of GO patients.


The human involucrin gene contains spatially distinct regulatory elements that regulate expression during early versus late epidermal differentiation.
Human involucrin (hINV) is a keratinocyte protein that is expressed in the suprabasal compartment of the epidermis and other stratifying surface epithelia. Involucrin gene expression is initiated early in the differentiation process and is maintained until terminal cell death. The distal regulatory region (DRR) is a segment of the hINV promoter (nucleotides -2473/-1953) that accurately recapitulates the normal pattern of suprabasal (spinous and granular layer) expression in transgenic mouse epithelia. To identify sequences that mediate expression at specific stages of differentiation, we divided the DRR into two segments, a 376 nucleotide upstream region (DRR(-2473/-2100)) and a 147 nucleotide downstream region (DRR(-2100/-1953)), and evaluated the ability of these sequences to drive expression in transgenic mice. The DRR(-2473/-2100) segment drives expression at a level comparable to that observed for the DRR, but expression is restricted to the upper granular layers (i.e., no spinous layer expression). In contrast, the DRR(-2100/-1953) segment does not drive expression. However, reassembling the DRR restores the complete range of expression. These results suggest that two distinct, spatially-separate elements are required to specify the complete differentiation-dependent program of involucrin gene expression. To identify specific transcription factor binding sites involved in this regulation, we mutated an activator protein-1 binding site, AP1-5, located within DRR(-2473/-2100) segment. This site binds AP1 transcription factors present in mouse epidermal extracts, and its mutation eliminates appropriate hINV expression. This result suggests that AP1 factors participate as components of a multi-component transcription factor complex that is required for regulation.


Threats of climate change and land use patterns enhance the susceptibility of future floods in India.
The main objective of this work is the future prediction of the floods in India due to climate and land change. Human activity and related carbon emissions are the primary cause of land use and climate change, which has a substantial impact on extreme weather conditions, such as floods. This study presents high-resolution flood susceptibility maps of different future periods (up to 2100) using a combination of remote sensing data and GIS modelling. To quantify the future flood susceptibility various flood causative factors, Global circulation model (GCM) rainfall and land use and land cover (LULC) data are envisaged. The present flood susceptibility model has been evaluated through receiver operating characteristic (ROC) curve, where area under curve (AUC) value shows the 91.57% accuracy of this flood susceptibility model and it can be used for future flood susceptibility modelling. Based on the projected LULC, rainfall and flood susceptibility, the results of the study indicating maximum monthly rainfall will increase by approximately 40-50 mm in 2100, while the conversion of natural vegetation to agricultural and built-up land is about 0.071 million sq. km. and the severe flood event area will increase by up to 122% (0.15 million sq. km) from now on.


Children and young women in eastern and southern Africa are key to meeting 2030 HIV targets: time to accelerate action.
New HIV infections and AIDS-related deaths among children and adolescent girls and young women (aged 15-24 years) in eastern and southern Africa continue to occur at unacceptably high rates. The COVID-19 pandemic has also severely undermined ongoing initiatives for HIV prevention and treatment, threatening to set the region back further in its efforts to end AIDS by 2030. Major impediments exist to attaining the UNAIDS 2025 targets among children, adolescent girls, young women, young mothers living with HIV, and young female sex workers residing in eastern and southern Africa. Each population has specific but overlapping needs with regard to diagnosis and linkage to and retention in care. Urgent action is needed to intensify and improve programmes for HIV prevention and treatment, including sexual and reproductive health services for adolescent girls and young women, HIV-positive young mothers, and young female sex workers.


Free vascularized fibular grafts in the treatment of congenital pseudarthrosis of the tibia.
Five patients with congenital pseudarthrosis of the tibia treated by a free vascularized fibular graft are described. Follow-up evaluation ranged from 15 to 81 months, with a mean of 40 months. Bony union was attained in three of five cases as determined roentgenographically. The remaining two cases failed to attain bony union. All cases except one, who was treated with a below-knee amputation, subsequently attained bony union. However, four cases had five fractures after bony union. We discussed unsolved problems regarding the free vascularized fibular graft and fracture after bony union.


Neuromelanin accumulation in patients with schizophrenia: A systematic review and meta-analysis.
Although schizophrenia is associated with increased presynaptic dopamine function in the striatum, it remains unclear if neuromelanin levels, which are thought to serve as a biomarker for midbrain dopamine neuron function, are increased in patients with schizophrenia. We conducted a systematic review and meta-analysis of magnetic resonance imaging (MRI) and postmortem studies comparing neuromelanin (NM) levels between patients with schizophrenia and healthy controls (HCs). Standard mean differences were calculated to assess group differences in NM accumulation levels between patients with schizophrenia and HCs. This study included 7 articles in total. Five studies employed NM-sensitive MRI (NM-MRI) and two were postmortem brain studies. The patient group (n = 163) showed higher NM levels in the substantia nigra (SN) than HCs (n = 228) in both the analysis of the seven studies and the subgroup analysis of the 5 NM-MRI studies. This analysis suggest increased NM levels in the SN may be a potential biomarker for stratifying schizophrenia, warranting further research that accounts for the heterogeneity of this disorder.


Fezl is required for the birth and specification of corticospinal motor neurons.
The molecular mechanisms controlling the differentiation of neural progenitors into distinct subtypes of neurons during neocortical development are unknown. Here, we report that Fezl is required for the specification of corticospinal motor neurons and other subcerebral projection neurons, which are absent from Fezl null mutant neocortex. There is neither an increase in cell death in Fezl(-/-) cortex nor abnormalities in migration, indicating that the absence of subcerebral projection neurons is due to a failure in fate specification. In striking contrast, other neuronal populations in the same and other cortical layers are born normally. Overexpression of Fezl results in excess production of subcerebral projection neurons and arrested migration of these neurons in the germinal zone. These data indicate that Fezl plays a central role in the specification of corticospinal motor neurons and other subcerebral projection neurons, controlling early decisions regarding lineage-specific differentiation from neural progenitors.


Mid trimester amniotic fluid soluble receptor tunica interna endothelial cell kinase-2 levels and risk for preeclampsia.
The purpose of this study was to determine if elevated concentration of soluble receptor tunica interna endothelial cell kinase-2 (Tie-2) in the amniotic fluid represent a risk factor for the subsequent development of preeclampsia (PE). Amniotic fluid samples were collected as a part of routine clinical diagnostics from women referred to clinical care due to genetic indications. A total of 12 women with preeclampsia and 26 normotensive pregnant women were included in the study. Mean gestational age at amniocentesis was 17.92 weeks of pregnancy in preeclampsia and 17.88 in control group, respectively. Concentrations of sTie-2 in the amniotic fluid were determined by a standardized enzyme immunoassay. Median concentration of Tie-2 in the amniotic fluid of PE patients was lower (median 1.109 ng/ml) compared with normotensive pregnant women (median 1.433 ng/Ml) but the difference was not statistically significant (p = 0.2973). Concentration of sTie-2 in the amniotic fluid did not significantly correlate with maternal age, gestational age at amniocentesis or delivery, as well as weight or length at birth. A difference in the gestational age at delivery in PE patients (mean 37.7 weeks) and normotensive pregnant controls (mean 39.8 weeks) was statistically significant (p = 0.0003). Birth weight and length of children delivered by PE women (mean 2863.3 g and 48.3 cm) were significantly lower compared with normal pregnancies (mean 3591.2 g and 51.4 cm, p = 0.0002 and p = 0.006, respectively). Our results suggest that amniotic fluid concentrations of sTie-2 do not predict development of PE and that further studies on biomarkers as predictors of PE should include other angiogenic biological response modifiers.


Mycobacterium fortuitum pacemaker infection: A case report.
Mycobacterium fortuitum is a rapidly growing mycobacterium, ubiquitous in soil and water, but it is an uncommon cause of infections in immunocompetent hosts. Cardiac device infections and bloodstream infections due to non-tuberculous mycobacteria are rare. We present the case of an 85-year-old patient with infective endocarditis and pacemaker lead infection secondary to M. fortuitum.


Idiotypic properties of the murine anti-arsonate antibody response: B- and T-cell influences.
In a previous report characterizing the arsonate (ABA)-specific plaque-forming cell (PFC) responses of A/J mice induced by ABA-KLH, two interesting characteristics of the idiotypic (Id) profile were noted: (1) an apparent Id selectivity in the isotype switch since the earliest appearing IgG PFC in the primary response were significantly more "cross-reactive Id" (CRI)-dominant than the IgM PFC population, and, (2) a temporal waning of CRI dominance with time among IgG PFC, from 75-100% CRI+ PFC to about 25-45% CRI+ PFC in secondary responses. Experiments were performed to determine whether these effects are largely attributable to T or to B cells. Mice were immunized with a T-independent (TI) form of ABA (ABA-Brucella abortus) and apparent Id selectivity was observed; the earliest IgG PFC averaged 75% CRI+ while IgM PFC were only 39% CRI+. Due to the TI nature of the Ag, this provides suggestive, but not conclusive, evidence that the Id asymmetry in the isotype switch may be attributable to the direct interaction of Ag with B cells. Other studies addressed the temporal shift in CRI dominance. First, it was found that preexposure of mice to either KLH or to ABA (on an irrelevant carrier) resulted in diminished CRI dominance in subsequent "primary" responses to ABA-KLH. Secondly, adoptive transfer experiments with B and T cells from virgin mice (Bv, Tv) or ABA-KLH-primed mice (Bp, Tp) showed that recipients of Bv + Tp or Bp + Tv generated anti-ABA PFC responses with intermediate CRI levels. The Tv cells had some preferential tendency to activate CRI+ clones in the Bp population. The results demonstrate that CRI levels are jointly determined by the immune status of both B and T cells. A simple model is offered which accounts for early Id dominance and its gradual decline and has as its central postulate the assumption that CRI+ B cells in the virgin ABA-specific repertoire have an affinity advantage over CRI- clones.


Single-layer end-on continuous suture of colonic anastomoses.
The single-layer end-on continuous suture technique for intestinal anastomoses on mobile intraperitoneal bowel segments is at least as safe and probably safer than a corresponding single-layer interrupted suture technique. Although the evaluation of this technique included a substantial number of surgeons who were performing their first anastomosis or who contributed only a single one to the series in a teaching university setting, there were no instances of clinical leak among 143 consecutive colonic anastomoses. Furthermore, 27 percent of the operations were performed as emergencies, thus optimal bowel preparation was lacking. The anastomosis time is distinctly shorter than the time needed for an interrupted single-layer technique, and contamination of the operative field is reduced to a minimum. The anastomosis is extremely simple, comfortable to perform, and reliable.


Interleukin-1 is identical to hemopoietin-1: studies on its therapeutic effects on myelopoiesis and lymphopoiesis.
Conditioned medium from the human tumor cell line HBT 5637 possesses a unique hematopoietic activity, originally termed hemopoietin-1. Hemopoietin-1 alone does not stimulate bone marrow colony formation or proliferative responses in vitro, but rather potentiates responses to other hematopoietic growth factors, such as CSF-1 and GM-CSF. In studies designed to characterize the molecular nature of this factor, it was found by molecular, biochemical biological and serological criteria that all the hemopoietin-1 like activity could be attributed to IL-1 alpha. The therapeutic potential of IL-1 was then tested in a system where myelopoiesis is depressed by whole body irradiation. After 750 R irradiation, mice were administered IL-1 twice daily for the duration of the experiment. Mice which received IL-1 treatment had an accelerated recovery of marrow colony forming capacity which was also reflected by significantly higher blood neutrophil levels as compared to control irradiated mice. IL-1 treated irradiated mice also had a significant increase in resistance to bacterial challenge 14 days post irradiation. Thus, IL-1 treatment was effective in augmenting myelopoiesis following sublethal whole body irradiation. The effects of the IL-1 treatment on the recovery of lymphocyte numbers was also assessed. Here the IL-1 treated irradiated mice had fewer lymphocytes and depressed mitogen responses by spleen cells. Indeed the thymus of the IL-1 treated irradiated mice remained chronically hypoplastic for the duration of the experiment. Although IL-1 treatment increased myeloid progenitors in the bone marrow, it caused a decrease in the frequency of pre-B cells. Thus, IL-1 administration is an effective treatment for accelerating myeloid recovery following the cytoreductive effects of irradiation, but the myelopoietic augmentation may be at the expense of lymphoid recovery.


"Babies born early?" - silences about prematurity and their consequences.
The principal aim of this study was to understand how communication between parents and health professionals concerning prematurity occurs, from delivery to admission to the neonatal Intensive Care Unit. This is an exploratory, descriptive study with a qualitative methodology. Data were collected using tape-recorded and Focal Groups technique interview with mothers of premature newborns and health professionals involved in caring for preterm infants, at southeast Brazil. The word "premature" was not said or heard during prenatal care. From the narratives, it was observed that there was a lack of information available to pregnant women about preterm birth, failure in medical care regarding signs and symptoms reported by pregnant women, and lack of communication between the medical teams, mothers and family during delivery and Neonatal Intensive Care Unit (NICU) admission. There is a fine line between born too soon and die too soon, that increases stress, fear and distance impacting negatively over communication between mothers and health professionals during antenatal care, childbirth and NICU admission.


Identification of two highly performing Leishmania infantum antigens for serodiagnosis of canine leishmaniosis.
In the aim of improving serodiagnosis of canine leishmaniosis, we analysed the humoral immune response of dog against Leishmania infantum parasite. The antigenic reaction of L. infantum polypeptides with sera from 31 dogs with parasitologically confirmed leishmaniosis was studied by using the immunoblot technique. Electrophoretic profile of the parasite extract showed more than 50 polypeptides, with molecular weights ranging from 12 to 170 kDa. Among these polypeptides, 37 antigen components, ranging from 14 to 91 kDa, were recognised by antibodies of L. infantum infected dogs. Three polypeptides (14, 16 and 76 kDa) reacted with all of the 31 serum samples. The other most frequently recognised antigens were those of 29.5, 32, 46, 59 and 66 kDa with a sensitivity of 87.1%, 93.6%, 96.8%, 87.1% and 80.6%, respectively. The 14 and 16 kDa bands were the most intense and remained detectable until a serum dilution of 1:6400. No reaction of these two major antigens was observed with sera collected from 50 Leishmania-free dogs, living in the leishmaniosis-free region of Rabat in Morocco, whereas the crude antigen used in IFAT or ELISA lead to three false positive results. Four antigen components of 29, 41, 55, and 70 kDa were recognised by some sera samples from negative controls. These results demonstrated the potential interest of the fractions of 14 and 16 kDa in immunodiagnosis of canine leishmaniosis.


Rapid versus slow ascending vasodilatation: intercellular conduction versus flow-mediated signalling with tetanic versus rhythmic muscle contractions.
In response to exercise, vasodilatation ascends from downstream arterioles into upstream feed arteries (FAs). We hypothesized that the signalling events underlying ascending vasodilatation variy with the intensity and duration of skeletal muscle contraction. In the gluteus maximus muscle of C57BL/6 mice, brief tetanic contraction evoked rapid onset vasodilatation (ROV) (<1 s) throughout the resistance network. Selective damage to endothelium midway between FAs and primary arterioles eliminated ROV only in FAs. Blocking SKCa and IKCa channels attenuated ROV, implicating hyperpolarization as the underlying signal. During rhythmic twitch contractions, slow onset vasodilatation (10-15 s) in FAs remained intact following loss of ROV and was eliminated following nitric oxide synthase inhibition. Tetanic contraction initiates hyperpolarization that conducts along endothelium into FAs. Rhythmic twitch contractions stimulate FA endothelium to release nitric oxide in response to elevated shear stress secondary to metabolic dilatation of arterioles. Complementary endothelial signalling pathways for ascending vasodilatation ensure increased oxygen delivery to active skeletal muscle. In response to exercise, vasodilatation initiated within the microcirculation of skeletal muscle ascends the resistance network into upstream feed arteries (FAs) located external to the tissue. Ascending vasodilatation (AVD) is essential for reducing FA resistance that otherwise restricts blood flow into the microcirculation. In the present study, we tested the hypothesis that signalling events underlying AVD vary with the intensity and duration of muscle contraction. In the gluteus maximus muscle of anaesthetized male C57BL/6 mice (aged 3-4 months), brief tetanic contraction (100 Hz for 500 ms) evoked rapid onset vasodilatation (ROV) in FAs that peaked within 4 s. By contrast, during rhythmic twitch contractions (4 Hz), slow onset vasodilatation (SOV) of FAs began after ∼10 s and plateaued within 30 s. Selectively damaging the endothelium with light-dye treatment midway between a FA and its primary arteriole eliminated ROV in the FA along with conducted vasodilatation of the FA initiated on the arteriole using ACh microiontophoresis. Superfusion of SKCa and IKCa channel blockers UCL 1684 + TRAM 34 attenuated ROV, implicating endothelial hyperpolarization as the underlying signal. Nevertheless, the SOV of FAs during rhythmic contractions persisted until inhibition of nitric oxide synthase with Nω -nitro-l-arginine methyl ester. Thus, ROV of FAs reflects hyperpolarization of downstream arterioles that conducts along the endothelium into proximal FAs. By contrast, SOV of FAs reflects the local production of nitric oxide by the endothelium in response to luminal shear stress, which increases secondary to arteriolar dilatation downstream. Thus, AVD ensures increased oxygen delivery to active muscle fibres by reducing upstream resistance via complementary signalling pathways that reflect the intensity and duration of muscle contraction.


Adjunctive ultrasonography to minimize iodinated contrast administration during carotid artery stenting: a randomized trial.
To report a single-center, prospective randomized controlled trial that compared contrast use during ultrasound-assisted carotid artery stenting (CAS) to CAS procedures without ultrasound. Between August 2010 and November 2011, 22 patients (18 men; mean age 72.8 years, range 62-84) with 25 severe symptomatic (n=3) or asymptomatic (n=22) carotid stenoses undergoing an endovascular intervention were randomly allocated (~1.1) to ultrasonography-assisted (n=13) or stand-alone (n=12) CAS. The primary endpoints were contrast use and number of selective cerebral injections. Secondary endpoints were procedure time, fluoroscopy time, any stroke, renal function assessment, major adverse cardiac events (MACE), and death. In the study period, 23 of 25 scheduled CAS procedures (12 ultrasound-assisted, 11 control) were completed in 20 patients; 2 procedures were aborted owing to friable plaque and difficult guidewire access, respectively. There were no deaths, stroke, MACE, or precipitation of dialysis-dependent renal failure in either group. Iodinated contrast usage was reduced by 61% (45.4±24.4 vs. 17.8±11.9 mL, p=0.002) and number of selective cerebral contrast injections by 49% (8.3 vs. 4.2, p=0.002). Neither time taken to complete the procedure (32.5 vs. 35.4 minutes, p=0.38) nor fluoroscopy time (14.5 vs. 13.9 minutes, p=0.54) differed significantly between the groups. Creatinine levels remained stable after CAS and did not differ between groups. Ultrasonography-assisted CAS is feasible and safe. Its use can significantly lower the usage of iodinated contrast and the number of selective cerebral circulation injections while not prolonging the length of the procedure or the fluoroscopy time.


Salvia divinorum: an hallucinogenic mint which might become a new recreational drug in Switzerland.
Salvia divinorum Epling & Jativa is an hallucinogenic mint traditionally used for curing and divination by the Mazatec Indians of Oaxaca, Mexico. Young people from Mexican cities were reported to smoke dried leaves of S. divinorum as a marijuana substitute. Recently, two S. divinorum specimens were seized in a large-scale illicit in-door and out-door hemp plantation. Salvinorin A also called divinorin A, a trans-neoclerodane diterpene, was identified in several organic solvent extracts by gas chromatography-mass spectrometry. The botanical identity of the plant was confirmed by comparing it to an authentic herbarium specimen. More plants were then discovered in Swiss horticulturists greenhouses. All these data taken together suggest that many attempts exist in Switzerland to use S. divinorum as a recreational drug. This phenomenon may be enhanced because neither the magic mint, nor its active compound are banned substances listed in the Swiss narcotic law.


Serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine in lung transplant recipients.
Lung transplant recipients have an increased risk for severe coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A third dose of a SARS-CoV-2 vaccine has been recommended for all solid organ transplant recipients, but data from lung transplant recipients specifically are scarce. In this study, the serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine was measured in 78 lung transplant recipients. Sixty-two percent (n = 48) had a serological response to vaccination, which was significantly higher than after the second vaccine dose (27 patients (35%); p = 0.0013). A positive serologic response was associated with having had COVID-19 (p = 0.01), and higher serum IgG level and complement mannose binding lectin pathway activity prior to vaccination (p = 0.04 and p = 0.03, respectively). Serologic response was not associated with the dose of mycophenolate mofetil or prednisone or other immune status parameters. Eleven patients (14%) developed COVID-19 after the second or third vaccine dose, but this did not associate with serologic response after the second vaccine dose (9% in patients who developed COVID-19 versus 39% in patients who did not develop COVID-19 (p = 0.09)), or with serologic response above cut-off values associated with clinical protection in previous studies. In conclusion, the response to mRNA-based SARS-CoV-2 vaccines in lung transplant recipients improves significantly after a third vaccine dose. Factors associated with a positive serologic response are having had COVID-19 prior to vaccination, and serum IgG and complement mannose binding lectin pathway activity prior to vaccination. Serologic response did not associate with clinical protection against COVID-19 in this study.


New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition.
We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains.


Alterations of NMDA receptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain ischemia.
Glutamate excitotoxicity mediated by NMDA receptor activation plays a key role in many aspects of ischemic brain injury, but the expression of NMDA receptor subunits NR1, NR2A and NR2B mRNA and their relationship to apoptosis is still unclear. In this study, we applied in situ hybridization and TUNEL staining to investigate the expression of NMDA receptor subunit mRNA and apoptosis in hippocampus of rats after transient forebrain ischemia. The results showed that in the CA1 region, NR1 mRNA expression was significantly increased following ischemia-reperfusion (IR), reaching peak levels at IR 24h, and then gradually decreasing until IR 7 days. NR2A and NR2B mRNA expression dropped to lowest levels at IR 6h and IR 12h, respectively, and then started to recover. The mRNA expression of both NR2A and NR2B then increased to peak levels at IR 48h, followed by a sustained decline until IR 7 days. In the CA3 region and dentate gyrus the range of variation in mRNA expression was significantly reduced gradually. At IR 24h, apoptosis-positive cells were observed mainly in the CA1 region. The number of apoptosis-positive cells continuously grew and showed a dramatic increase at IR 48h and peaked at IR 72h. Then, the number of apoptosis-positive cells started to decrease, but at IR 7 days the apoptosis-positive cells still remained. These results indicate that the alterations of NMDA receptor subunit mRNA expression may contribute to the ischemic apoptosis of hippocampus after transient forebrain ischemia.


Study of surface enhanced fluorescence of CdSeS/ZnS alloyed quantum dots using cytop layer as a dielectric spacer.
Recently, the surface enhanced fluorescence technique has been helpful for several biological applications. Some researchers have reported the SEF of fluorophores such as dye molecules and QDs using dielectric spacers formed by several approaches. Herein, for the first time, we report the SEF spectra of CdSeS/ZnS alloyed quantum dots (QDs) that have high photostability, less toxicity, and high biocompatibility. Interestingly, the thin cytop layers formed by a simple approach are used as "dielectric spacers" between Au nanoparticles in the plasmon-active substrate (PAS) and the QDs. For comparison, the spectra of QDs dispersed directly on (i) bare PAS, (ii) bare glass substrate, and (iii) cytop coated glass substrate are also recorded. The enhancement factor is found to vary from one to two orders of magnitude. Since the SEF enhancement depends on the electric field intensity enhancement (EFIE) in the PASs, Finite Element Method (FEM) simulations are performed to estimate the EFIE and its dependence on the thickness of the cytop layer and size of the nanogap between nanoparticles in the PASs.


Agreement between factor XIII activity and antigen assays in measurement of factor XIII: A French multicenter study of 147 human plasma samples.
Factor XIII (FXIII) deficiency is a rare hemorrhagic disorder whose early diagnosis is crucial for appropriate treatment and prophylactic supplementation in cases of severe deficiency. International guidelines recommend a quantitative FXIII activity assay as first-line screening test. FXIII antigen measurement may be performed to establish the subtype of FXIII deficiency (FXIIID) when activity is decreased. The aim of this multicenter study was to evaluate the analytical and diagnostic levels of performance of a new latex immunoassay, K-Assay® FXIII reagent from Stago, for first-line measurement of FXIII antigen. Results were compared to those obtained with the Berichrom® FXIII chromogenic assay for measurement of FXIII activity. Of the 147 patient plasma samples, 138 were selected for analysis. The accuracy was very good, with intercenter reproducibility close to 7%. Five groups were defined on FXIII activity level (<5% (n = 5), 5%-30% (n = 23), 30%-60% (n = 17), 60%-120% (n = 69), above 120% (n = 24)), without statistical differences between activity and antigen levels (P value >0.05). Correlation of the K-Assay® with the Berichrom® FXIII activity results was excellent (r = 0.919). Good agreement was established by the Bland and Altman method, with a bias of +9.4% on all samples, and of -1.4% for FXIII levels lower than 30%. One patient with afibrinogenemia showed low levels of Berichrom® FXIII activity but normal antigen level and clot solubility as expected. The measurement of FXIII antigen using the K-Assay® is a reliable first-line tool for detection of FXIII deficiency when an activity assay is not available.


Metformin alters insulin signaling and viability of human granulosa cells.
To study whether insulin signaling pathways in the ovary are altered by metformin. In vitro human granulosa cell culture system. Academic research environment. Infertility patients undergoing oocyte retrieval for IVF/ICSI. Cell viability and phosphorylated protein kinase B (PKB/AKT) and p44/42 mitogen-activated protein kinase (MAPK) expression of human primary and HGL5 granulosa cells. Basal cell viability of primary granulosa cells was significantly increased relative to control by metformin preincubation, without an additional stimulatory effect of insulin or IGF. Phosphorylated AKT expression in lysates of the human granulosa cell line HGL5 was significantly increased in contrast to decreased phosphorylated MAPK expression by metformin preincubation. Besides systemic effects, the ovulation inducing action of metformin may at least partially be due to direct effects on insulin signaling intermediates and follicular growth patterns in the ovary.


Adenosquamous carcinoma of the colon.
Two cases of primary adenosquamous carcinomas of the sigmoid colon and rectum are presented. Clinical features and pathologic findings of both primary and metastatic lesions are reported (including immunohistochemistry and electron microscopy). We emphasize that the presence of a metastatic squamous tumor in a patient with an unknown primary does not exclude the possibility of colonic carcinoma. Comparison with other reports in the American medical literature indicates that these are very aggressive tumors that may have a worse prognosis than the more common form of colonic adenocarcinoma. Furthermore, the squamous component, in particular, may have a greater potential for metastasizing and can do so as an undifferentiated-appearing carcinoma. In view of this, the authors suggest that very poorly differentiated areas within colonic adenocarcinomas should be very carefully evaluated by means of immunoperoxidase stains and/or electron microscopy in an attempt to identify squamous features.


Selective neuronal vulnerability in Alzheimer's disease.
Alzheimer's disease (AD) is defined by a deficiency in specific behavioural and/or cognitive domains, pointing to selective vulnerabilities of specific neurons from different brain regions. These vulnerabilities can be compared across neuron subgroups to identify the most vulnerable neuronal types, regions, and time points for further investigation. Thus, the relevant organizational frameworks for brain subgroups will hold great values for a clear understanding of the progression in AD. Presently, the neuronal vulnerability has yet urgently required to be elucidated as not yet been clearly defined. It is suggested that cell-autonomous and non-cell-autonomous mechanisms can affect the neuronal vulnerability to stressors, and in turn modulates AD progression. This review examines cell-autonomous and non-cell-autonomous mechanisms that contribute to the neuronal vulnerability. Collectively, the cell-autonomous mechanisms seem to be the primary drivers responsible for initiating specific stressor-related neuronal vulnerability with pathological changes in certain brain areas, which then utilize non-cell-autonomous mechanisms and result in subsequent progression of AD. In summary, this article has provided a new perspective on the preventative and therapeutic options for AD.


Internal Fixation of Finger Fractures: Field Sterility for Surgery and Earlier Removal of K-Wires Are Safe.
Field sterility for K-wire insertion outside the main operating room is much cheaper and greener (ie, there is less waste). It permits increased access to more affordable surgery because unnecessary sedation and full sterility are eliminated. Early pain-guided protected movement of K-wired finger fractures at 3 to 5 days leads to less stiffness. It will not result in loss of reduction or infection around K-wires if patients avoid "pain" (ie, do not perform movements that hurt). Early protected movement and early removal of K-wires at 2 to 4 weeks contribute to less stiffness after operative hand/finger fracture reduction and stabilization.


Localization of 5-hydroxytryptamine to neurons and endoneurial mast cells in rat sensory ganglia.
5-Hydroxytryptamine (5-HT) localization has been studied in the spinal and trigeminal ganglia of adult rats using immunofluorescence, peroxidase-antiperoxidase immunocytochemistry and [3H] 5-HT uptake radioautography, the latter two at the ultrastructural level. Endoneurial mast cells, identified by alcian blue staining, formed 8 and 14% of all mast cells and neurons in spinal and trigeminal ganglia respectively and had a median diameter of 7.6 microns. Light and electron microscopic immunocytochemistry showed that these mast cells contained 5-HT-like immunoreactivity. Some 75% of them accumulated exogenous [3H]5-HT in vitro. A population of small-diameter neurons, which did not stain with alcian blue, was also labelled with anti-5-HT serum and accumulated [3H]5-HT. The possible roles of 5-HT in sensory ganglia are discussed.


Implementing daily soft tissue image guidance with reduced margins for post-prostatectomy radiotherapy: research-based changes to clinical practice.
We have previously demonstrated that daily soft tissue matching with reduced anisotropic margins provides an ideal balance between prostate bed coverage and meeting organ at risk constraints. The aim of this study was to evaluate the implementation of this approach in clinical practice. Thirty-eight radiation therapists (RTs) completed offline IGRT training involving six patients. After training was completed, this approach was implemented clinically. The first 24 patients were evaluated with a central review of match displacements and geographic miss (GM). An assessment of treatment times and planning parameters was also performed. During offline training, the anterior-posterior (AP) match discrepancy had the largest mean variation ranging from -0.46 to 0.06 cm and undetected geographic miss occurred in 17% of alignments. The mean time taken to treat the first 24 patients ranged from 12.2 to 20.6 min. The smaller anisotropic margin resulted in similar target coverage but achieved reduced doses to the bladder (V65Gy from 36% to 27%, V40Gy from 54% to 51%) and rectum (V65Gy from 20% to 19%, V60Gy from 27% to 24%, V40Gy from 42% to 38%). The matches of 806 CBCT images in 24 patients were reviewed. The mean match ranged from -0.12 to 0.17 cm AP, -0.14 to 0.14 cm superior-inferior (SI) and -0.04 to 0.04 cm left-right (LR). An undetected geographic miss was found in the prostate bed in 17 (2.1%) images and lymph nodes in 2 (0.2%) images. Daily soft tissue IGRT with reduced anisotropic margins for post-prostatectomy radiotherapy has been successfully implemented. RTs performed better with real-time online matching than they did in offline training, perhaps influenced by having several RTs perform online matching. Daily soft tissue IGRT did not prolong treatment time.


[Ionic mechanisms of burst activity in grape snail neurons].
The membrane steady-state current-voltage relations and ionic current developing under membrane potential shifts were investigated in the snail bursting neurons by the clamp method. The steady-state current-voltage relation revealed a nonlinear region. Replacement of sodium by tris-HCl completely removed this region. The membrane hyperpolarization resulted in the development of an outward current which became inactivated after achieving its maximum. The reversal potential of the outward current was about --55 mV. The membrane depolarization led to a slow inward current which also inactivated. The ionic nature of these membrane currents is discussed and a model of slow wave generation in the bursting neurons is suggested.


Author Correction: Exome sequencing of Finnish isolates enhances rare-variant association power.
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.


Phenol sensing in nature is modulated via a conformational switch governed by dynamic allostery.
The NtrC family of proteins senses external stimuli and accordingly stimulates stress and virulence pathways via activation of associated σ54-dependent RNA polymerases. However, the structural determinants that mediate this activation are not well understood. Here, we establish using computational, structural, biochemical, and biophysical studies that MopR, an NtrC protein, harbors a dynamic bidirectional electrostatic network that connects the phenol pocket to two distal regions, namely the "G-hinge" and the "allosteric linker." While the G-hinge influences the entry of phenol into the pocket, the allosteric linker passes the signal to the downstream ATPase domain. We show that phenol binding induces a rewiring of the electrostatic connections by eliciting dynamic allostery and demonstrates that perturbation of the core relay residues results in a complete loss of ATPase stimulation. Furthermore, we found a mutation of the G-hinge, ∼20 Å from the phenol pocket, promotes altered flexibility by shifting the pattern of conformational states accessed, leading to a protein with 7-fold enhanced phenol binding ability and enhanced transcriptional activation. Finally, we conducted a global analysis that illustrates that dynamic allostery-driven conserved community networks are universal and evolutionarily conserved across species. Taken together, these results provide insights into the mechanisms of dynamic allostery-mediated conformational changes in NtrC sensor proteins.


Synergic quantum generative machine learning.
We introduce a new approach towards generative quantum machine learning significantly reducing the number of hyperparameters and report on a proof-of-principle experiment demonstrating our approach. Our proposal depends on collaboration between the generators and discriminator, thus, we call it quantum synergic generative learning. We present numerical evidence that the synergic approach, in some cases, compares favorably to recently proposed quantum generative adversarial learning. In addition to the results obtained with quantum simulators, we also present experimental results obtained with an actual programmable quantum computer. We investigate how a quantum computer implementing generative learning algorithm could learn the concept of a maximally-entangled state. After completing the learning process, the network is able both to recognize and to generate an entangled state. Our approach can be treated as one possible preliminary step to understanding how the concept of quantum entanglement can be learned and demonstrated by a quantum computer.


The dopamine D₁ receptor agonist (S)-[¹¹C]N-methyl-NNC 01-0259 is not sensitive to changes in dopamine concentration--a positron emission tomography examination in the monkey brain.
Dopamine D₂ receptor positron emission tomography (PET) radioligands have proven useful for indirect assessment of the endogenous dopamine concentration in the living brain. On the contrary, dopamine D₁ receptor antagonist radioligands have shown no sensitivity to changes in the dopamine concentration. A recent approach to enhance the sensitivity of radioligands to the dopamine concentration has been the development of dopamine D₂ receptor agonist radioligands. The aim of this study was to evaluate the dopamine sensitivity of a dopamine D₁ receptor agonist radioligand. For this purpose, we developed (S)-[¹¹C]N-methyl-NNC 01-0259 ((S)-[¹¹C]1) and characterized the receptor binding of (S)-[¹¹C]1 using in vitro receptor binding assays and in vivo PET measurements in monkeys. In vitro, both enantiomers of 1 were partial dopamine D₁ receptor agonists, with (S)-1 having a 10-50 times higher affinity than (R)-1. PET studies in monkey confirmed the stereoselectivity of [¹¹C]1 in vivo. In monkey, administration of the dopamine D₁-like receptor antagonist (R)-(+)-SCH 23390 decreased the striatal binding potential of (S)-[¹¹C]1 by 97%, but administration of the dopamine concentration enhancer d-amphetamine did not affect (S)-[¹¹C]1 binding. We conclude that the agonist (S)-[¹¹C]1 provides specific binding to dopamine D₁-like receptors, possibly representing binding to the high-affinity state of the receptors. The partial dopamine D₁ receptor agonist radioligand has, however, no enhanced sensitivity to endogenous dopamine concentrations in comparison with antagonist radioligands.


An on-membrane quantitative analysis system for glycyrrhizin in licorice roots and traditional Chinese medicines.
An on-membrane quantitative analysis system has been developed for determining glycyrrhizin (GC) in licorice roots and traditional Chinese medicines. A GC standard and the extracts of licorice roots and traditional Chinese medicines were applied to a polyethersulfone (PES) membrane and were developed by acetonitrile/water/formic acid (45:55:2, by volume), then treated with a NaIO4 solution followed by bovine serum albumin (BSA), resulting in a GC-BSA conjugate on a PES membrane. Anti-GC monoclonal antibody was bound and then a second antibody labeled with peroxidase directed against the first antibody. Finally a substrate reacted with the enzyme and gave staining. The stained membrane was scanned and coloring spots were analyzed quantitatively using graphic analysis by NIH Image software, indicating at least 0.5 microg of GC was clearly detectable. GC can be analyzed quantitatively between 1.0 and 8.0 microg.


The influence of education and personality on risk propensity in nurse managers.
The current healthcare environment is demanding innovation. Nurse managers are positioned strategically to creatively change and innovate the patient care delivery process, if they are willing to take risks. The authors discuss a study that tests whether a nurse manager's education, years of experience, and personality are related to their propensity to take risks in administrative decision making. Results of the study indicate that nurse managers who achieved at least a bachelors degree, had higher autonomy orientations, and had lower control orientations were more likely to choose higher risk options in nursing administrative decisions. The authors found that self-esteem and years of experience were not related to nurse manager risk propensity.


Sclerotherapy for superficial venules and telangiectasias of the lower extremities.
Sclerotherapy remains the best single treatment for telangiectasias and superficial venules of the lower extremities. It has been used successfully for decades. It is, however, a somewhat tedious and time-consuming procedure and requires great patience on the part of the physician. With careful attention to the details of the procedure and with necessary practice and experience on the part of the physician, a good result will be obtained. To summarize: Use one of the safe, modern sclerosing solutions: hypertonic sodium chloride 18 to 25 per cent, Aethoxysklerol 0.25 to 1.0 per cent, or Sclerodex. Good illumination, liberal use of alcohol on the skin, and 2 to 3 X magnification will increase the visibility of the tiny vessels. Use 3-ml Luer-Lok syringes and 30-gauge needles and thread the needle carefully into the vessel while using slow and steady injection with light pressure. Always provide post-treatment compression with cotton balls, tape, and compression hosiery. Because the majority of patients are most gratified, serious risks are minimal, and most side effects are of a transitory nature, sclerotherapy is a most worthwhile technique to master and include in one's armamentarium of simple, office-based cosmetic dermatologic procedures.


Lipidomics: new approaches to the studies of cell signaling and prospects of use in medicine.
A new modern stage in the development of lipid biochemistry is presented: lipidomics, which emerged on the basic of new highly sensitive fractionation methods, primarily, mass spectroscopy. Lipidomics is defined mainly as systemic evaluation of all molecular types of lipids in an object, their cell functions, and molecules with which they react. Lipidomic approaches identifying picomole levels of individual lipids in combination with modern genome technology provide detailed information about the involvement of minor phospholipids in the cell signaling processes. Brief data on the functions of lysophospholipids as second messengers of signal transfer, their effects on cell processes, and possible involvement in the pathogenesis of some diseases are presented. It is expected that introduction of lipidomics in biomedical studies will promote the detection of targets for new drugs and development of new diagnostic tests.


Surface-Induced Dissociation for Protein Complex Characterization.
Native mass spectrometry (nMS) enables intact non-covalent complexes to be studied in the gas phase. nMS can provide information on composition, stoichiometry, topology, and, when coupled with surface-induced dissociation (SID), subunit connectivity. Here we describe the characterization of protein complexes by nMS and SID. Substructural information obtained using this method is consistent with the solved complex structure, when a structure exists. This provides confidence that the method can also be used to obtain substructural information for unknowns, providing insight into subunit connectivity and arrangements. High-energy SID can also provide information on proteoforms present. Previously SID has been limited to a few in-house modified instruments and here we focus on SID implemented within an in-house-modified Q Exactive UHMR. However, SID is currently commercially available within the Waters Select Series Cyclic IMS instrument. Projects are underway that involve the NIH-funded native MS resource (nativems.osu.edu), instrument vendors, and third-party vendors, with the hope of bringing the technology to more platforms and labs in the near future. Currently, nMS resource staff can perform SID experiments for interested research groups.


Adoption of clinical decision support systems in a developing country: Antecedents and outcomes of physician's threat to perceived professional autonomy.
The basic objective of this research is to study the antecedents and outcomes of professional autonomy which is a central construct that affects physicians' intention to adopt clinical decision support systems (CDSS). The antecedents are physicians' attitude toward knowledge sharing and interactivity perception (about CDSS) and the outcomes are performance expectancy and intention to adopt CDSS. Besides, we include (1) the antecedents of attitude toward knowledge sharing-subjective norms, social factors and OCB (helping behavior) and (2) roles of physicians' involvement in decision making, computer self-efficacy and effort expectancy in our framework. Data from a stratified sample of 335 Malaysian physicians working in 12 public and private hospitals in Malaysia were collected to test the hypotheses using Structural Equation Modeling (SEM). The important findings of our research are: (1) factors such as perceived threat to professional autonomy, performance expectancy, and physicians' involvement in making decision about CDSS have significant impact on physicians' intention to adopt CDSS; (2) physicians' attitude toward knowledge sharing, interactivity perception and computer self-efficacy of physicians play a crucial role in influencing their perceived threat to professional autonomy; and (3) social network, shared goals and OCB (helping behavior) impact physicians' attitude toward knowledge sharing. The findings provide a comprehensive understanding of the factors that influence physicians' intention to adopt CDSS in a developing country. The results can help hospital managers manage CDSS implementation in an effective manner.