New chromogenic peptide substrates for factor X.
The factor Xa-sensitive substrate BZ-Ile-Glu-Gly-Arg-p-nitroanilide has been made more sensitive by making ester and amide derivatives of the gamma-carboxyl group of the glutamyl residue. The morpholinyl and piperidyl amides react 2.5 times more rapidly with factor Xa.


Organic ultraviolet filters regulate hyaluronan metabolism in human epidermal keratinocytes through the phosphatidylinositol 3-kinase pathway.
Chronic exposure of skin to ultraviolet (UV) radiation is responsible for skin ageing, which includes degradation of the epidermal and dermal layers. Filtering UV light is key in the sunscreen industry. We studied the effects of organic UV filters on hyaluronan (HA) metabolism and skin hydration in human HaCaT keratinocytes. The gene expression of HA receptors, HA synthase (HAS), hyaluronidase (HYAL), and water channel aquaporin 3 (AQP3) was evaluated by quantitative RT-PCR. The state of oxidative stress was determined by measuring the intracellular levels of reactive oxygen species (ROS). The results showed that five organic UV filters reduced the extracellular contents of HA, and a phosphatidylinositol 3-kinase (PI3K) inhibitor partially restored the decreased HA levels after octinoxate, octocrylene, and oxybenzone treatment. The expression levels of HA receptors, including cluster of differentiation 44 (CD44), receptor for hyaluronic acid-mediated motility (RHAMM), and toll-like receptors (TLRs), were determined. Avobenzone, octinoxate, oxybenzone, and padimate O exerted inhibitory effects on RHAMM expression. Oxybenzone led to a significant increase in CD44 and AQP3 expression. Both octinoxate and octocrylene increased TLR4 expression but decreased ROS accumulation by activating the PI3K pathway. However, the organic UV filters differentially regulated the mRNA expression of HAS and HYAL. Taken together, these results suggest that certain organic UV filters regulate HA metabolism in human keratinocytes in a PI3K pathway-dependent manner.


Randomised controlled study of conjunctival autograft versus amniotic membrane graft in pterygium excision.
To determine whether amniotic membrane can be used as an alternative to conjunctival autograft after pterygium excision. 287 eyes with either primary or recurrent pterygium were included in this study. All eyes were randomised to undergo conjunctival autograft or amniotic membrane transplantation after pterygium excision by a single surgeon. 106 eyes in primary pterygium and 14 eyes in the recurrent group were treated with conjunctival autograft, and 148 eyes in primary pterygium and 19 eyes in the recurrent group were treated with amniotic membrane transplantation. Patients were followed up at 6 weeks and 6 months after operation. The main outcome measurement was recurrence rate after surgery. In the conjunctival group, the recurrence rate was 12.3%, 21.4% and 13.1% for primary, recurrent and all pterygia, respectively. In the amniotic membrane group, the recurrence rate was 25.0%, 52.6% and 28.1% for primary, recurrent and all pterygia, respectively. The recurrence rate for all pterygia in the amniotic membrane group was significantly higher than that in the conjunctival group (p = 0.003). Amniotic membrane graft had a higher recurrence rate than conjunctival autograft. However, it is an alternative choice, especially for advanced cases with bilateral heads or patients who might need glaucoma surgery later.


The interplay between PEGylated nanoparticles and blood immune system.
During the last two decades, an increasing number of reports have pointed out that the immunogenicity of polyethylene glycol (PEG) may trigger accelerated blood clearance (ABC) and hypersensitivity reaction (HSR) to PEGylated nanoparticles, which could make PEG modification counterproductive. These phenomena would be detrimental to the efficacy of the load and even life-threatening to patients. Consequently, further elucidation of the interplay between PEGylated nanoparticles and the blood immune system will be beneficial to developing and applying related formulations. Many groups have worked to unveil the relevance of structural factors, dosing schedule, and other factors to the ABC phenomenon and hypersensitivity reaction. Interestingly, the results of some reports seem to be difficult to interpret or contradict with other reports. In this review, we summarize the physiological mechanisms of PEG-specific immune response. Moreover, we speculate on the potential relationship between the induction phase and the effectuation phase to explain the divergent results in published reports. In addition, the role of nanoparticle-associated factors is discussed based on the classification of the action phase. This review may help researchers to develop PEGylated nanoparticles to avoid unfavorable immune responses based on the underlying mechanism.


Oral-Health-Related Quality of Life in Children and Adolescents.
This article describes child oral health-related quality of life measures and provides some examples of their use in determining the effect of clinical interventions, such as dental treatment under general anesthesia, orthodontic treatment, and treatment of orofacial clefting.


Establishment of Muller cell cultures from adult rat retina.
During a recent study of the effects of photoreceptor degeneration on Muller cells, we observed that unlike glia from normal adult retinas, glia from degenerating rat retinas could be cultured and maintained in vitro for several weeks. Using a variety of cell type specific antisera, we show that at least 70% of cells in these cultures are derived from Muller cells.


Hospital bed height influences biomechanics during bed egress: A comparative controlled study of patients with Parkinson disease.
Although a significant proportion of patient falls occur during egress from the hospital bed, the biomechanical adaptations during egress from different bed heights are still largely unknown. The purpose of this study was to evaluate the effect of hospital bed height on natural transition during egress in patients with Parkinson disease (PD). Twelve patients with PD and fourteen healthy elderly adults (HEA) were recruited and the natural transition during egress from three different bed heights (low, medium and high) were recorded for each participant using a motion capture system and force plates. The bed egress time, joint kinematics, ground reaction force and center of mass (CoM) were compared using a two-factor repeated ANOVA to determine the effects of three bed heights and two groups. The results showed that patients with PD had a significantly increased bed egress time, decreased peak of pelvis anterior tilt, hip flexion, and anteroposterior distance between pelvis center and CoM compared to HEA. Additionally, both PD and HEA groups increased the peak of trunk, hip and knee flexions to generate forward CoM momentum and joint torque to rise from a low bed height. These findings indicated that patients with PD invoked a more conservative movement pattern than HEA during egress to improve postural stability. The low bed height increased demands of balance and postural control during egress which exacerbates the risk of falls for patients with PD.


Characteristics of elevated aerosol layer over the Indian east coast, Kattankulathur (12.82oN, 80.04°E): A northeast monsoon region.
The elevated aerosol layer (EAL) plays a vital role in weather and climate by modifying the Earth's radiation budget. In the present study, the EAL occurrence and its characteristics in the pre-monsoon season using micropulse lidar (MPL) observations during 2016-2018 and Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) during 2007-2018 over Kattankulathur is being reported. We have collected 147 days (101 cases) of MPL (CALIPSO) observations during clear sky conditions in the pre-monsoon 2016-2018 (2007-2018), out of which EAL is observed for 56 days (61 cases). The EAL width is generally found to be ~2.0 km and occurs between ~1.0 km and 5.0 km. Three different types of EALs are categorized based on their altitudinal occurrence using the zero-crossing method. The EALs with their base at ~1.0-1.5 km, ~1.5-2.0 km, and ~ 2.0-3.0 km are taken as types I, II, and III, which occur for 9, 20, and 27 days, respectively. The EAL significantly modifies the total columnar aerosol optical depth (AOD). It is found that AOD, in total, within ABL and EAL, are ~0.72 (0.61), 0.28 (0.25), and 0.45 (0.36) using MPL (CALIPSO), respectively. The aerosols within ABL contribute ~38 % (41 %) while EAL ~ 62 % (59 %) to the total AOD obtained using MPL (CALIPSO). We observed that the ABL and EAL are characterized by different aerosol subtypes, such as dust marine (31 %) and smoke (~ 27 %) aerosols. Other aerosol subtypes, such as dust and polluted dust, commonly occur within the ABL (54 %) and EAL (52 %).


Adrenocortical Carcinoma: A Clinician's Perspective.
Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prognostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, mitotane and cytotoxic chemotherapy have been utilized with a modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases to guide the personalized use of immunotherapeutic and novel targeted therapies.


Abdominal tuberculosis in the 1970s: a continuing problem.
Eight cases of abdominal tuberculosis (5 indigenous and 3 immigrants) treated in Cardiff in the 5-year period 1972-6 were studied to determine clinical presentation, errors in diagnosis and usefulness of investigations. The heterogeneous presentation is reflected in the 7 types of lesion seen in the 8 cases. Anorexia and weight loss were present in all cases and abdominal colic and post-prandial discomfort were common. No patient had diarrhoea, constipation or intestinal obstruction. The clinical diagnosis was wrong 7 out of 8 times. Investigations were unhelpful in the diagnosis and where a lesion was found on barium studies, a diagnosis of Crohn's disease or carcinoma was made. The same was true of the findings at laparotomy. The examinations most useful in the diagnosis were histopathological examination for caseation and demonstration of acid-fast bacilli by alcohol and acid-fast tissue stains, or by a culture technique. The need for a greater awareness of abdominal tuberculosis, not only in immigrants but also in the indigenous population of Britain, is apparent.


Modulation of coffee aroma via the fermentation of green coffee beans with Rhizopus oligosporus: I. Green coffee.
Modulation of coffee aroma via the biotransformation/fermentation of different coffee matrices during post-harvest remains sparingly explored despite some studies showing their positive impacts on coffee aroma. Therefore, this is an unprecedented study aimed at modulating coffee aroma via the fermentation of green coffee beans with a food-grade fungus Rhizopus oligosporus. The objective of part I of this two-part study was to characterize the volatile and non-volatile profiles of green coffee beans after fermentation. Proteolysis during fermentation resulted in 1.5-fold increase in the concentrations of proline and aspartic acid which exhibited high Maillard reactivity. Extensive degradation of ferulic and caffeic acids led to 2-fold increase in the total concentrations of volatile phenolic derivatives. 36% of the total volatiles detected in fermented green coffee beans were generated during fermentation. Hence, the work presented demonstrated that R. oligosporus fermentation of green coffee beans could induce modification of the aroma precursors of green coffees.


Regulatory effect of two Trichinella spiralis serine protease inhibitors on the host's immune system.
Trichinella spiralis (T. spiralis) is widely distributed throughout the world and can cause serious zoonotic parasitic diseases. Serine protease inhibitors (SPIs) have unique enzyme inhibitory activity and occupy an important position in the interaction between parasites and hosts. In order to further understand the immunoprotective effect of SPIs on T. spiralis invasion in vivo, the Kazal and Serpin type SPI of T. spiralis (TsKaSPI and TsAdSPI) were mixed with Freund's adjuvant in equal volume to immunize mice. The results showed that the expression of IgG1 and IgG2a in serum, the proliferation of spleen cells, and the expression level of cytokines were all increased. The results of flow cytometry showed that the expression of CD4+CD25+Foxp3+ Tregs, CD8+CD28- T cells, CD19+CD5+CD1dhi Bregs in spleen were also increased. Therefore, both TsKaSPI and TsAdSPI could induce strong humoral and cellular immune responses. And the results of adult reduction rate and pathological changes of intestine after adult invasion also indicated that both TsKaSPI and TsAdSPI could prevent T. spiralis from invading intestine. To explore the regulatory effects of TsKaSPI and TsAdSPI on the immune function of macrophage, the results of ELISA showed that the expression of cytokines in cell supernatant were increased. And the results of Western blot showed that both TsKaSPI and TsAdSPI could induce phosphorylation of JAK2 and STAT3 receptors, thereby affecting the signal transduction of macrophages. This experiment demonstrated that SPIs could act as effector molecules affecting the immune function of host when infected with T. spiralis.


Association of promoter polymorphisms in MMP2 and TIMP2 with prostate cancer susceptibility in North India.
The importance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in tumor progression is well documented. MMP2/TIMP2 system has a significant impact on the development and progression of cancer and genetic polymorphisms in the promoters of MMP2 (-1306C/T, 735C/T) and TIMP2 (-418G/A, -303C/T) are correlated with decreased enzyme activity. We sought to determine whether genetic polymorphisms in MMP2 and TIMP2 polymorphisms may be associated with varying risk of prostate cancer (PCa) in men in North India. Genotyping was done by PCR-restriction fragment length polymorphism method in 190 histologically confirmed PCa patients and 200 unrelated, healthy, age-matched individuals of similar ethnicity. Patients with MMP2 (-1306) CT genotype as well as T allele were at higher risk of PCa (p = 0.018; OR = 1.68 and p = 0.015; OR = 1.52). This effect was even more evident in the case of the T allele carrier (CT + TT) (p = 0.011; OR = 1.71). MMP2 (735) C>T, TIMP2 (-418) G>C and TIMP2 (-303) C>T polymorphism demonstrated no association. However, TIMP2 (-418) GC was found to be involved in progression of PCa but not in initiation. Haplotype results demonstrated that MMP2 (1306T-735C) and TIMP2 (418G-303T) were associated with a 1.5- and 1.8-fold increased risk, respectively. Our data indicated that MMP2-1306C>T gene polymorphism contributes to PCa susceptibility. These findings suggested MMP2 variants as a predictor of PCa progression risk among North Indian men. We assume that analysis of these gene polymorphisms can help identify patient subgroups at high risk of poor disease outcome.


Contribution of amygdalar and lateral hypothalamic neurons to visual information processing of food and nonfood in monkey.
Visual information processing was investigated in the inferotemporal cortical (ITCx)-amygdalar (AM)-lateral hypothalamic (LHA) axis which contributes to food-nonfood discrimination. Neuronal activity was recorded from monkey AM and LHA during discrimination of sensory stimuli including sight of food or nonfood. The task had four phases: control, visual, bar press, and ingestion. Of 710 AM neurons tested, 220 (31.0%) responded during visual phase: 48 to only visual stimulation, 13 (1.9%) to visual plus oral sensory stimulation, 142 (20.0%) to multimodal stimulation and 17 (2.4%) to one affectively significant item. Of 669 LHA neurons tested, 106 (15.8%) responded in the visual phase. Of 80 visual-related neurons tested systematically, 33 (41.2%) responded selectively to the sight of any object predicting the availability of reward, and 47 (58.8%) responded nondifferentially to both food and nonfood. Many of AM neuron responses were graded according to the degree of affective significance of sensory stimuli (sensory-affective association), but responses of LHA food responsive neurons did not depend on the kind of reward indicated by the sensory stimuli (stimulus-reinforcement association). Some AM and LHA food responses were modulated by extinction or reversal. Dynamic information processing in ITCx-AM-LHA axis was investigated by reversible deficits of bilateral ITCx or AM by cooling. ITCx cooling suppressed discrimination by vision responding AM neurons (8/17). AM cooling suppressed LHA responses to food (9/22). We suggest deep AM-LHA involvement in food-nonfood discrimination based on AM sensory-affective association and LHA stimulus-reinforcement association.


Orthogonal adsorption onto nano-graphene oxide using different intermolecular forces for multiplexed delivery.
Nano-graphene oxide can adsorb both doxorubicin and zwitterionic dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes in an orthogonal and non-competing manner with high capacities based on different surface and intermolecular forces taking place on the heterogeneous surface of the graphene oxide. The system forms stable colloids, allowing co-delivery of both cargos to cancer cells.


The efficacy of single-lead implantable cardioverter-defibrillator with atrial sensing dipole to detect atrial fibrillation and to reduce inappropriate therapy according to atrial sensing ON or OFF: Rationale and design of the SMART-CONTROL study, a prospective multicenter randomized trial.
Few studies have compared the efficacy of single-lead implantable cardioverter-defibrillator (ICD) with atrial sensing dipole (VDD-ICD) and conventional single-chamber ICD from the aspect of atrial fibrillation (AF) detection or inappropriate ICD therapy reduction. In the SMART-CONTROL trial (NCT03932604), we primarily aim to investigate whether the atrial sensing capability of VDD-ICD is useful in AF detection and inappropriate therapy reduction by randomly activating or deactivating the atrial sensing function. This study was designed as a prospective, multicenter, open-label, randomized trial to enroll 640 patients with no history of clinical AF or rhythm control for AF within 1 year who were undergoing the implantation of VDD-ICD system. Patients are assigned randomly to atrial sensing "ON" or "OFF" group, with crossover allowed during follow-up. The coprimary outcomes are the incidence of AF detection and inappropriate ICD therapy over a 2-year follow-up period. The secondary outcomes include non-AF atrial tachyarrhythmia, ventricular tachyarrhythmia with or without ICD therapy, thromboembolic events, bleeding, heart failure hospitalization, mortality, a composite of adverse cardiovascular events, and long-term atrial sensing stability or variability. We expect that this trial can evaluate the efficacy of a single-lead ICD system on various clinical outcomes including AF detection and inappropriate therapy reduction, and ultimately provide guidance to selection of ICD system.


The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer.
Advanced epithelial ovarian, fallopian tube and primary peritoneal cancers (EOC) are a leading cause of gynaecological cancer-associated mortality and angiogenesis plays a key role in their growth. Vascular endothelial growth factor inhibitors (VEGFi) disrupt angiogenesis and improve the response rate, progression-free survival and in some cases, overall survival, when administered with and following cytotoxic chemotherapy, irrespective of the platinum sensitivity of EOC. Recent data have identified new indications for VEGFi in EOC: repeated exposure to VEGFi in the first- and then second-line treatment has sustained clinical efficacy; combinations of VEGFi with poly (ADP-ribose) polymerase inhibitors (PARPi) have proven effective as first-line or second-line maintenance regimens. However, recent trial data have not shown improved outcomes with combinations of VEGFi and immune checkpoint inhibitors. There remains a critical need to optimise patient selection for these effective yet somewhat toxic and expensive treatments. The search continues for validated biomarkers to optimise the use of VEGFi, of which the most promising at present is plasma Tie2. Based upon these studies, we propose a model of care incorporating VEGFi into the treatment of EOC, highlighting the need to change from the prescription of single courses of VEGFi, to allow use and re-use as clinically indicated.


Prophylactic acetylsalicylic acid attenuates the inflammatory response but fails to protect exercise-induced liver damage in exercised rats.
This study evaluated the effects of acetylsalicylic acid (ASA) on exercise-induced inflammatory response, muscle damage, and liver injury in rats. Wistar-Kyoto (WKY) rats were divided into six groups: control (C), exercise (E), C+20mg ASA, E+20mg ASA, C+100mg/kg ASA, and E+100mg ASA groups. ASA or a vehicle was orally administered through gavage 1h before a treadmill test. Upon trial completion, blood was drawn at 1, 12, and 24h for biochemical analysis, and livers were excised at 24h for a histological assessment. Our results revealed that 100mg/kg ASA significantly reduced interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the E groups; however, the IL-10 level was considerably increased. Moreover, aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and histological hepatic damage increased significantly in the E+100mg ASA group compared with the corresponding changes in the E group. These results suggest that the prophylactic administration of particularly high-dose ASA alleviates exercise-induced inflammatory response but exacerbates liver injury.


Monitoring of minimal residual disease in acute myeloid leukemia with t(8;21)(q22;q22).
The fusion gene AML1/ETO is a molecular marker for monitoring minimal residual disease (MRD) in acute myeloid leukemia with the t(8;21)(q22;q22) translocation. To evaluate the dynamic variation and prognostic significance of AML1/ETO, bone marrow samples from 52 patients at different periods were examined qualitatively (32 patients) or quantitatively (20 patients) using nested RT-PCR and RQ-PCR, respectively. In the qualitative group, AML1/ETO in 71.88 and 95.45 % patients became negative at six and 24 months after CR, respectively. Patients in long-term remission were all RT-PCR-negative. Patients negative for AML1/ETO at 6-12 months and 12-18 months after CR had lower relapse rate (P = 0.003 and 0.000), higher relapse-free survival (RFS) (P = 0.000 and 0.000), and overall survival (P = 0.001 and 0.000) than patients with positive AML1/ETO. Quantitative analysis showed that there was no trend where higher relapse rate occurred in patients with higher levels of AML1/ETO transcripts at diagnosis (P > 0.05). Patients whose AML1/ETO transcripts decreased by more than 2 log at CR had higher RFS (P = 0.02). At the checkpoints of 3 and 5/6 months after CR, patients with lower AML1/ETO copy numbers showed lower probability of relapse (P = 0.039 and 0.004). An increase of AML1/ETO transcripts (0.5 log) at any time after CR indicated increased risk of relapse (P = 0.002). Our study shows that both qualitative and quantitative detection of AML1/ETO have prognostic value in MRD monitoring. Negative or continuous low expression of AML1/ETO indicates increased disease-free survival.


5-hydroxytryptamine-induced relaxation of neonatal porcine vena cava in vitro.
5-hydroxytryptamine (5-HT) caused concentration-dependent relaxation of isolated rings from porcine vena cava contracted with alpha-methyl 5-HT or prostaglandin F2 alpha. Relaxation was not blocked by propranolol (1 micron), atropine (1 micron), indomethacin (3 microns), mepyramine (1 micron), cimetidine (1 micron), or cocaine (10 microns). Further receptor analysis could not be performed by antagonism of the relaxant response but was possible using 5-HT induced increases in cyclic AMP. Methysergide (1 micron) but not cyproheptadine (0.1 micron), specifically antagonised the 5-HT induced increase in cyclic AMP with an estimated pA2 of 7.19. The alpha-methyl analogue of 5-HT, a potent agonist at M and D receptors, did not cause relaxation or elevate cyclic AMP. These results suggest that the 5-HT receptor described here is not of the classical M or D type and unlike that described thus far in the vasculature. This receptor shares some similarities with brain 5-HT1 receptors since both may be linked with adenylate cyclase.


Systematic Review of Treatment of Patients with Achalasia: Heller Myotomy, Pneumatic Dilation, and Peroral Endoscopic Myotomy.
The aim of this systematic review is to assess all comparative randomized controlled trials evaluating Heller myotomy, pneumatic dilation, and peroral endoscopic myotomy. Achalasia is an esophageal motility disorder associated with degeneration of the myenteric plexus; it causes significant symptoms and impacts patient quality of life (QOL). The optimal treatment for patients with achalasia and the impact of these interventions on QOL remain unclear. PubMed, Embase, Scopus, and Cochrane were searched from inception to April 2020. Randomized controlled trials that compared the 3 interventions were included. Primary outcome was QOL at 12 to 36 months after the operation. Secondary outcomes included reintervention, dysphagia, leak/perforation, and GERD recurrence. Nine publications of 6 studies were included. Of the 9 publications, there was no significant difference in QOL at 12 to 36 months except for one study in which QOL was significantly higher in patients who underwent Heller myotomy as opposed to pneumatic dilation at 3 years; however, at 5 years there was no difference. Pneumatic dilation was associated with the highest rates of dysphagia recurrence and reintervention, but peroral endoscopic myotomy had the lowest. The treatment of achalasia should be chosen in accordance with patient goals. After any of the 3 interventions, QOL appears to be similar. However, peroral endoscopic myotomy may be associated with the lowest rates of perforation/leak, dysphagia, and reintervention and may be the lowest risk option. However, there are barriers to widespread use due to challenges in training and adoption.


Evidence for heterogeneous turnover of rat liver lysosome hydrolases.
The activity of several Lysosome Hydrolases in the liver of rats submitted to intensive treatment with cycloheximide has been tested. From their results the authors suggest that the lysosomal turnover is not only heterogenous but also rapid.


Antihypertensive and Statin Medication Adherence Among Medicare Beneficiaries.
Medication adherence is important for optimal management of chronic conditions, including hypertension and hypercholesterolemia. This study describes adherence to antihypertensive and statin medications, individually and collectively, and examines variation in adherence by demographic and geographic characteristics. The 2017 prescription drug event data for beneficiaries with Medicare Part D coverage were assessed. Beneficiaries with a proportion of days covered ≥80% were considered adherent. Adjusted prevalence ratios were estimated to quantify the associations between demographic and geographic characteristics and adherence. Adherence estimates were mapped by county of residence using a spatial empirical Bayesian smoothing technique to enhance stability. Analyses were conducted in 2019‒2021. Among the 22.5 million beneficiaries prescribed antihypertensive medications, 77.1% were adherent; among the 16.1 million prescribed statin medications, 81.9% were adherent; and among the 13.5 million prescribed antihypertensive and statin medications, 70.3% were adherent to both. Adherence varied by race/ethnicity: American Indian/Alaska Native (adjusted prevalence ratio=0.83, 95% confidence limit=0.82, 0.842), Hispanic (adjusted prevalence ratio=0.90, 95% confidence limit=0.90, 0.91), and non-Hispanic Black (adjusted prevalence ratio=0.87, 95% confidence limit=0.86, 0.87) beneficiaries were less likely to be adherent than non-Hispanic White beneficiaries. County-level adherence ranged across the U.S. from 25.7% to 88.5% for antihypertensive medications, from 36.0% to 93.8% for statin medications, and from 20.8% to 92.9% for both medications combined and tended to be the lowest in the southern U.S. This study highlights opportunities for efforts to remove barriers and support medication adherence, especially among racial/ethnic minority groups and within the regions at greatest risk for adverse cardiovascular outcomes.


Basiliximab induction therapy for live donor kidney transplantation: a long-term follow-up of prospective randomized controlled study.
The effect of basiliximab induction therapy on long-term patient and graft survival is not yet clear. We aimed to evaluate if there is any advantage of routine basiliximab induction on the long-term outcome of living related donor kidney transplantation. One hundred adult recipients with their first kidney allograft were randomized into two treatment groups, one group received basiliximab and the second served as a control. All patients received a maintenance triple immunosuppressive therapy (steroids, cyclosporine (CsA) micro-emulsion and azathioprine) and were followed up thoroughly for 7 years. Basiliximab significantly reduced the proportion of patients who experienced acute rejection in the first year (18/50) when compared to the control group (31/50), and in 7 years (28/50) when compared to (37/50) in controls. The cumulative steroid dose used throughout the whole study period was significantly lower in the basiliximab group. The overall incidence of post-transplant complications was comparable among the two treatment groups. There was no significant difference in patient or graft survival; 7 years patient and graft survival were 92, 76% for basiliximab and 92, 80% for the control group, respectively. Routine basiliximab induction significantly reduced the incidence of acute rejection without any noticeble beneficial effect on the long-term renal transplantation outcome.


Hepatitis B viral load in dried blood spots: A validation study in Zambia.
Access to hepatitis B viral load (VL) testing is poor in sub-Saharan Africa (SSA) due to economic and logistical reasons. To demonstrate the feasibility of testing dried blood spots (DBS) for hepatitis B virus (HBV) VL in a laboratory in Lusaka, Zambia, and to compare HBV VLs between DBS and plasma samples. Paired plasma and DBS samples from HIV-HBV co-infected Zambian adults were analyzed for HBV VL using the COBAS AmpliPrep/COBAS TaqMan HBV test (Version 2.0) and for HBV genotype by direct sequencing. We used Bland-Altman analysis to compare VLs between sample types and by genotype. Logistic regression analysis was conducted to assess the probability of an undetectable DBS result by plasma VL. Among 68 participants, median age was 34 years, 61.8% were men, and median plasma HBV VL was 3.98logIU/ml (interquartile range, 2.04-5.95). Among sequenced viruses, 28 were genotype A1 and 27 were genotype E. Bland-Altman plots suggested strong agreement between DBS and plasma VLs. DBS VLs were on average 1.59logIU/ml lower than plasma with 95% limits of agreement of -2.40 to -0.83log IU/ml. At a plasma VL ≥2,000IU/ml, the probability of an undetectable DBS result was 1.8% (95% CI: 0.5-6.6). At plasma VL ≥20,000IU/ml this probability reduced to 0.2% (95% CI: 0.03-1.7). In a Zambian laboratory, we observed strong agreement between DBS and plasma VLs and high sensitivity in DBS at plasma VL ≥2,000IU/ml. As HBV treatment expands, DBS could increase access to HBV VL testing and care in SSA settings.


IRE1beta inhibits chylomicron production by selectively degrading MTP mRNA.
Microsomal triglyceride transfer protein (MTP) is needed to assemble chylomicrons in the endoplasmic reticulum (ER) of enterocytes. We explored the role of an ER stress protein, inositol-requiring enzyme 1beta (IRE1beta), in regulating this process. High-cholesterol and high-fat diets decreased intestinal IRE1beta mRNA in wild-type mice. Ire1b(-/-) mice fed high-cholesterol and high-fat diets developed more pronounced hyperlipidemia because these mice secreted more chylomicrons and expressed more intestinal MTP, though not hepatic MTP, than wild-type mice did. Chylomicron secretion and MTP expression also were increased in primary enterocytes isolated from cholesterol-fed Ire1b(-/-) mice. There was no correlation between ER stress and MTP expression. Instead, cell culture studies revealed that IRE1beta, but not its ubiquitous homolog IRE1alpha, decreased MTP mRNA through increased posttranscriptional degradation. Conversely, knockdown of IRE1beta enhanced MTP expression. These studies show that IRE1beta plays a role in regulating MTP and in chylomicron production.


Insulin-like growth factor I activity is stored in the yolk of the avian egg.
Growth factors of maternal origin may be incorporated into the vertebrate egg and play a role in early phases of embryo growth and differentiation. An avian insulin-like growth factor I (IGF-I) activity from unfertilized chicken egg-yolk has been partially purified by HPLC. The material is slightly more hydrophobic than recombinant human IGF-I. It reacts in a human IGF-I radioimmunoassay and is specifically depleted by anti-human IGF-I antibodies. Like authentic IGF-I, the extracts enriched in IGF-I activity stimulated the accumulation of delta-crystallin mRNA in epithelial cells from chick embryo lens with a potency approximately equivalent to its IGF-I immunoactivity.


Presbyopic LASIK using the Supracor algorithm and micromonovision in presbyopic myopic patients: 12-month visual and refractive outcomes.
To evaluate the visual and refractive outcomes for presbyopia and myopia treatment using the Teneo 317 M2 platform and the myopic Supracor algorithm. Percy Military Hospital and Private Laser Victor Hugo Center, Paris, France. Observational retrospective nonrandomized study. 50 eyes (25 patients) treated with bilateral myopic Supracor and micromonovision using the Teneo 317 M2 platform and followed up for 12 months. Study outcomes included binocular and monocular visual acuities (without correction for distance and near vision), the spherical equivalent, predictability, stability, safety, optical aberrations, and complications. The mean age was 50.6 ± 2.7 years, and the mean preoperative spherical equivalent was -2.6 ± 1.4 diopters. At 12 months postoperatively, the mean binocular uncorrected distance visual acuity was 0.02 ± 0.03 logMAR, and 24 patients (96%) achieved an acuity of 20/25 or better. The binocular uncorrected near visual acuity was equal to Jaeger 1 in 18 patients (72%) and Jaeger 2 or better in 23 patients (92%). 12 eyes (24%) had lost 1 Snellen line, and 1 eye (2%) had lost 2 Snellen lines of monocular corrected distance visual acuity. No cases required retreatment; however, 1 eye (2%) underwent revision surgery because of diffuse lamellar keratitis. This study suggests that Supracor using the Teneo 317 M2 platform is a safe and effective technique for myopia and presbyopia treatment. Supracor is therefore a viable alternative to monovision for presbyopia and myopia. However, a careful patient selection is essential to satisfy realistic expectations.


Sleep disordered breathing and daytime quality of life in children with allergic rhinitis during treatment with intranasal budesonide.
Nasal obstruction is recognized as an important cause of sleep disordered breathing. Congestion of the nasal mucosa and obstruction are common symptoms of allergic rhinitis. Daytime sleepiness is a common finding in symptomatic allergic rhinitis. Effective therapy of the nasal congestion of allergic rhinitis should alter sleep patterns in patients with symptomatic allergic rhinitis. To measure objective changes in polysomnograms (sleep studies) of children with allergic rhinitis before and after therapy with intranasal budesonide and to measure changes in the quality of life of these patients during treatment. Open clinical trial with objective measurements (polysomnography) and subjective data (Rhinitis Quality of Life Questionnaire [RQLQ]). Evaluations were performed before, during, and at completion of therapeutic intervention. The 14 studied children tolerated the procedures and treatment without problems. The mean number of sleep arousals per hour (all apneas and hypopneas) decreased from a baseline of 8.4 to 1.2 (P = .005) after treatment. The change was mainly in hypopneic episodes (7.5-0.9, P = .003). Objective responses on the RQLQ showed improvements consistent with improved sleep and lessened rhinitis symptoms. Decreasing the nasal congestion associated with allergic rhinitis can improve sleep measured by objective sleep studies and lead to improvement in daytime quality of life.


A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results.
This ongoing, randomized, double-blind, active-controlled phase 3 international trial demonstrated the noninferior efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) compared with atazanavir boosted by ritonavir (ATV/RTV) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) at 48 weeks. Here, we report the week 96 results. Of 708 treated subjects, virological success (Food and Drug Administration snapshot) was maintained at week 96 with EVG/COBI/FTC/TDF and ATV/RTV + FTC/TDF (83% vs 82%, difference 1.1%, 95% confidence interval -4.5% to 6.7%). Study drug discontinuations due to adverse events were low (4% vs 6%). Median increases from baseline in serum Cr (mg/dL) in EVG/COBI/FTC/TDF vs ATV/RTV + FTC/TDF at week 96 (0.12 vs 0.08) were similar to those at week 48 (0.12 vs 0.08). EVG/COBI/FTC/TDF showed similar mean decreases (%) in bone mineral density from baseline vs ATV/RTV + FTC/TDF (hip: -3.16 vs -4.19, P = 0.069; spine: -1.96 vs -3.54, P = 0.049). Overall, week 96 results support durable efficacy and safety of EVG/COBI/FTC/TDF in HIV-1-infected patients.


The BE-ALIVE score: assessing 30-day mortality risk in patients presenting with acute coronary syndromes.
To create and validate a simple scoring system for predicting 30-day mortality in patients presenting with acute coronary syndromes (ACS) at their moment of admission. 2407 consecutive patients presenting to Harefield Hospital with measured arterial blood gases, from January 2011 to December 2020, were studied to build the training set. 30-day mortality in this group was 17.2%. A scoring algorithm that was built using binary logistic regression of variables available on admission was then converted to an additive risk score. The resultant scoring system is the BE-ALIVE score, which incorporates the following factors:Base Excess (1 point for <-2 mmol/L), Age (<65 years: 0 points, 65-74: 1 point, 75-84: 2 points, ≥85: 3 points), Lactate (<2 mmol/L: 0 points, 2-4.9: 1 point, 5-9.9: 3 points, ≥10: 6 points), Intubated (2 points), Left Ventricular function (mildly impaired or better: -1 point, moderately impaired: 1 point, severely impaired: 3 points) and External/out of hospital cardiac arrest 2 points).The scoring system was validated using a testing set of 515 patients presenting to Harefield Hospital in 2021. The validation metrics were excellent with a c-statistic of 0.9, Brier's score 0.06 vs a naïve classifier of 0.15, Spiegelhalter's z-statistic probability of 0.267 and a calibration slope of 1.08. The BE-ALIVE score is a simple and accurate scoring system to predict 30-day mortality in patients presenting with ACS. Appreciating this mortality risk can allow prompt involvement of appropriate care such as the shock team.


Deficiency of purinergic P2Y receptors in aganglionic intestine in Hirschsprung's disease.
Hirschsprung's disease is characterized by the absence of ganglion cells in the distal bowel and extends proximally for varying distances. In recent years, the purinergic P2Y receptors have begun to receive much attention as they have been recognised as major ATP receptors in many regions of the body, including the intestine. ATP has long been established as an inhibitory neurotransmitter in the enteric nervous system. The aim of our study was to analyse the expression of P2Y1 and P2Y2 receptors in the intestine of patients with Hirschsprung's disease. Frozen sections were cut from rectal tissue segments taken from both the aganglionic and ganglionic regions of patients with Hirschsprung's disease, as well as tissue from normal rectal biopsies, which were used as controls. Sections were incubated overnight with P2Y1 and P2Y2 receptor antibodies and results were analysed by light microscopy. Both P2Y1 and P2Y2 immunoreactivity was absent from the submucosal and myenteric plexuses of aganglionic tissue compared to ganglionic tissue and normal controls, in which large number of immunoreactive neurons were evident, arranged in ganglia in both plexuses and positive nerve fibres, in both the smooth and circular muscles. Our results show a lack of expression of P2Y1 and P2Y2 receptors in the aganglionic gut in Hirschsprung's disease. The absence of these receptors suggests the absence of the inhibitory neurotransmitter ATP, which may help to explain the contracted state of the aganglionic gut in Hirschsprung's disease.


Localization of a biotinylated cathepsin B oligonucleotide probe in human prostate including invasive cells and invasive edges by in situ hybridization.
The cysteine endopeptidase cathepsin B (CB) can degrade basement membrane (BM) proteins (such as laminin, type IV collagen, and fibronectin) at both acid and neutral pHs suggesting that CB has a role in tumor invasion and distant metastasis. The distribution and intensity of CB protein localization vary in normal prostate, benign prostatic hyperplasia (BPH), and neoplastic prostate. These considerations have led us to examine whether the distribution of CB localization in malignant and normal cells is due to storage or active synthesis of CB. In the present study, we examined the localization patterns of CB at the mRNA level in normal prostate, BPH, and well to moderately differentiated neoplastic prostate, focusing on invasive groups of cells and invasive edges of malignant tumors. We used a 25-base biotinylated oligonucleotide CB cDNA "sense" probe to localize CB message in prostate samples obtained from radical prostatectomies. We have determined that CB is actively synthesized by the epithelia of normal, hyperplastic, and neoplastic prostate including some invasive cells in the invasive edges. In both normal and BPH, CB mRNA was localized predominantly in acinar basal cells with some localization in cuboidal/columnar cells. In contrast, in neoplastic prostate, CB mRNA was localized predominantly in columnar cells and in groups of invasive cells and invasive edges. Thus, in malignant prostate the predominant cell types expressing CB differed from those of the normal prostate and BPH. Analysis of CB mRNA localizations indicated a heterogeneity in staining distribution in prostate cancer with some invasive groups of cells and invasive edges exhibiting CB mRNA and others exhibiting little or no reaction products.(ABSTRACT TRUNCATED AT 250 WORDS)


Studies on the pathogenesis of ischemic cell injury XV. Reversal of ischemic cell injury in hamster trachea and human bronchus by explant culture.
Hamster tracheal epithelium survived 3 hours of total ischemia at 37 degrees C as demonstrated by its ability to be maintained in organ culture for 7 days subsequent to the ischemic episode. Epithelium ischemic for longer periods did not survive in culture. Human bronchial epithelium obtained from surgically resected lungs showed the acute effects of ischemia, i.e., the cells had dilated endoplasmic reticulum and swollen mitochondria. These cellular effects of ischemia were, however, reversed by placing the bronchus in explant culture. Bronchus obtained at autopsy, 2 to 3 hours following death, showed epithelial cells suffering severe ischemic cell injury, most of which did not survive in culture, but in some cases, a few basal cells survived to form a non-keratinizing squamous epithelium.


Surgeon's and Patient's Radiation Exposure Through Vertebral Body Cement Augmentation Procedures: A Prospective Multicentric Study of 49 Cases.
Vertebral body cement augmentation as a treatment option for osteoporotic or traumatic fractures has become increasingly popular during the past decade. However, these surgical procedures require numerous fluoroscopic examinations, resulting in high radiation exposure for the patient and the surgical team. The aim of this study was to evaluate the level of radiation exposure of the spine surgeon and the patient during these percutaneous procedures. Forty-nine patients admitted for single- or 2-level vertebral compression fracture were prospectively included and treated with vertebral body cement augmentation. For each procedure, radiation dose was measured on the surgeon's whole body, lens, and extremities as well as patient irradiation. Each surgeon wore 2 thermoluminescent dosimeters to measure lens and extremities radiation exposure and 1 electronic personal dosimeter. Patient clinical and surgical data, effective dose to patient, and surgeon were analyzed. Mean operative time was 31.5 ± 11.7 minutes. The average fluoroscopic time was 61.0 ± 27.1 seconds. The average whole-body radiation dose per procedure was 1.4 ± 2.1 μSv. The average equivalent dose to lens and extremities were 44 μSv and 59 μSv, respectively. Values of radiation doses for surgeon and patient were lower than those reported in the previous literature. The recommended annual dose limit is set to 500 mSv for extremities and 150 mSv for lens. According to our results, the exposure dose to the eye exceeds the annual limit after 3500 procedures. However, there is increasing concern among surgeons about radiation exposure, and there is still a need for solutions as preventive measures.


A comprehensive metabolomics analysis of Torreya grandis nuts with the effective de-astringent treatment during the postharvest ripening stage.
Astringency removal is important for the quality of Torreya grandis nut and occurs after harvest. Here, we evaluated the effect of NaHCO3 treatment on astringency removal and compared the differential metabolites of the seed coat and kernel using a UHPLC QQQ-MS-based metabolomics approach. The result revealed the nut astringency was primarily enriched in the seed coat with more soluble tannins. The NaHCO3 treatment greatly shortened the de-astringency process, as indicated by a faster conversion of soluble tannins to insoluble tannins and more acetaldehyde production. Besides, a total of 293 metabolites, including 92 phenolic acids and 37 flavonoids, were tentatively characterized in the seed coat. A further comparative analysis of the metabolomics indicated epigallocatechin, gallocatechin, catechin, procyanidin B1, B2, B3 and C1 to be the major metabolites influenced by the NaHCO3 treatment. This study provides new insights regarding the metabolite differences of Torreya grandis nuts processed with different de-astringent treatments.


Effects of verapamil on left ventricular diastolic filling in children with hypertrophic cardiomyopathy.
The effects of oral verapamil on resting left ventricular (LV) diastolic filling were examined in 10 children and adolescents with hypertrophic cardiomyopathy. Measurements of diastolic filling were made from gated technetium-99m radionuclide angiograms with postbeat rejection of data outside a 5% RR-interval window. LV time-activity curves were generated and the rapid-filling phase fit with a 3 degrees polynomial to calculate the peak filling rate and the time from end-systole to the point of peak filling. All patients had a radionuclide angiogram performed before and after 0.25 to 3 years of oral verapamil therapy. Verapamil did not change the LV ejection fraction but increased the peak filling rate (3.24 +/- 0.15 to 4.62 +/- 1.05 end-diastolic volume/s,p less than 0.01) and reduced the time to peak filling (217 +/- 57 to 168 +/- 63 ms, p less than 0.01). An increase in exercise endurance as measured by exercise treadmill test and subjective symptomatic improvement were also seen after verapamil therapy. Thus, in children with hypertrophic cardiomyopathy, symptomatic improvement and LV diastolic filling parameters improved with long-term oral verapamil.


Correction to: Intraoperative indocyanine green fluorescence imaging in breast surgery.
In the original article published, some of the superscript characters in Table 1 (column p value with superscript references to the footnotes) were incorrectly inserted by the typesetters.


Use of chitinase to assess ruminal fungi associated with plant residues in vitro.
Treatment of fibrous residue from in vitro digestion trials with chitinase was evaluated gravimetrically and microscopically to determine the associated fungal biomass. The percent dry weight removed by chitinase with time paralleled changes in the number of sporangia associated with leaves. The fungal biomass contributed about 12% dry matter to the residue of leaves incubated with ruminal fluid plus streptomycin and penicillin.


Synergistic effects of cAMP-dependent signalling pathways and IL-1 on IL-6 production by H19-7/IGF-IR neuronal cells.
cAMP-dependent signalling cascades regulate a number of CNS functions including brain inflammation processes. In this study, we characterized IL-1-induced IL-6 production in hippocampal cells using H19-7/IGF-IR cells and investigated the effect of changes in intracellular cAMP levels on IL-1 activity. IL-1 potently induced IL-6 mRNA expression with a corresponding increase in IL-6 release, in a time- and dose-dependent manner with a maximal at 24 h and with an EC50 value of 0.11 ng/ml. Cell pre-treatment with the IL-1sR antagonist produced a rightward shift of IL-1 dose-response effect with a corresponding decrease in IL-1 potency. IL-1-induced IL 6 release was attenuated in the presence of the p38 MAPK inhibitor SB203580 but was not significantly affected by the PKA inhibitor KT 5720. Western blotting analysis of phospho-CREB cell content showed a marked increase in CREB activation. Similar results were obtained by pharmacologically increasing cAMP using dibutyryl cyclic adenosine monophosphate (dbcAMP) or the cAMP-specific type-4 phosphodiesterase inhibitor rolipram. Both dbcAMP and rolipram increased IL-6 production to about 50% of IL-1 effect. However, in the presence of IL-1, IL-6 production was further potentiated by either dbcAMP and rolipram, reaching 300% and 500% IL-1-induced levels. These data implicate the role of cAMP-dependent pathways on IL-6 production in neuronal cells and suggest novel synergistic mechanisms of regulation of cytokine production in brain.


Preparation of high-concentration substitutional carbon-doped TiO2 film via a two-step method for high-performance photocatalysis.
In this paper, we present a facile two-step method for preparing a high-concentration substitutional carbon-doped TiO2 (TiO2-x C x ) film. First, the titanium substrate undergoes gas carburizing, followed by micro-arc oxidation (MAO) to form a carbon-doped TiO2 film on the surface. The process can be described as direct oxidation of titanium carbide (O→TiC x ). The experimental results reveal that compared with traditional thermal annealing, this process could increase the carbon doping concentration to 6.07 at% and x to 0.24 in TiO2-x C x . The TiO2-x C x film exhibits a significant red-shift in the band-gap transition, a narrow band gap of 2.77 eV, and excellent photocatalytic performance, more than two times higher than that of undoped TiO2 film. This method is simple, efficient, economical, environmentally friendly, and adapts to mass production. This experimental strategy can also be used in preparing other doped elements.


Management of Malignant Pleural Effusions in U.S. Veterans: A Retrospective Review.
To compare malignant pleural effusion (MPE) treatment outcomes and complications among patients receiving indwelling pleural catheter (IPC), talc pleurodesis (TPS), or dual therapy. Outcomes were determined by measuring length of stay (LOS) and post-procedure dyspnea scores. Complications were measured by comparing intervention failures and adverse events. The Veterans Affairs' Corporate Data Warehouse was utilized to retrospectively review the charts of 314 MPE subjects. Dyspnea scores were estimated by researchers and LOS was determined by adding the duration of stay for all admissions post procedure. Complications were recorded through chart review. IPC exhibited higher failure rates than the other approaches 1 year post intervention. Pneumonia/chest infection rate and lung entrapment were also more prevalent. There was no significant difference in dyspnea rates. LOS illustrated a significant difference between groups, with talc patients spending a median of 7 days in the hospital immediately post procedure, while IPC and IPC + TPS patients spent a median of 3 and 2 days, respectively. Patients receiving IPC or combination treatment spend fewer days in the hospital than TPS patients. However, IPC appears to be associated with more adverse events and higher long-term failure rates than other management strategies.


Assessing mechanical catheter dysfunction in automated tidal peritoneal dialysis using cycler software: a case control, proof-of-concept study.
New recommendations on evaluation of peritoneal membrane function suggest ruling out catheter dysfunction when evaluating patients with low ultrafiltration capacity. We introduce the use of a combination of parameters obtained from the cycler software PD Link with HomeChoicePro (Baxter International Inc., Illinois, United States) cyclers for predicting catheter dysfunction in automated peritoneal dialysis patients (APD). Out of 117 patients treated at the Medical University of Vienna between 2015 and 2021, we retrospectively identified all patients with verified catheter dysfunction (n = 14) and compared them to controls without clinical evidence of mechanical catheter problems and a recent X-ray confirming PD catheter tip in the rectovesical/rectouterine space (n = 19). All patients had a coiled single-cuff PD catheter, performed tidal PD, and received neutral pH bicarbonate/lactate-buffered PD fluids with low-glucose degradation products on APD. Icodextrin-containing PD fluids were used for daytime dwells. We retrieved cycler data for seven days each and tested parameters' predictive capability of catheter dysfunction. Total number of alarms/week > 7 as single predictive parameter of catheter dislocation identified 85.7% (sensitivity) of patients with dislocated catheter, whereas 31.6% (1-specificity) of control patients were false positive. A combination of parameters (number of alarms/week > 7, total drain time > 22 min, ultrafiltration of last fill < 150 mL) where at least two of three parameters appeared identified the same proportion of patients with catheter dislocation, but was more accurate in identifying controls (21.1% false positive). In contrast to yearly PET measurements, an easily applicable combination of daily cycler readout parameters, also available in new APD systems connected to remote monitoring platforms shows potential for diagnosis of catheter dysfunction during routine follow-up.


Rationale, study design and analysis plan of the lung imaging morphology for ventilator settings in acute respiratory distress syndrome study (LIVE study): Study protocol for a randomised controlled trial.
Different acute respiratory distress syndrome (ARDS) phenotypes may explain controversial results in clinical trials. Lung-morphology is one of the ARDS-phenotypes and physiological studies suggest different responses in terms of positive-end-expiratory-pressure (PEEP) and recruitment-manoeuvres (RM) according to loss of aeration. To evaluate whether tailored ventilator regimens may impact ARDS outcomes, our group has designed a randomised-clinical-trial of ventilator settings according to lung morphology in moderate-to-severe ARDS (LIVE study). Patients will be enrolled within the first 12hours of ARDS onset. In both groups, volume-controlled ventilation with low tidal-volumes (Vt) will be used to target a plateau pressure≤30 cmH2O. In the control group, the PEEP level and inspired fraction of oxygen (FiO2) will be set using the ARDSNet table; a Vt of 6 mL/kg of predicted body weight (PBW) will be set and prone position (PP) will be applied. In the intervention arm, the ventilator will be set according to lung morphology (focal/non-focal) that will be assessed according to CT-scan±chest x-ray+lung echography. For focal ARDS patients, a Vt of 8 mL/kg PBW will be used along with low PEEP and PP. For non-focal ARDS patients, a Vt of 6 mL/kg PBW will be used with RM and PEEP to reach a plateau pressure≤30 cmH2O. The primary outcome is all-cause 90-day mortality and the secondary outcomes are: in-hospital mortality, mortality at day 28, 60, 180 and 365; ventilator-free days at day 30, quality of life at one year; ventilator-associated pneumonia rate; barotrauma; ICU and hospital length of stay. This RCT is registered on Clinicaltrials.gov under identifier NCT02149589.


Ferrostatin-1 Ameliorated Oxidative Lipid Damage in LPS-induced Acute Lung Injury.
Ferroptosis is a new type of regulated cell death that is characterized by the overwhelming iron-dependent accumulation of lethal lipid reactive oxygen species and is involved in various diseases. However, the relationship between ferroptosis and lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains largely unknown. In this study, iron metabolism and ferroptosis-related gene mRNA levels in the lung tissues of LPS-induced ALI mice at different time points were detected. Then, the histological, cytokines production, and iron levels of LPS-induced ALI mice with or without the pretreatment of the ferroptosis inhibitor ferrostatin-1 (Fer-1) were measured after mice received the ferroptosis inhibitor ferrostatin-1 (Fer-1) intraperitoneally before LPS administration. Ferroptosis-related protein (GPX4, NRF2, and DPP4) expression was measured in the in vivo and in vitro ALI model. Finally, ROS accumulation and lipid peroxidation was measured in in vivo and in vitro study. Our results showed that iron metabolism and ferroptosis-related gene mRNA demonstrated significant variation in LPS-treated pulmonary tissues. The ferroptosis inhibitor Fer-1 markedly attenuated the histologic injuries of the lung tissue and suppressed the production of cytokines in bronchoalveolar lavage fluid (BALF). Fer-1 administration reduced the levels of NRF2 and DPP4 protein induced by the LPS challenge. Furthermore, Fer-1 reversed the tendency of iron metabolism, MDA, SOD, and GSH levels induced by LPS administration in in vivo and in vitro. Taken together, ferroptosis inhibition by ferrostatin-1 alleviated acute lung injury through modulating oxidative lipid damages induced by the LPS challenge.


Bioaccumulation and potential impacts of persistent organic pollutants and contaminants of emerging concern in guitarfishes and angelsharks from Southeastern Brazil.
The present study aimed to determine persistent organic pollutants (POPs) and contaminants of emerging concern in endangered angelshark and guitarfish species from southeastern Brazil, and to investigate potential impacts of these compounds on morphometric indexes. Pesticides of emerging concern, pharmaceutical and personal care products (PPCPs), polycyclic aromatic hydrocarbons (PAHs), and polybrominated diphenyl ethers (PBDEs) were determined in hepatic and muscular tissues of Pseudobatos horkelii, P. percellens, Squatina guggenheim, and Zapteryx brevirostris obtained from artisanal and industrial fisheries operating in southeastern Brazil. Accumulation profiles and effects of contaminants on condition factor and hepatosomatic index were investigated. No differences were detected regarding species contaminant concentration, potentially due to similarities in habits, occurrence and trophic position shared by guitarfishes and angelsharks. Polycyclic aromatic hydrocarbons (23.2-495.3 ng g -1), and PPCPs such as diclofenac (<LOQ - 448.4 ng g-1) and methylparaben (<LOQ - 645.5 ng g-1) presented the highest concentrations, regardless of the species. Effects of elasmobranch size were not significant on contaminant levels, indicating the lack of bioaccumulation over time. We suggest that the exposure to contaminants in elasmobranchs inhabiting this region is highly dependent on the economic activities and high urban development in southeastern Brazil. Regarding potential impacts of such exposure, the condition factor was only negatively influenced by PBDEs concentrations, whereas the hepatosomatic index was not influenced by any contaminant. Despite this, our results indicate that guitarfishes and angelsharks are exposed to POPs and contaminants of emerging concern potentially toxic to aquatic organisms. In this context, more refined biomarkers should be used to predict potential impacts of these contaminants on elasmobranch's health.


Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin.
An association between oncogenic transformation and repression of different components of the MHC class I antigen processing machinery (APM) have been described in murine model systems. In order to discover whether a similar correlation exists, human tumor cell lines of distinct histology with altered ras protein were analyzed for the expression of APM components utilizing RT-PCR and Western blot analyses. A heterogeneous expression pattern of MHC class I antigens, TAP peptide transporter, proteasome subunits, proteasome activator PA28 and the chaperones calnexin, calreticulin as well as tapasin was displayed by these tumor cell lines. Single or combined deficiencies in the expression and/or function of TAP, LMP2, LMP10 and tapasin were demonstrated in 11 of 12 cell lines studied, whereas the expression of calnexin, calreticulin, beta2-microglobulin, LMP7 and PA28alpha was unaltered or only weakly decreased. The impaired expression of TAP, LMP subunits and tapasin was not associated with altered ras, but resulted in reduced MHC class I surface expression. In particular, a significant allele- and locus-specific downregulation of the HLA-A and HLA-B haplotypes was found. IFN-gamma treatment corrected the TAP, LMP and tapasin deficiencies and enhanced the constitutive PA28alpha, LMP7, calnexin and calreticulin expression which was accompanied with increased levels of MHC class I antigens. Thus, dysregulation rather than structural alterations of different APM components might be one mechanism of colon carcinoma, small cell lung carcinoma and pancreatic carcinoma cell lines to evade immune recognition.


Lipid bilayer polypeptide interactions studied by molecular dynamics simulation.
A model membrane with a polypeptide alpha-helix inserted has been simulated by molecular dynamics at a temperature well above the gel/liquid crystalline phase transition temperature. Order parameters of the lipids and other equilibrium and dynamic quantities have been calculated. Three systems, polyglycine constrained into an alpha-helical configuration, glycophorin with similarly conformationally constrained backbone and finally glycophorin free to change its backbone conformation, have been studied. In all cases there was an ordering of the chains close to the helix. This effect was, however, much smaller for glycophorin with its rather bulky side chains than for polyglycine. The dynamics of the lipids were affected by the neighbouring helix, not drastically however. Lateral diffusion and reorientational time correlations of lipids close to the helix were slower than for the bulk ones, but not more than two or three times. Thus, we did not find any evidence of bound or frozen boundary lipids.


Dosage-sensitivity shapes how genes transcriptionally respond to allopolyploidy and homoeologous exchange in resynthesized Brassica napus.
The gene balance hypothesis proposes that selection acts on the dosage (i.e. copy number) of genes within dosage-sensitive portions of networks, pathways, and protein complexes to maintain balanced stoichiometry of interacting proteins, because perturbations to stoichiometric balance can result in reduced fitness. This selection has been called dosage balance selection. Dosage balance selection is also hypothesized to constrain expression responses to dosage changes, making dosage-sensitive genes (those encoding members of interacting proteins) experience more similar expression changes. In allopolyploids, where whole-genome duplication involves hybridization of diverged lineages, organisms often experience homoeologous exchanges that recombine, duplicate, and delete homoeologous regions of the genome and alter the expression of homoeologous gene pairs. Although the gene balance hypothesis makes predictions about the expression response to homoeologous exchanges, they have not been empirically tested. We used genomic and transcriptomic data from 6 resynthesized, isogenic Brassica napus lines over 10 generations to identify homoeologous exchanges, analyzed expression responses, and tested for patterns of genomic imbalance. Groups of dosage-sensitive genes had less variable expression responses to homoeologous exchanges than dosage-insensitive genes, a sign that their relative dosage is constrained. This difference was absent for homoeologous pairs whose expression was biased toward the B. napus A subgenome. Finally, the expression response to homoeologous exchanges was more variable than the response to whole-genome duplication, suggesting homoeologous exchanges create genomic imbalance. These findings expand our knowledge of the impact of dosage balance selection on genome evolution and potentially connect patterns in polyploid genomes over time, from homoeolog expression bias to duplicate gene retention.


Predictors of respiratory function deterioration after transfer of critically ill patients.
Critically ill patients are often transferred due to the growing number of diagnostic procedures required to be performed outside the intensive care unit. These transfers have proved to be very critical. The aim of this study was to evaluate predictors for the deterioration of respiratory function in critically ill patients after transfer. Prospective, clinical, observational study. 1800-bed university teaching hospital. 98 mechanically ventilated patients were investigated during transfer. Before transfer, all patients were classified according to the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Therapeutic Intervention Scoring System (TISS). Haemodynamics and arterial blood gases were measured at 11 different times. Arterial oxygen tension (PaO2), fractional inspired oxygen (FIO2), PaO2/FIO2 ratio, lowest PaO2/FIO2 ratio, minimal PaO2 and maximal FIO2, APACHE II score, TISS before transfer, age and duration of transfer were analysed as potential predictors for deterioration of respiratory function after transfer. Variables were analysed using Classification and Regression Trees and Clustering by Response. In 54 transports (55%) there was a decrease in the PaO2/FIO2 ratio, and a decrease of more than 20% from baseline was noted in 23 of the transferred patients (24%). Age > 43 years and FIO2 > 0.5 were identified as predictors for respiratory deterioration. Our predictors were able to indicate deterioration after transfer correctly in 20 of 22 patients (91%), combined with a false-positive rate in 17 of 49 (35%).


The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite.
The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 +/- 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 +/- 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 +/- 182 ml) and (+)PQ (930 +/- 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life (-)PQ 54 +/- 29 min; (+)PQ 123 +/- 33 min) and smaller area under the curve to infinity (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 +/- 0.26 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 +/- 0.02 ml min-1 and 0.14 +/- 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites (0.24 +/- 0.13 ml min-1 and 0.29 +/- 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.


Psychophysical and electrofunctional contrast sensitivity in cataractous patients treated with bendazac-lysine salt.
The clinical progression of the cataract may be influenced by drugs which reduce the denaturation of lens proteins. One of the most promising drugs is the bendazac-lysine salt. The drug was used in a double-blind study of a group of patients with initial cortical cataract in order to evaluate the changes in visual acuity and contrast sensitivity by means of a psychophysical and an electrophysiological method. After 6 months of treatment with bendazac the mean values of visual acuity showed a statistically significant increase in respect to baseline values, as well as an improvement of the threshold of contrast for most spatial frequencies. In the eyes treated with placebo there was no statistical difference between the visual acuity at baseline and after the treatment, but an increase of the contrast threshold for many spatial frequencies. The treatment with bendazac, when compared to the administration of placebo, leads to a statistically significant improvement of the contrast threshold and induces a global improvement on the visual conditions.


Percutaneous angioscopy: improved technique.
Ten angioscopies with a pressure infusion set resulted in similar visualization times and irrigation volumes as 42 angioscopies with a specially constructed roller pump. Diagnostic image quality, however, was obtained almost exclusively with the roller pump. Three examinations were nondiagnostic. Total viewing time per patient was approximately 1 min with the roller pump and 2 min with the pressure infusion system. In the 30 patients examined, angioscopy changed the initially chosen form of therapy in 5 patients.


Lipase-like 5 enzyme controls mitochondrial activity in response to starvation in Caenorhabditis elegans.
The C. elegans lipase-like 5 (lipl-5) gene is predicted to code for a lipase homologous to the human gastric acid lipase. Its expression was previously shown to be modulated by nutritional or immune cues, but nothing is known about its impact on the lipid landscape and ensuing functional consequences. In the present work, we used mutants lacking LIPL-5 protein and found that lipl-5 is important for normal lipidome composition as well as its remodeling in response to food deprivation. Particularly, lipids with signaling functions such as ceramides and mitochondrial lipids were affected by lipl-5 silencing. In comparison with wild type worms, animals lacking LIPL-5 were enriched in cardiolipins linked to polyunsaturated C20 fatty acids and coenzyme Q-9. Differences in mitochondrial lipid composition were accompanied by differences in mitochondrial activity as mitochondria from well-fed lipl-5 mutants were significantly more able to oxidize respiratory substrates when compared with mitochondria from well-fed wild type worms. Strikingly, starvation elicited important changes in mitochondrial activity in wild type worms, but not in lipl-5 worms. This indicates that this lipase is a determinant of mitochondrial functional remodeling in response to food withdrawal.


Tree species as a potential source of bio-herbicides for controlling Parthenium hysterophorus L.
To assess the herbicidal potential of Eugenia jambolana Lam., Ricinus communis L., Ziziphus jujuba L. and Ziziphus mauritiana L. against noxious weed Parthenium hysterophorus L., germination bioassay using their 1%, 2%, 3%, 4% and 5% (w/v) and seedling growth bioassay using their 5% (w/v) (on dry weight basis) aqueous leaf extracts (ALE) were conducted. ALE of R. communis showed maximum reductions in germination percentage (79%), germination index (89%) and seedling biomass (88%) as well as maximum delays in mean germination time (211%) and time to 50% germination (265%) of parthenium whereas maximum reductions in its seedling length (47%) and seedling vigour index (97%) were shown by Z. mauritiana. Reciprocal dose-response relationship by probit regression analysis revealed that LC50 values of R. communis and Z. mauritiana are 1.04% and 1.44%, respectively. Therefore, R. communis and Z. mauritiana are potential sources of bio-herbicides against this weed.


[Arthroscopic reconstruction of scaphoid nonunions].
Minimally invasive arthroscopically assisted reconstruction of scaphoid nonunions. Delayed union or nonunion of the scaphoid with sclerosis and with indication for bone transplantation. Limited arthritic changes at the radial styloid. Severe humpback deformity with dorsal intercalated segment instability. Midcarpal arthritic changes. Supine position with the forearm upright and in neutral position, the elbow flexed by 90°, axial traction of 3 to 4 kg. Standard wrist arthroscopy via the 3-4 and the 4-5 portal and the midcarpal joint via the radial and ulnar portal, respectively, with sodium chloride as arthroscopy medium. Change of the optic to the ulnar midcarpal portal and opening of the nonunion with an elevator via the radial midcarpal portal. Resection of the sclerosis with a 3.0 mm burr while irrigating the joint. Harvesting of cancellous bone via the second extensor compartment. On the hand table, closed reduction by joy-stick K‑wires if needed and insertion of K‑wires for the scaphoid screw. Insertion of the screw without entering of the distal thread into the bone. Arthroscopic insertion of the bone transplant by a blunt drill sleeve via the radial portal with steady compression by the obturator. Complete insertion of the screw under arthroscopic control of the compression of the nonunion space with arthroscopic control of stability with the probe. Six weeks forearm cast including the thumb metacarpophalangeal joint, radiographic control and non-load bearing movements for two more weeks, CT scan in the oblique sagittal plane after 8 weeks, and increase of load, as well as physiotherapy on demand depending on the radiographic results. To date, 17 patients with a mean age of the nonunion of 18 months were treated. In 14 patients, bony union was achieved after 8 weeks. In one patient, an extraosseous screw placement was corrected. In another patient with extraosseous screw placement, persisting nonunion was treated with an angular stable plate. One scaphoid demonstrated an asymptomatic tight nonunion after 14 months, while one scaphoid with sclerosis of the proximal pole did not heal.


A clickable probe for versatile characterization of S-nitrosothiols.
S-nitrosation of cysteine thiols (SNOs), commonly referred to as S-nitrosylation, is a cysteine oxoform that plays an important role in cellular signaling and impacts protein function and stability. Direct labeling of SNOs in cells with the flexibility to perform a wide range of cellular and biochemical assays remains a bottleneck as all SNO-targeted probes to date employ a single analytical modality such as biotin or a specific fluorophore. We therefore developed a clickable, alkyne-containing SNO probe 'PBZyn' based on the o-phosphino-benzoyl group warhead that enables multi-modal analysis via click conjugation. We demonstrate the utility of PBZyn to assay SNOs using in situ cellular imaging, protein blotting and affinity purification, as well as mass spectrometry. The flexible PBZyn probe will greatly facilitate investigation into the regulation of SNOs.


In silico analysis and characterization of medicinal mushroom cystathionine beta-synthase as an angiotensin converting enzyme (ACE) inhibitory protein.
Angiotensin-converting enzyme (ACE) regulates blood pressure and has been implicated in several conditions including lung injury, fibrosis and Alzheimer's disease. Medicinal mushroom Ganordema lucidum (Reishi) cystathionine beta-synthase (GlCBS) was previously reported to possess ACE inhibitory activities. However, the inhibitory mechanism of CBS protein remains unreported. Therefore, this study integrates in silico sequencing, structural and functional based-analysis, protein modelling, molecular docking and binding affinity calculation to elucidate the inhibitory mechanism of GlCBS and Lignosus rhinocerus (Tiger milk mushroom) CBS protein (LrCBS) towards ACE. In silico analysis indicates that CBSs from both mushrooms share high similarities in terms of physical properties, structural properties and domain distribution. Protein-protein docking analysis revealed that both GlCBS and LrCBS potentially modulate the C-terminal domain of ACE (C-ACE) activity via regulation of chloride activation and/or prevention of substrate entry. GICBS and LrCBS were also shown to interact with ACE at the same region that presumably inhibits the function of ACE.


The effects of pad geometry and material properties on the biomechanical effectiveness of 26 commercially available hip protectors.
Wearable hip protectors (padded garments) represent a promising strategy to decrease impact force and hip fracture risk during falls, and a wide range of products are currently marketed. However, little is known about how design features of hip protectors influence biomechanical effectiveness. We used a mechanical test system (simulating sideways falls) to measure the attenuation in femoral neck force provided by 26 commercially available hip protectors at three impact velocities (2, 3, and 4m/s). We also used a materials testing machine to characterize the force-deflection properties of each device. Regression analyses were performed to determine which geometric (e.g., height, width, thickness, volume) and force-deflection properties were associated with force attenuation. At an impact velocity of 3m/s, the force attenuation provided by the various hip protectors ranged between 2.5% and 40%. Hip protectors with lower stiffness (measured at 500N) provided greater force attenuation at all velocities. Protectors that absorbed more energy demonstrated greater force attenuation at the higher impact velocities (3 and 4m/s conditions), while protectors that did not directly contact (but instead bridged) the skin overlying the greater trochanter attenuated more force at velocities of 2 and 3m/s. At these lower velocities, the force attenuation provided by protectors that contacted the skin overlying the greater trochanter increased with increasing pad width, thickness, and energy dissipation. By providing a comparison of the protective value of a large range of existing hip protectors, these results can help to guide consumers and researchers in selecting hip protectors, and in interpreting the results of previous clinical trials. Furthermore, by determining geometric and material parameters that influence biomechanical performance, our results should assist manufacturers in designing devices that offer improved performance and clinical effectiveness.


Disturbed colocalization of multidrug resistance protein 2 and radixin in human cholestatic liver diseases.
Endocytic retrieval of multidrug resistance protein 2 (MRP2) is closely associated with cholestasis and may be attributed to the disturbed linking of MRP2 and radixin, a cross-linker between actin filaments and membrane proteins. This study aimed to investigate the role of radixin in the altered localization of MRP2 in various human cholestatic liver diseases. Using immunofluorescence microscopy, we investigated the localization and expression of MRP2 and radixin in various cholestatic liver diseases, such as drug-induced liver injury, obstructive jaundice, primary sclerosing cholangitis and autoimmune hepatitis. Changes in localization and expression were analyzed using Scion Image (software). In the icteric drug-induced liver injury, MRP2 was localized outside as well as inside of ZO-1 staining, indicating endocytic retrieval from the canalicular membrane into the pericanalicular compartments of the hepatocytes. The colocalization of MRP2 and radixin observed in the controls was disturbed, and MRP2 fluorescence disappeared in the canaliculi with disrupted radixin staining. Disturbed colocalization of MRP2 and radixin as well as endocytic retrieval of MRP2 was found in the poorly drained obstructive jaundice. When drainage was good, MRP2 was exclusively colocalized with radixin. Similar findings were observed in autoimmune hepatitis and primary sclerosing cholangitis. In the controls, the immunostaining intensity curves for MRP2 and radixin were steeply elevated in the canaliculi. The intensity curves for MRP2 and radixin were broadened in the icteric drug-induced liver injury and poorly drained obstructive jaundice, indicating endocytic retrieval into the hepatocytes. The peak fluorescence intensities for MRP2 and radixin decreased in the icteric liver. Disturbed colocalization of MRP2 and radixin was common in various cholestatic liver diseases, which may be associated with endocytic retrieval of MRP2 due to failure in anchoring MRP2 in the canalicular membrane.


Lipopolysaccharide-induced inflammation or unilateral ureteral obstruction yielded multiple types of glycosylated Lipocalin 2.
The amount of urinary glycoprotein lipocalin 2 (LCN2) has been known to increase after kidney injury because of failed reabsorption by the proximal tubules or direct secretion from injured tissues. However, the relationship between urinary tract obstruction and the isoform diversity of LCN2 has not been examined. The urinary levels of LCN2 isoforms were examined in male mice after an intraperitoneal injection of lipopolysaccharide (LPS) or in a mouse model of unilateral ureter obstruction (UUO). The LCN2 levels in sera, bladder urine, renal pelvic urine, and tissue samples were also analyzed. Endo- and exoglycosidases were used to investigate the different N-glycan patterns of LCN2. Two isoforms of urinary LCN2 with different molecular weights were identified in an immunoblotting analysis, and the levels of both isoforms were increased 6 h after LPS administration. The primary LCN2 isoform was the lower molecular weight 22-kDa isoform, which was detected in the serum, urine, liver and kidney. In contrast, the 24-kDa LCN2 isoform was detected only in urine. In the UUO experiments, the levels of the 24-kDa LCN2 were increased in the bladder urine but not in the urine accumulated in the renal pelvis due to UUO. The 22-kDa LCN2 was identified in the renal pelvic urine from UUO mice. The peptide-N glycosidase F digestion of the two urinary LCN2 isoforms generated a single protein. Moreover, the two urinary LCN2 proteins were sensitive to neuraminidase and resistant to endoglycosidase H (Endo H). The LCN2 in the serum, lung and kidney was resistant to Endo H, as observed in urine, whereas the LCN2 in the liver and the ureter were degraded by this enzyme. These results suggest that the difference in the molecular weights of the LCN2 proteins was due to their N-glycan structure. The high molecular weight LCN2 in urine could be detected after the inflammatory response to LPS and UUO. Furthermore, the sensitivity to Endo H identified the presence of two types of carbohydrate moieties, depending on the tissue in which the LCN2 was produced. These findings are useful for widening the clinical applicability of urinary LCN2 analyses.


How sticky? How tight? How hot? Imaging probes for fluid viscosity, membrane tension and temperature measurements at the cellular level.
We review the progress made in imaging probes for three important physical parameters: viscosity, membrane tension, and temperature, all of which play important roles in many cellular processes. Recent evidences showed that cell migration speed can be modulated by extracellular fluid viscosity; membrane tension contributes to the regulation of cell motility, exo-/endo-cytosis, and cell spread area; and temperature affects neural activity and adipocyte differentiation. We discuss the techniques implementing imaging-based probes to measure viscosity, membrane tension, and temperature at subcellular resolution dynamically. The merits and shortcomings of each technique are examined, and the future applications of the recently developed techniques are also explored.


[Psychosocial adjustment after epilepsy surgical treatment].
Epilepsy is a matter of interest to several medical specialities: neurology, neurosurgery, pathology, psychiatry, and other fields of knowledge such as psychology and sociology. Although a high prevalence of psychopathological disorders is often reported among epileptic patients who are candidates for neurosurgery, this cannot explain the problems that may be experienced by patients after surgery. Numerous related aspects such as neurological, psychological and sociological factors cause disturbances. This study suggests that systematic psychological and social management might help in the transition from chronic disability to wellness by means of improved adjustment potential.


Nocardia farcinica infection of a cochlear implant in an immunocompetent boy.
The first case of an infection caused by Nocardia farcinica on a cochlear implant and its progression is described. As it is difficult to diagnose Nocardia spp., the identification was confirmed by phylogenetic analysis using 16S rDNA sequencing.


Educating general practitioners about prenatal testing: approaches and challenges.
To examine the effects of an education intervention on the knowledge and practice behaviours of general practitioners (GPs) regarding prenatal screening and diagnostic testing in Melbourne, Australia. A single group, pre-test, repeated post-test design was used. Information on demographics, knowledge, behaviours and skills was collected via a self-administered questionnaire prior to the educational intervention. Responses to individual questions were coded and scores calculated, as well as a percent total score. Following the education, data were again collected, immediately afterwards (Post-Q) and six-to-eight months later (Foll-Q). Data for all three time points were collected from 63 GPs and showed a variable, and relatively poor knowledge regarding aspects of prenatal testing, especially before education. The percent mean total score at baseline was 51.2+/-1.59% (CI 48.02 to 54.39), which increased significantly (p<0.001) in both Post-Q (62.88+/-1.51%; CI 59.86 to 65.89) and Foll-Q (58.92+/-1.6%; CI 55.71 to 62.12). The educational intervention significantly increased knowledge and practice behaviour of GPs, even up to eight months later, but this could be improved further, to a considerable extent. There is a need for ongoing multi-faceted approaches to educating GPs on prenatal testing to ensure that they are engaged in appropriate practice.


Mitral Doppler indices are superior to two-dimensional echocardiographic and hemodynamic variables in predicting responsiveness of cardiac output to a rapid intravenous infusion of colloid.
We hypothesized that mitral flow (MF) Doppler measurements could be used to predict cardiac output (CO) responsiveness to fluid challenge. Fourteen patients with normal systolic and diastolic function, scheduled for coronary artery bypass graft surgery, were evaluated as part of a pilot study in which preload was varied immediately before the beginning of cardiopulmonary bypass. A Validation group of 36 patients with different levels of systolic and diastolic function received a rapid infusion of 500 mL of 10% pentastarch. By use of transesophageal echocardiography, we measured left ventricular end-diastolic area, pulsed Doppler indices of the MF and pulmonary venous flow, and standard hemodynamic variables during acute volemic variations. A baseline measurement was first recorded, followed by measurements taken after a decrease (211 +/- 87 mL) and then an increase (176 +/- 149 mL) in preload (pilot study) and before and after 500 mL of pentastarch (validation study). In the pilot study, we found that a low velocity/time integral (VTI) E wave/A wave (E/A) ratio was associated with a larger increase in CO secondary to an increase in preload (r = 0.64, P < 0.05). Stepwise linear regression identified Doppler measurements of the mitral VTI E/A ratio as the most important variable to predict the increase in CO after fluid infusion. In the validation study, a mitral E/A ratio <1.26 before fluid infusion best predicted a 20% increase in stroke volume (receiver operating characteristic curve, 71%; P < 0.05), whereas no other hemodynamic or echocardiographic variable predicted preload responsiveness. We conclude that the MF Doppler filling pattern is an important factor to predict the increase in CO after intravascular fluid challenge in patients undergoing coronary artery bypass grafting. In the presence of low cardiac output, the clinician's ability to identify which patients are more likely to benefit from volume administration to improve hemodynamic status while avoiding fluid overload is important. The analysis of Doppler measurement of the mitral flow as an indirect indicator of the individual diastolic pressure/volume relationship may be useful to predict the intravascular volume responsiveness in patients undergoing coronary artery bypass graft surgery.


Pilot estuarine mesocosm study on the environmental fate of Silver nanomaterials leached from consumer products.
Although nanosilver consumer products (CPs) enjoy widespread availability, the environmental fate, leaching, and bioaccumulation behaviors of silver nanoparticles (AgNPs) from these products are not well understood. In this work, three nanosilver CPs, two AgNP standards, and an ionic silver (Ag(+)) standard were studied in estuarine mesocosms. The CPs exhibited long-term release of significant amounts of silver over a 60d residence time in the mesocosms, and ultimately released 82 - 99% of their total silver loads. Measurements of total silver as a function of time, by inductively coupled plasma mass spectrometry (ICP-MS), indicated that the silver was transferred from the water column and accumulated in the estuarine biota, including hard clams, grass shrimp, mud snails, cordgrass stalks and leaves, biofilms, intertidal sediment, and sand. The ICP-MS results and calculations of bioconcentration and trophic transfer factors indicated that significant amounts of silver were taken up by the organisms through trophic transfer. Silver was also adsorbed from the seawater into the biofilms, sediment, and sand, and from the sand into the clams.


Selective cytotoxicity of azatyrosinamides against ras-transformed NIH 3T3 cells.
This study aims to develop novel azatyrosinamide compounds structurally modified from ras-specific antioncogenic azatyrosine. Analogues 4-15 were prepared and their inhibition on the growth of wild-type and ras-transformed NIH 3T3 cell lines was compared. Compound 12 was found to be the most active with IC50 16.5+/-2.2 microM which is 458-fold more potent than that of azatyrosine. The selective toxicity, defined as IC(50 wild-type)/IC(50 ras-transformed) for this compound was 138.5.


Epidemiological and transcriptome data identify potential key genes involved in iron overload for type 2 diabetes.
Many previous studies have reported the association between iron overload (IO) and type 2 diabetes mellitus (T2DM). However, the underlying molecular mechanism is not clear. Epidemiological data from the National Health and Nutrition Examination Survey 2017-2018 (NHANES) was used to systematically explore the association between IO and diabetes. Furthermore, transcriptome data from Gene Expression Omnibus (GEO) were analyzed using bioinformatics methods to explore the underlying functional mechanisms at the molecular level. Data from NHANES showed a "W" shape relationship between serum iron (frozen) and the risk of diabetes (P < 0.001) as well as a "∧" shape correlation between serum unsaturated iron binding capacity (UIBC) and the risk of diabetes (P = 0.007). Furthermore, the serum iron (frozen) was positively associated with fasting plasma glucose and HOMAB (P < 0.05), and UIBC was positively associated with fasting insulin (P < 0.05). Transcriptome data showed that two IO-related genes [Transferrin receptor (TFRC) and Solute carrier family-11 member-2 (SLC11A2)] were down-regulated in T2DM. The correlation analysis showed that expression levels of TFRC and SLC11A2 were significantly and positively correlated with genes involved in insulin secretion (P < 0.05). Protein-protein interaction network analysis showed that TFRC and SLC11A2 interacted with four key genes, including VAMP2, HIF1A, SLC2A1, and RAB11FIP2. We found that IO status was associated with increased FPG and aggravated HOMAB, and two IO-related genes (TFRC and SLC11A2) might induce the occurrence of T2DM by influencing insulin secretion, which provides potential therapeutic targets for T2DM patients.


Simultaneous separation of basic and acidic proteins using 1-butyl-3-methylimidazolium-based ion liquid as dynamic coating and background electrolyte in capillary electrophoresis.
1-Butyl-3-methylimidazolium tetrafluoroborate ionic liquids (1B-3MI-TFB ILs) were employed as a coating material and BGE in CE for simultaneous separation of basic and acidic proteins such as lysozyme, cytochrome C, ribonuclease A, albumin, and alpha-lactalbumin. 1B-3MI-TFB ILs effectively reversed the surface charges on the capillary inner surface, preventing the adsorption of positively charged proteins onto the silica surface, as well as associated with proteins, thus benefiting the separation efficiencies and reproducibility. Consequently, simultaneous baseline separation of five proteins was achieved within 14 min by using 10 mM of 1B-3MI-TFB ILs as dynamic coating and the only running electrolyte at the voltage of +20 kV. The proposed coating technique is simple, less time-consuming, reproducible, and also stable enough for proteins separation without the need of additives. Symmetrical peaks with efficiencies up to 670,000 plates/m were obtained. Recoveries of proteins with RSD (for migration times) of 0.23-0.42% (run-to-run) and 2.5-3.8% (day-to-day) were achieved, respectively. The applicability of the proposed method in proteins separation was evaluated by the separation of egg white samples.


Heteropoly acid-driven assembly of glutathione into redox-responsive underwater adhesive.
Dynamic adhesives were fabricated based on the ionic co-assembly of glutathione and heteropoly acids (HPAs). The underwater attachment and detachment of the adhesives were achieved based on the redox properties of glutathione. We demonstrated that the formation of disulfide bonds of glutathione plays a pivotal role in the formation of robust 3D network structures as well as the improvement of cohesion.


Proteolytic Activity Attenuates the Response of Endothelial Cells to Fluid Shear Stress.
Recent evidence indicates that several experimental pathophysiological conditions are associated with elevated protease activity in plasma, which impacts endothelial function. We hypothesize that extracellular structures bound to the endothelial cell (EC) membrane may be degraded by proteolytic activity and cause the cells to respond abnormally to physiological shear stress (12 dyn/cm(2)). To test this hypothesis, cultured bovine aortic endothelial cells (BAECs) were exposed to low levels of a serine protease, trypsin. Extracellular mechanosensor densities of the glycocalyx and vascular endothelial growth factor receptor 2 (VEGFR-2) were determined. Metabolic dysfunction was tested by examining insulin receptor and glucose uptake levels. Protease treatment impaired the cells' ability to align in the direction of fluid flow after 12 hours of shear stress; however, cells realigned after an additional 12 hours of shear stress with protease inhibition. Proteases caused reduction in the densities of glycocalyx, VEGFR-2, and insulin receptor in static and shear conditions, except for static VEGFR-2 cells. Under static conditions, protease-treated endothelial cells had reduced glucose uptake compared to untreated controls. Under shear, however, glucose uptake for protease-treated BAECs was greater than untreated controls. In conclusion, protease activity in plasma alters the exofacial membrane components of ECs and may interfere with mechanotransduction.