Unveiling the hidden economic toll of biological invasions in the European Union.
Biological invasions threaten the functioning of ecosystems, biodiversity, and human well-being by degrading ecosystem services and eliciting massive economic costs. The European Union has historically been a hub for cultural development and global trade, and thus, has extensive opportunities for the introduction and spread of alien species. While reported costs of biological invasions to some member states have been recently assessed, ongoing knowledge gaps in taxonomic and spatio-temporal data suggest that these costs were considerably underestimated. We used the latest available cost data in InvaCost (v4.1)-the most comprehensive database on the costs of biological invasions-to assess the magnitude of this underestimation within the European Union via projections of current and future invasion costs. We used macroeconomic scaling and temporal modelling approaches to project available cost information over gaps in taxa, space, and time, thereby producing a more complete estimate for the European Union economy. We identified that only 259 out of 13,331 (~ 1%) known invasive alien species have reported costs in the European Union. Using a conservative subset of highly reliable, observed, country-level cost entries from 49 species (totalling US$4.7 billion; 2017 value), combined with the establishment data of alien species within European Union member states, we projected unreported cost data for all member states. Our corrected estimate of observed costs was potentially 501% higher (US$28.0 billion) than currently recorded. Using future projections of current estimates, we also identified a substantial increase in costs and costly species (US$148.2 billion) by 2040. We urge that cost reporting be improved to clarify the economic impacts of greatest concern, concomitant with coordinated international action to prevent and mitigate the impacts of invasive alien species in the European Union and globally. The online version contains supplementary material available at 10.1186/s12302-023-00750-3.


Skin manifestations of mercury poisoning.
Eight patients with skin lesions attributed to methylmercury exposure are reported. The outbreak of poisoning occurred in Iraq as a result of the handling and ingestion of treated grain and home-made bread. The skin manifestations were rather rare and varied in severity and histological appearance.


The trypsin-inhibitory, immunostimulatory and antiproliferative activities of a napin-like polypeptide from Chinese cabbage seeds.
A heterodimeric 13.8 kDa napin-like polypeptide has previously been isolated from Chinese cabbage (Brassica parachinensis) seeds with a procedure involving ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, FPLC-ion exchange chromatography on Mono S and FPLC-gel filtration on Superdex 75. In the present study the N-terminal sequence of the 8.8 kDa subunit of the polypeptide (PQGPQQRPPKLLQQQTNEEHE) was found to have pronounced homology to napins, albumins and trypsin inhibitors, but demonstrated little similarity to the 5 kDa subunit. The polypeptide stimulated nitrite production by mouse peritoneal macrophages and reduced the viability of leukaemia (L1210) cells. It inhibited trypsin with a higher potency than it inhibited chymotrypsin, but was devoid of ribonuclease and antifungal activities.


Analysis of sputum microbial metagenome in COPD based on exacerbation frequency and lung function: a case control study.
The role of the sputum microbiome in chronic obstructive pulmonary disease (COPD) progression remains elusive. As the advent of the new culture-independent microbial sequencing technique makes it possible to disclose the complex microbiome community of the respiratory tract. The aim of this study was to use metagenomic next-generation sequencing (mNGS) to confirm whether there are differences in sputum microbiome of COPD between different exacerbation frequencies and lung function. Thirty-nine COPD patients were divided into a frequent exacerbators (FE) group (n = 20) and a non-frequent exacerbators (NFE) (n = 19) group according to their exacerbation history, or a mild group (FEV1/pre ≥ 50%, n = 20) and a severe group (FEV1/pre < 50%, n = 19) according to the lung function. Sputum was collected during their stable phase, followed by DNA extraction, untargeted metagenomic next-generation sequencing (mNGS) and bioinformatic analysis. mNGS identified 3355 bacteria, 71 viruses and 22 fungi at the specie level. It was found that Shannon index and Simpson index in FE group was lower than that in NFE group (p = 0.005, 0.008, respectively) but similar between mild and severe groups. Out of top 10 bacteria taxa, Veillonella, Fusobacterium and Prevotella jejuni had a higher abundance in NFE group, Rothia had a higher abundance in mild group. Linear discriminant analysis revealed that many bacterial taxa were more abundant in NFE group, and they mostly belonged to Actinobacteria, Bacteroidetes and Fusobacteria phyla. Frequency of exacerbations was also found to be negatively correlated with alpha diversity (with Shannon index, r = - 0.423, p = 0.009; with Simpson index, r = - 0.482, p = 0.002). No significant correlation was observed between alpha diversity and FEV1/pre. Microbiome diversity in FE group was lower than that in NFE group. There was a significant difference in microbiome taxa abundance between FE and NFE groups, or mild and severe groups. These findings demonstrated that sputum microbiome community dysbiosis was associated with different exacerbation frequencies and lung function in stable COPD.


Impact of 68Ga-NOTA-MAL-MZHER2 PET imaging in advanced gastric cancer patients and therapeutic response monitoring.
Clinical PET imaging of human epidermal growth factor receptor 2 (HER2) can noninvasively detect HER2 overexpression in lesions. A novel 68Ga-NOTA-MAL-MZHER2 (68Ga-HER2) affibody was developed for clinical PET/CT, and its safety, tissue dosimetry, ability to detect HER2-positive lesions, and utility for HER2-targeted therapy in patients with advanced gastric cancer (AGC) were evaluated. Thirty-four patients with AGC (23 with HER2-positive and 11 with HER2-negative primary lesions) were included and underwent PET/CT after an injection of approximately 3.7 MBq/kg body weight 68Ga-HER2 affibody. Thirteen patients (8 HER2-positive and 5 HER2-negative patients) were scanned at 1, 2, and 3 h post-injection to determine the best imaging timepoint, and the remaining patients were scanned at the optimized timepoint. All patients underwent standard 18F-FDG PET/CT within 7 d to identify viable lesions. The SUVmax of lesions larger than 1.0 cm were analyzed. Five lesion maxima were analyzed for each organ. (1) The 68Ga-HER2 affibody was safe and effective, and optimal image contrast was observed 2 h post-injection; the average effective absorbed dose was 0.0215 mSv/MBq. (2) The HER2-positive group had significantly higher 68Ga-HER2 affibody uptake than the HER2-negative group (SUVmax 10.7 ± 12.5 vs 3.8 ± 1.7, p = 0.005). The specificity and sensitivity were 100 and 55.4%, respectively, with a SUVmax cutoff value of 6.6. The SUVmax of the lesions ranged from 1.6 to 73.0, suggesting heterogeneity in HER2 expression. (3) 68Ga-HER2 affibody uptake showed an organ-dependent difference in patients with HER2-positive expression. Bone metastases had the highest uptake (SUVmax 40.5 ± 24.9), followed by liver metastases (SUVmax 11.9 ± 3.9) and lymph node metastases (SUVmax 5.6 ± 3.7), while the uptake in other lesions, including in the primary lesion, was relatively lower (SUVmax 7.3 ± 3.7). (4) Patients receiving therapy had a non-significantly lower lesion SUVmax than patients not receiving therapy (SUVmax 8.8 ± 4.9 vs 11.8 ± 15.2) (p = 0.253). Additionally, the 68Ga-HER2 affibody detected positive lesions in 1/11 patients with HER2-negative primary gastric cancer, which was confirmed by second generation gene sequencing. (5) Moreover, ten patients underwent baseline PET/CT followed by targeted anti-HER2 therapy. Patients with lesions showing high avidity to the 68Ga-HER2 affibody showed longer progression-free survival (PFS) than those with lesions showing low avidity (4-9 m vs 2-3 m). 68Ga-HER2 affibody PET/CT is a feasible method to noninvasively detect the HER2 status in AGC patients and enable early detection with a low dose. Ongoing anti-HER2 therapy did not influence 68Ga-HER2 affibody imaging, which allowed repeated evaluations to monitor the HER2 status after anti-HER2 therapy. This method provides an in vivo understanding of AGC biology that will ultimately help oncologists improve individualized therapy plans.


An adaptive integral terminal sliding mode controller to track the human upper limb during front crawl swimming.
Injuries are inevitable during swimming. The main goal of athletes especially competitive ones and coaches is to do the most mechanically effective movement patterns. In this case, biomechanical assessments could be beneficial in the management and prevention of injuries and pain in swimmers' vulnerable joints. As the upper limb in swimming causes the highest propulsive force, the arm is exposed to more injuries. A skeletal model with 5 degrees of freedom is developed to simulate the swimmer's arm during front crawl swimming. This model includes shoulder and elbow joints with all of their degrees of freedom. An adaptive integral sliding mode (AITSM) controller is employed to track the desired joint trajectories during swimming. This controller can converge the tracking errors to zero in finite time. For tuning the controller gains regardless of the upper bounds of the system uncertainties, an adaptive controller is applied. The results demonstrate the performance of the AITSM strategy in tracking the desired trajectory of an underwater arm model during swimming. During the down sweep to catch phase, arm movements cause more stress in the shoulder than the elbow. The applied moment at the shoulder is almost triple of the elbow's moment. Therefore, the most vulnerable joint is the shoulder. By considering shoulder strength, the injury risk is predicted about 10% for the considered swimmer.HighlightsThe human upper limb during front crawl swimming is simulated.A 5-DOF skeletal model is considered to simulate the arm.An adaptive integral sliding mode (AITSM) controller is employed to track the desired trajectory.The results show that the controller has the proper performance to track the desired motion.The most vulnerable joint is the shoulder and higher moments are induced at this joint.


Crystal structure of an uncleaved serpin reveals the conformation of an inhibitory reactive loop.
The three-dimensional structure of an uncleaved serpin, a variant of human antichymotrypsin engineered to be an inhibitor of human neutrophil elastase, has been determined by X-ray crystallographic methods and is currently being refined at 2.5 A resolution. It contains an intact reactive loop in a distorted helical conformation. A comparison of the current model with that of its cleaved counterpart suggests that the conformational 'stress' of the serpin in its uncleaved and uncomplexed state may not be confined solely to the reactive loop or beta-sheet A. It is intriguing that strand s4A is not pre-inserted into beta-sheet A of the native serpin, and this has profound implications for the mechanism of serpin function.


Concentrations and human health implications of heavy metals in wild aquatic organisms captured from the core area of Daya Bay's Fishery Resource Reserve, South China Sea.
Heavy metal concentrations in edible organisms from the core area of Daya Bay's Fishery Resource Reserve, South China Sea, were determined. Samples of 14 crustacean, fish, and shellfish species were collected and analyzed. The As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn concentrations were 0.18-1.16, 0.002-0.919, 0.40-2.85, 0.07-4.10, 0.004-0.055, 0.14-1.19, 0.014-0.070, and 4.57-15.94μg/g wet weight, respectively. The As concentrations were higher than the Chinese maximum permissible levels in all of the fish and shellfish species and two crustacean species, indicating that consumption of these wild species by humans may pose health risks. However, calculations of the health risks posed to humans indicated that no significant adverse health effects would be associated with consuming these species.


TikTok and YouTube Videos on Overactive Bladder Exhibit Poor Quality and Diversity.
We sought to assess the quality, understandability, actionability, and diversity of speakers in videos on TikTok and YouTube regarding overactive bladder. Using Application Program Interface, the top 500 TikTok and 120 YouTube videos on overactive bladder were retrieved. Videos unrelated to overactive bladder, those not in English, longer than 10 minutes, or lacking both text and audio were excluded. Surgical technique videos for providers were also excluded. Videos were scored by trained raters using 2 validated instruments: PEMAT (Agency for Healthcare Research and Quality's Patient Education Materials Assessment Tool) for actionability and understandability, and the DISCERN instrument for quality of consumer health information. We also examined for evidence of misinformation and commercial bias. One hundred thirty-six TikTok videos and 75 YouTube videos met inclusion criteria. Eighty-eight percent of TikTok videos had poor PEMAT actionability scores (a score below 75%), as compared to 60% of YouTube videos. Both YouTube and TikTok videos scored low on PEMAT understandability. Ninety-eight percent of TikTok videos and 65% of YouTube videos were poor quality (DISCERN score <3). YouTube videos had higher actionability and quality than TikTok videos (P < .001) but did not differ on understandability (P = .769). Twenty-three percent of TikTok and 11% of YouTube videos had high misinformation (score >3). Commercial bias was present in 10% of TikTok and 19% of YouTube videos. Actionability, understandability, and quality for overactive bladder-related content is poor on YouTube and TikTok. With increasing access to social media, it is important that health care providers and organizations invest resources in patient education on health literacy.


Factors Associated with Eczema Clinical Trial Awareness, Interest, and Participation in Adults.
Despite the need for improved eczema therapies and a rapid increase in available eczema clinical trials, participation remains low. The aim of this study was to identify factors associated with clinical trial awareness, interest, and barriers to enrolment and participation. An online survey, administered 1 May to 6 June 2020 to adults (≥ 18 years) with eczema in the USA, was analysed. Among 800 patients included, mean age was 49.4 years, most respondents were female (78.1%), White (75.4%), non-Hispanic (91.4%), and geographically living in an urban/suburban area (Rural-Urban Continuum Codes (RUCC) 1-3, 90.8%). Only 9.7% of respondents reported previous participation in clinical trials, while 57.1% had considered participation and 33.2% never considered participation. Higher satisfaction with current eczema therapy, clinical trial literacy, and confidence in finding eczema trial information were all associated with clinical trial awareness, interest, and successful participation. Younger age and having atopic dermatitis were associated with increased awareness, while female gender was a barrier to interest and successful participation.


Proteomics revealed the crosstalk between copper stress and cuproptosis, and explored the feasibility of curcumin as anticancer copper ionophore.
As an essential micronutrient element in organisms, copper controls a host of fundamental cellular functions. Recently, copper-dependent cell growth and proliferation have been defined as "cuproplasia". Conversely, "cuproptosis" represents copper-dependent cell death, in a nonapoptotic manner. So far, a series of copper ionophores have been developed to kill cancer cells. However, the biological response mechanism of copper uptake has not been systematically analyzed. Based on quantitative proteomics, we revealed the crosstalk between copper stress and cuproptosis in cancer cells, and also explored the feasibility of curcumin as anticancer copper ionophore. Copper stress not only couples with cuproptosis, but also leads to reactive oxygen species (ROS) stress, oxidative damage and cell cycle arrest. In cancer cells, a feedback cytoprotection mechanism involving cuproptosis mediators was discovered. During copper treatment, the activation of glutamine transporters and the loss of Fe-S cluster proteins are the facilitators and results of cuproptosis, respectively. Through copper depletion, glutathione (GSH) blocks the cuproptosis process, rescues the activation of glutamine transporters, and prevents the loss of Fe-S cluster proteins, except for protecting cancer cells from apoptosis, protein degradation and oxidative damage. In addition, the copper ionophore curcumin can control the metabolisms of lipids, RNA, NADH and NADPH in colorectal cancer cells, and also up-regulates positive cuproptosis mediators. This work not only established the crosstalk between copper stress and cuproptosis, but also discolored the suppression and acceleration of cuproptosis by GSH and curcumin, respectively. Our results are significant for understanding cuproptosis process and developing novel anticancer reagents based on cuproptosis.


Nanoparticles in the brain: a potential therapeutic system targeted to an early defect observed in many neurodegenerative diseases.
Currently, there are no effective treatments or cures for many neurodegenerative diseases affecting an aging baby-boomer generation. The ongoing problem with many of the current therapeutic treatments is that most are aimed at dissolving or dissociating aggregates and preventing cell death, common neuropathology often seen towards the end stage of disease. Often such treatments have secondary effects that are more devastating than the disease itself. Thus, effective therapeutics must be focused on directly targeting early events such that global deleterious effects of drugs are minimized while beneficial therapeutic effects are maximized. Recent work indicates that in many neurodegenerative diseases long distance axonal transport is perturbed, leading to axonal blockages. Axonal blockages are observed before pathological or behavioral phenotypes are seen indicating that this pathway is perturbed early in disease. Thus, developing novel therapeutic treatments to an early defect is critical in curing disease. Here I review neurodegenerative disease and current treatment strategies, and discuss a novel nanotechnology based approach that is aimed at targeting an early pathway, with the rationale that restoring an early problem will prevent deleterious downstream effects. To accomplish this, knowledge exchange between biologists, chemists, and engineers will be required to manufacture effective novel biomaterials for medical use.


Organization of the striate-recipient zone of the cats lateralis posterior-pulvinar complex and its relations with the geniculostriate system.
The extrageniculate visual thalamus of the cat is divisible into several major subdivisions but only one receives dense fiber projections from the striate cortex. In the present study, modern axon transport techniques and acetylcholinesterase histochemistry were used to examine the internal organization of this striate-recipient zone and some of its afferent and efferent connections. A detailed study of the corticothalamic fiber projections of the striate cortex clarified the topographic organization and boundaries of the striate-recipient zone. The nature and course of "projection lines" within the zone were defined and the subdivision was shown to correspond closely to a region of relatively weak acetylcholinesterase staining. Corticothalamic projections from two regions of the extrastriate visual cortex, area 19 and the medial division of the Clare-Bishop complex, converge with those from area 17 in the striate-recipient zone, but these extrastriate areas have more widespread projections to the extrageniculate thalamus than does the striate cortex. A weak subcortical projection to the striate-recipient zone was demonstrated, apparently originating in the superior colliculus. Retrograde tracing experiments indicated that the corticothalamic inputs of the striate-recipient zone are precisely reciprocal by thalamocortical projections. Extrageniculate thalamic projections to area 17 arise exclusively from this thalamic subdivision and are highly topographically ordered. The striate-recipient zone projects massively and apparently retinotopically to area 19 and to the medial division of the Clarc-Bishop area, as well as area 21(a), but these extrastriate areas receive additional afferents from other subdivisions of the extrageniculate thalamus. These findings appear to rule out a "non-specific" functional role for the striate-recipient zone. In its topographic organization, its reciprocal connections with areas of the visual cortex, and its sheer volume, the zone seems comparable to the dorsal lateral geniculate nucleus and may be fairly considered a satellite of the geniculocortical system. Certain of the zone's organizational and connectional features may be clues to its functional role and its possible homologues in other mammalian forms.


Predicting Collapse in Osteonecrosis of the Femoral Head Using a New Method: Preserved Angles of Anterior and Lateral Femoral Head.
Femoral head collapse (FHC) is associated with a poor prognosis in osteonecrosis of the femoral head (ONFH). Preserved angles (PAs), including the lateral preserved angle (LPA), the anterior preserved angle (APA) and the combined preserved angle (CPA), can be used to quantify the extent of femoral head necrosis and predict the risk of femoral head collapse. The purpose of this retrospective cohort study was to assess the efficacy of these preserved angles in the prediction of femoral head collapse using plain radiographs. Patients with ONFH treated conservatively between January 2010 and January 2019 were analyzed retrospectively to assess the risk of FHC. A logistic regression model was used to evaluate the independent prognostic factors associated with FHC, including age, sex, etiology, onset of symptom, The Japanese Investigation Committee classification, and PAs (LPA, APA, and CPA). A total of 137 patients, with 180 hips, had follow-up of at least two years and were included. During the follow-up period, FHC occurred in 89 hips (49.44%) after the initial diagnosis. Multivariable analysis indicated that CPA (odds ratio [OR] = 0.95; 95%CI = 0.93-0.97; P < 0.01) was a stronger predictor of femoral head collapse compared with the Japanese Investigation Committee classification (OR = 2.40, 95%CI = 0.92-6.25; P > 0.01). The receiver operating characteristic and survival curve analyses revealed that the predictive cutoff point for the CPA was 118.7° (sensitivity = 96.70%, specificity = 79.78%, log-rank test: P < 0.01). Assessment of preserved angles on plain radiographs is a simple method to quantify the extent of lateral and anterior necrosis of the femoral head. Specifically, CPA has a potential value in predicting femoral head collapse.


Effects of early separation of young rats from the mother on their open-field behavior.
Changes were studied in the open-field behavior of young rats prematurely separated from their mothers at different ages. Premature separation from the mother on days 15 and 18 of life increased their fear or emotional behavior, as measured by the amount of defecation and locomotor activity. The changes in rats' open-field behavior were due to the absence of the mother rather than to an inadequate food supply after the day of separation.


Extraction mechanisms of charged organic dye molecules into silica-surfactant nanochannels in a porous alumina membrane.
Extraction mechanisms of charged organic dye molecules are examined for an assembly of silica-surfactant nanochannels with a channel diameter of 3.4 nm, which is formed inside the pores of an anodic alumina membrane by a surfactant-template method. Experimental results confirm that the extraction mechanism depends on the sign of a charge of the dye molecules. The extraction of the cationic rhodamine 6G is predominantly caused by an ion-pair extraction process, whereas an anion-exchange process is mainly responsible for the extraction of the anionic sulforhodamine B. These extraction mechanisms are discussed by considering the microstructures of the silica-surfactant nanochannels.


Changes of insular function in lifelong premature ejaculation patients before and after SSRI administration.
Lifelong premature ejaculation (PE) is regarded as one of the most common male sexual dysfunction. We aimed to detect whether insula-related brain functional networks are altered in lifelong PE patients and whether such alterations are "normalised" after selective serotonin reuptake inhibitors (SSRI) administration. Twenty-three drug-naive lifelong PE patients and 30 healthy controls (HC) were recruited in current study. All subjects underwent resting-state functional magnetic resonance imaging (fMRI) scan at first. One hour after dapoxetine administration, all patients underwent fMRI scanning again. The degree centrality (DC), amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) analysis, and ROI-based functional connectivity (FC) analysis were applied to calculate the abnormalities in insula-related functions among three groups. Compared to HC group, PE patients at baseline showed significantly altered DC, ALFF, and ReHo value of the bilateral insula, which subsequently showed a "normalised" trend after dapoxetine administration. Additionally, compared to HC group, PE patients at baseline showed significantly decreased FC between insula and precentral gyrus, inferior frontal gyrus, middle/inferior temporal gyrus, and caudate, while patients after dapoxetine administration showed increased insula-related FC in anterior cingulate cortex and decreased FC in thalamus and middle/inferior temporal gyrus. The main effects of dapoxetine were located in precentral gyrus, inferior frontal gyrus, caudate, and limbic system. Our findings report altered brain mechanism of insula in lifelong PE patients and also indicate that dapoxetine can "normalise" the abnormal function of the insula to certain extent in lifelong PE patients.


Metalloproteases and rotator cuff disease.
The molecular changes occurring in rotator cuff tears are still unknown, but much attention has been paid to better understand the role of matrix metalloproteinases (MMP) in the development of tendinopathy. These are potent enzymes that, once activated, can completely degrade all components of the connective tissue, modify the extracellular matrix (ECM), and mediatethe development of painful tendinopathy and tendon rupture. To control the local activity of activated proteinases, the same cells produce tissue inhibitors of metalloproteinases (TIMP) that bind to the enzymes and prevent degradation. The balance between the activities of MMPs and TIMPs regulates tendon remodeling, whereas an imbalance produces a collagen dis-regulation and disturbances intendons. ADAMs (a disintegrin and metalloproteinase) are cell membrane-linked enzymes with proteolytic and cell signaling functions. ADAMTSs (ADAM with thrombospondin motifs) are secreted into the circulation, and constitute a heterogenous family of proteases with both anabolic and catabolic functions. Biologic modulation of endogenous MMP activity to basal levels may reduce pathologic tissue degradation and favorably influence healing after rotator cuff repair. Further studies are needed to better define the mechanism of action, and whether these new strategies are safe and effective in larger models.


Construction of hybrid viruses in vitro and their possible use for the production of specific viral or cellular proteins.
The use of plasmid and bacteriophage vectors for cloning of DNA segments from procaryotes and eucaryotes is described. A similar approach is being developed with DNA viruses like simian virus 40 or adenovirus 2. Such hybrid viruses may permit the amplification of specific genes and the overproduction of the corresponding proteins.


Extracellular α-synuclein leads to microtubule destabilization via GSK-3β-dependent Tau phosphorylation in PC12 cells.
α-Synuclein (ASN) plays an important role in pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. Novel and most interesting data showed elevated tauopathy in PD and suggested relationship between ASN and Tau protein. However, the mechanism of ASN-evoked Tau protein modification is not fully elucidated. In this study we investigated the role of extracellular ASN in Tau hyperphosphorylation in rat pheochromocytoma (PC12) cells and the involvement of glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5) in ASN-dependent Tau modification. Our results indicated that exogenously added ASN increases Tau phosphorylation at Ser396. Accordingly, the GSK-3β inhibitor (SB-216763) prevented ASN-evoked Tau hyperphosphorylation, but the CDK5 inhibitor had no effect. Moreover, western blot analysis showed that ASN affected GSK-3β via increasing of protein level and activation of this enzyme. GSK-3β activity evaluated by its phosphorylation status assay showed that ASN significantly increased the phosphorylation of this enzyme at Tyr216 with parallel decrease in phosphorylation at Ser9, indicative of stimulation of GSK-3β activity. Moreover, the effect of ASN on microtubule (MT) destabilization and cell death with simultaneous the involvement of GSK-3β in these processes were analyzed. ASN treatment increased the amount of free tubulin and concomitantly reduced the amount of polymerized tubulin and SB-216763 suppressed these ASN-induced changes in tubulin, indicating that GSK-3β is involved in ASN-evoked MT destabilization. ASN-induced apoptotic processes lead to decrease in PC12 cells viability and SB-216763 protected those cells against ASN-evoked cytotoxicity. Concluding, extracellular ASN is involved in GSK-3β-dependent Tau hyperphosphorylation, which leads to microtubule destabilization. GSK-3β inhibition may be an effective strategy for protecting against ASN-induced cytotoxicity.


Transgenic Pinus radiata from Agrobacterium tumefaciens-mediated transformation of cotyledons.
A method for Agrobacterium tumefaciens-mediated transformation of Pinus radiata cotyledon explants was developed using commercially available open-pollinated seed. Pinus radiata is the most widely planted commercial conifer species in the Southern Hemisphere. Reports on transformation of this species have relied on particle bombardment of embryogenic callus derived from immature embryos. The main drawback to the method is the small number of genotypes that are amenable to transformation and regeneration. Since more than 80% of genotypes of radiata pine can be regenerated using cotyledons from mature seed, cotyledon explants were cocultivated with A. tumefaciens strain AGL1 containing a plasmid coding for the neomycin phosphotransferase II (nptII) gene and the beta-glucuronidase (GUS) gene (uidA). Transformed shoots were selected using either geneticin or kanamycin. Critical factors for successful transformation were survival of the cotyledons after cocultivation and selection parameters. Of the 105 putative transformants that were recovered from selection media, 70% were positive for integration of the nptII gene when analysed by PCR. GUS histochemical assay for uidA expression was unreliable because of reaction inhibition by unidentified compounds in the pine needles. Further, only 4 of the 26 independent transformants characterised by PCR and Southern analysis contained an intact copy of both genes. The remaining 22 transformants appeared to have a truncated or rearranged copy of the T-DNA. It is possible that the truncation/rearrangements are due to the Cauliflower mosaic virus (CaMV) 35S promoter. Analysis of the T-DNA junction sites and sequencing of the introduced DNA will help elucidate the nature of T-DNA insertion so that genetic modification of radiata pine can be targeted effectively.


Assessment of the Passive Tension of the First Dorsal Interosseous and First Lumbrical Muscles Using Shear Wave Elastography.
Quantitative evaluation of passive tension of the intrinsic muscles of the hand is necessary to assess contracture of the intrinsic muscles accurately. The aim of this study was to evaluate the shear modulus, which is related to passive muscle tension, of the first dorsal interosseous (FDI) and first lumbrical (FL) muscles using shear wave elastography. Subjects were 18 healthy males. The shear modulus of the FDI and FL muscles was assessed at several proximal interphalangeal (PIP), distal interphalangeal (DIP), metacarpophalangeal (MCP), and wrist joint positions. The position in which the MCP joint was flexed 60° past 0° with PIP-DIP joint extension and that in which the MCP joint was extended 30° past 0° with PIP-DIP joint flexion were respectively defined as the slack and stretched positions. We analyzed whether the shear modulus was affected by finger position (slack or stretched), wrist position (30° flexion past 0° and 30° extension past 0°), and muscle (FDI or FL). Shear modulus in the stretched position was significantly higher than that in the slack position. The shear modulus of the FL muscle at 30° wrist extension was significantly higher than that at 30° flexion. The shear modulus of the FL muscle was significantly higher than that of the FDI muscle in the stretched position with the wrist at 30° flexion and extension, and in the slack position with the wrist at 30° extension. The shear modulus of the FDI and FL muscles increased with MCP joint extension and PIP-DIP joint flexion. The difference in the muscle characteristics between the FDI and FL muscles should be considered when evaluating or treating contractures of the intrinsic muscles. Shear wave elastography can evaluate the condition of the intrinsic muscles of the hand quantitatively.


Ccomparison of cisternal and lumbar cerebrospinal fluid pH in high altitude natives.
Samples of cisternal or lumbar cerebrospinal fluid were obtained from 20 young male volunteers born and living at high altitude (3500 to 4800 m). The pH, carbon dioxide and oxygen tensions, and bicarbonate concentration were measured and compared with those in the arterial and jugular venous blood. A consistent difference between the two CSF compartments was noted, particularly a lower pH (0.05), a higher PCO2 (7 Torr), and a lower PO2 (7 Torr) at the lumbar site. Mean bicarbonate concentration was not significantly different at the two sites. The main factor is PCO2, which controls the pH variation. These differences were more marked in high-altitude natives than in man at sea level. The existence of a consistent inhomogeneity of CSF acid-base content emphasizes the inaccuracy of using lumbar CSF pH to estimate the ECF pH as regulator of pulmonary ventilation and determinant of cerebral blood flow.


Possible role of the WDR3 gene on genome stability in thyroid cancer patients.
The role of the WDR3 gene on genomic instability has been evaluated in a group of 115 differentiated thyroid cancer (DTC) patients. Genomic instability has been measured according to the response of peripheral blood lymphocytes to ionizing radiation (0.5 Gy). The response has been measured with the micronucleus (MN) test evaluating the frequency of binucleated cells with MN (BNMN), both before and after the irradiation. No differences between genotypes, for the BNMN frequencies previous the irradiation, were observed. Nevertheless significant decreases in DNA damage after irradiation were observed in individuals carrying the variant alleles for each of the three genotyped SNPs: rs3754127 [-8.85 (-15.01 to -2.70), P<0.01]; rs3765501 [-8.98 (-15.61 to -2.36), P<0.01]; rs4658973 [-8.70 (-14.94 to -2.46), P<0.01]. These values correspond to those obtained assuming a dominant model. This study shows for the first time that WDR3 can modulate genome stability.


On architectures of circuits implemented in simulated Belousov-Zhabotinsky droplets.
When lipid vesicles filled with Belousov-Zhabotinsky (BZ) excitable chemical medium are packed in tight assembles, waves of excitation may travel between the vesicles. When several waves meet in a vesicle some fragments may deflect, others can annihilate or continue their travel undisturbed. By interpreting waves as Boolean values we can construct logical gates and assemble them in large circuits. In numerical modelling we show two architectures of one-bit half-adders implemented in BZ-vesicles.


An Indonesian pregnant woman with systemic lupus erythematosus and cardiac tamponade: A case report.
Systemic lupus erythematosus (SLE) during pregnancy with cardiac tamponade is a rare case. A 33-year-old pregnant woman complained of worsening shortness of breath, hair loss, and joint pain. Laboratory investigation revealed the poor condition of the patient so therapeutic abortion was recommended. Transthoracic echocardiography confirmed cardiac tamponade and pericardiocentesis was performed. The ANA test showed a flare SLE and she was given immunosuppressant therapy. Repeat echocardiography demonstrated minimal pericardial effusion. The patient refused cyclophosphamide. Follow-up echocardiography evaluation at fifth-month revealed minimal pericardial effusion. However, patient refused to be hospitalized. A combination of pericardiocentesis and immunosuppressant therapy is an effective strategy to treat cardiac tamponade in pregnancy with SLE. Immunosuppressants and pericardiocentesis followed by cyclophosphamide are the cornerstones of management of SLE and cardiac tamponade in pregnant patients.


Pharmacological assessment of the role of nitric oxide in mice infected with lethal and nonlethal species of malaria.
This pharmacological investigation sought to determine whether nitric oxide (NO) had an antiparasitic effect and/or mediated pathology in mice infected with nonlethal P. chabaudi or lethal P. berghei. Nitric oxide synthase (NOS) inhibitors were evaluated for their ability to inhibit the rise in reactive nitrogen intermediates (RNI) induced by bacterial lipopolysaccharide (LPS) in mice. The more effective compound, aminoguanidine (AG) inhibited the rise in RNI induced by P. chabaudi and increased mortality, but had no effect on parasitaemia. Inducers and donors of NO were screened for their ability to increase RNI and the most effective agents evaluated for their ability to modify P. berghei infection. S-Nitrosoglutathione had little effect, but LPS decreased parasitaemia and mortality. An inconsistent relationship is evident between the abilities of these agents to modify NO activity and their effects on malaria in mice. Increased mortality in mice with P. chabaudi treated with AG indicates a reduction in resistance. The absence of an effect on parasitaemia by a NOS inhibitor or NO donor indicates either RNI have insignificant antimalarial action in vivo or the efficacy of the compounds is inadequade. Resistance to P. berghei in LPS-treated mice demonstrates an antiparasitic effect, but this may be attributable to factors other than NO.


The impact of proteinase-induced matrix degradation on the release of VEGF from heparinized collagen matrices.
The in vivo application of engineered matrices in human wound healing processes is often hampered by the slow rate of vascularization. Therefore much research is directed towards enhancing the angiogenic properties of such matrices. One approach for enhancing the vascularization is the incorporation of angiogenic growth factors. Recently, we and others have reported on immobilizing such factors into collagen matrices either by covalent attachment or by physical binding to covalently incorporated heparin. Especially the latter procedure has been shown to lead to substantial increase rates in vascularization in in vivo experiments. The increases have been proposed to depend on the sustained release of the incorporated angiogenic growth factors from the heparinized collagen matrices. In this paper, we report on investigations to study the release of vascular endothelial growth factor (VEGF) from collagen matrices under conditions which mimic potential in vivo situations. Relevant proteinase concentrations were deduced from in vitro experiments in which we evaluated the secretion of selected matrix metalloproteinases from fibroblasts in contact with collagen. The release of VEGF from non-modified, cross-linked and heparinized collagen matrices in the absence and in the presence of varying concentrations of proteinases was then determined by ELISA and liquid scintillation counting. The release behaviour appears to be controlled by both the presence of heparin and the levels of proteinases applied. Experiments with matrices containing radioactively labelled heparin suggest that VEGF release results from the consecutive and simultaneous release of three species of VEGF molecules that differ in their binding affinities to the differently modified collagen matrices. The species binding specifically to heparin most likely accounts for the previously observed increases in angiogenic potential between loading VEGF to non-heparinized and heparinized collagen matrices.


Metagenomic landscape of taxonomy, metabolic potential and resistome of Sardinella longiceps gut microbiome.
Fish gut microbiota, encompassing a colossal reserve of microbes represents a dynamic ecosystem, influenced by a myriad of environmental and host factors. The current study presents a comprehensive insight into Sardinella longiceps gut microbiome using whole metagenome shotgun sequencing. Taxonomic profiling identified the predominance of phylum Proteobacteria, comprising of Photobacterium, Vibrio and Shewanella sp. Functional annotation revealed the dominance of Clustering based subsystems, Carbohydrate, and Amino acids and derivatives. Analysis of Virulence, disease and defense subsystem identified genes conferring resistance to antibiotics and toxic compounds, like multidrug resistance efflux pumps and resistance genes for fluoroquinolones and heavy metals like cobalt, zinc, cadmium and copper. The presence of overlapping genetic mechanisms of resistance to antibiotics and heavy metals, like the efflux pumps is a serious cause of concern as it is likely to aggravate co-selection pressure, leading to an increased dissemination of these resistance genes to fish and humans.


Variability of haemocyte and haemolymph parameters in European flat oyster Ostrea edulis families obtained from brood stocks of different geographical origins and relation with infection by the protozoan Bonamia ostreae.
A research project to compare productive traits (growth and mortality), disease susceptibility and immune capability between Ostrea edulis stocks was performed. This article reports the results on the immune capability and its relation with infection by the intrahaemocytic protozoan Bonamia ostreae. Four to five oyster spat families were produced from each of four European flat oyster populations (one from Ireland, one from Greece and two from Galicia, Spain) in a hatchery. The spat were transferred to a raft in the Ría de Arousa (Galicia) for on growing for 2 years. Total haemocyte count (THC) and differential haemocyte count (DHC) were estimated monthly through the second year of growing-out. Three types of haemocytes were distinguished: granulocytes (GH), large hyalinocytes (LHH) and small hyalinocytes (SHH). Significant correlations between the mean relative abundance of GH and SHH of the families and the mean prevalence of B. ostreae, the overall incidence of pathological conditions and the cumulative mortality of the families were found; these correlations supported the hypothesis that high %GH and low %SHH would enhance oyster immune ability and, consequently, would contribute to lower susceptibility to disease and longer lifespan. Infection by B. ostreae involved a significant increase of circulating haemocytes, which affected more markedly the LHH type. The higher the infection intensity the higher the %LHH. This illustrates the ability of B. ostreae to modulate the immune responses of the O. edulis to favour its own multiplication. A significant reduction of the phenoloxidase activity in the haemolymph of oysters O. edulis infected by B. ostreae was observed. Nineteen enzymatic activities in the haemolymph of O. edulis and Crassostrea gigas (used as a B. ostreae resistant reference) were measured using the kit api ZYM, Biomerieux. Qualitative and quantitative differences in enzyme activities in both haemocyte and plasma fractions between B. ostreae noninfected O. edulis from different origins were recorded. However, no clear positive association between enzyme activity and susceptibility to bonamiosis was found. The only enzyme detected in the resistant species C. gigas that was not found in the susceptible one O. edulis was beta-glucosidase (in plasma). B. ostreae infected O. edulis showed significant increase of some enzyme activities and the occurrence of enzymes that were not detected in noninfected oysters. These changes could be due to infection-induced enzyme synthesis by the host or to enzyme synthesis by the parasite.


Differential modulation of aryl hydrocarbon receptor regulated enzymes by arsenite in the kidney, lung, and heart of C57BL/6 mice.
During the last couple of decades, efforts have been made to study the toxic effects of individual aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or heavy metals typified by arsenic As(III). However, little is known about the combined toxic effects of TCDD and As(III) in vivo. Previous reports from our laboratory and others have demonstrated that As(III), by itself or in the presence of AhR ligands, such as TCDD, is capable of differentially altering the expression of various phase I and phase II AhR-regulated genes in in vitro systems. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) on the AhR-regulated genes using C57Bl/6 mice. Our results demonstrated that As(III) alone inhibited Cyp1a1 and Cyp1a2 in the kidney, while it induced their levels in the lung and did not affect their mRNA levels in the heart. As(III) also induced Nqo1 and Gsta1 in all tested tissues. Upon co-exposure to As(III) and TCDD, As(III) inhibited the TCDD-mediated induction of Cyp1a1 in the kidney and heart, Cyp1a2 in the kidney and heart, while it potentiated TCDD-mediated induction of Cyp1a1 in the lung, and Nqo1 and Gsta1 in the kidney and lung. In conclusion, the present study demonstrates for the first time that As(III) modulates constitutive and TCDD-induced AhR-regulated genes in a time-, tissue-, and AhR-regulated enzyme-specific manner.


The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells.
Arrested autophagy may contribute to the pathogenesis of Alzheimer's disease. Because we found that chloroquine (CQ) causes arrested autophagy but clioquinol (ClioQ), a zinc ionophore, activates autophagic flux, in the present study, we examined whether ClioQ can overcome arrested autophagy induced by CQ or mutant presenilin-1 (mPS1). CQ induced vacuole formation and cell death in adult retinal pigment epithelial (ARPE-19) cells, but co-treatment with ClioQ attenuated CQ-associated toxicity in a zinc-dependent manner. Increases in lysosome dilation and blockage of autophagic flux by CQ were also markedly attenuated by ClioQ treatment. Interestingly, CQ increased lysosomal pH in amyloid precursor protein (APP)/mPS1-expressing Chinese hamster ovary 7WΔE9 (CHO-7WΔE9) cell line, and ClioQ partially re-acidified lysosomes. Furthermore, accumulation of amyloid-β (Aβ) oligomers in CHO-7WΔE9 cells was markedly attenuated by ClioQ. Moreover, intracellular accumulation of exogenously applied fluorescein isothiocyanate-conjugated Aβ(1-42) was also increased by CQ but was returned to control levels by ClioQ. These results suggest that modulation of lysosomal functions by manipulating lysosomal zinc levels may be a useful strategy for clearing intracellular Aβ oligomers.


Monitoring of monocyte functional state after extracorporeal circulation: a flow cytometry study.
Cardiovascular surgery with cardiopulmonary bypass (CPB) induces systemic inflammation and postoperative complications depending on pro- and anti-inflammatory mechanisms. Activated polymorphonuclear cells and monocytes may be responsible for morbidity associated with CPB. Knowledge of the monocyte functional state in particular may help to develop protective interventions. Samples were drawn from venous peripheral blood (basal condition, at 4 and 24 h after CPB) and coronary blood (before and after cardioplegic arrest) of 14 patients undergoing cardiac surgery. The following phenotypic and functional parameters of the monocyte population were studied by flow cytometry: surface molecules expression (CD18, CD11a, CD11b, CD14, CD15, CD45, HLA-DR, and Toll-like receptor [TLR]-4), myeloperoxidase (MPO) content, and intracellular cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-6, and IL-8). Cardiac surgery with CPB induced down-modulation of surface molecules expression on peripheral monocytes, especially at 24 h after CPB, for CD18, CD11a, and CD11b (P < 0.003) and for the CD15 adhesive cluster (P = 0.0028) and HLA-DR (P < 0.001). At 4 h after CPB, downregulation was observed for CD14 (P = 0.004), CD45 (P = 0.014), and CD15 (P = 0.0056). A loss of MPO was detected in venous peripheral (at 24 h after CPB, P = 0.01) or coronary (at reperfusion, P < 0.02) blood. The CD15 cluster complex exhibited a down-modulation in coronary blood (at reperfusion, P = 0.0003). Spontaneous intracellular production of IL-1beta, IL-6, and IL-8 decreased at 24 h after CPB (P < 0.05). The down-modulation of integrins and adhesive receptor expression and the loss of MPO suggest a strong activation and shedding reaction of circulating monocyte after CPB, further exacerbated by contact with coronary ischemic vessels. The changes of differentiation antigens may reflect the appearance of a partially immature population immediately after CPB. The reduced proinflammatory cytokine production, observed at 24 h after CPB, suggests a functional polarization of circulating monocytes.


Computed tomography of supratentorial astrocytoma.
In a group of 40 astrocytomas the C.T. appearance was correlated with the grade of malignancy. On the plain scan the majority presented an irregular, nonhomogeneous low density lesion, better demarcatable in high than in low grade astrocytomas. Contrast enhancement was seen in 28 of the 32 high grade astrocytomas, 50% of the annular, 25% of the nodular and 25% of the mixed type. Six of the 8 low grade astrocytomas showed no contrast enhancement and 1 showed an annular type lesion. A relationship was found between the degree of contrast enhancement and the vascularity. Mass effect was observed in all but 1 patient, but more pronounced in high grade astrocytomas. At the first interpretation 98% were recognized as a lesion, 93% as a tumor and 68% as an astrocytoma. One false negative and no false postive C.T.scans were obtained. In review, high and low grade malignancies were correctly differentiated in 90%. As a screening method, the combination of EEG and echo equalled C.T.; in establishing a definite diagnosis angiography was inferior to C.T. Solely on the basis of the C.T. appearance, astrocytomas can hardly be differentiated from the other malignant brain tumors, but the grade of malignancy can be predicted reliably.


Identification of an unusual AT(D)Pase-like activity in multifunctional NAD glycohydrolase from the venom of Agkistrodon acutus.
NAD-glycohydrolases (NADases) are ubiquitous enzymes that possess NAD glycohydrolase, ADPR cyclase or cADPR hydrolase activity. All these activities are attributed to the NADase-catalyzed cleavage of C-N glycosyl bond. AA-NADase purified from the venom of Agkistrodon acutus is different from the known NADases, for it consists of two chains linked with disulfide-bond(s) and contains one Cu(2+) ion. Here, we show that AA-NADase is not only able to cleave the C-N glycosyl bond of NAD to produce ADPR and nicotinamide, but also able to cleave the phosphoanhydride linkages of ATP, ADP and AMP-PNP to yield AMP. AA-NADase selectively cleaves the P-O-P bond of ATP, ADP and AMP-PNP without the cleavage of P-O-P bond of NAD. The hydrolysis reactions of NAD, ATP and ADP catalyzed by AA-NADase are mutually competitive. ATP is the excellent substrate for AA-NADase with the highest specificity constant k(cat)/K(m) of 293+/-7mM(-1)s(-1). AA-NADase catalyzes the hydrolysis of ATP to produce AMP with an intermediate ADP. AA-NADase binds with one AMP with high affinity determined by isothermal titration calorimetry (ITC). AMP is an efficient inhibitor against NAD. AA-NADase has so far been identified as the first unique multicatalytic enzyme with both NADase and AT(D)Pase-like activities.


Narrative Review of the Post-Operative Management of Prostate Cancer Patients: Is It Really the End of Adjuvant Radiotherapy?
Despite three randomized trials indicating a significant reduction in biochemical recurrence (BCR) in high-risk patients, adjuvant radiotherapy (aRT) was rarely performed, even in patients harboring high-risk features. aRT is associated with a higher risk of urinary incontinence and is often criticized for the lack of patient selection criteria. With a BCR rate reaching 30-70% in high-risk patients, a consensus between urologists and radiation oncologists was needed, leading to three different randomized trials challenging aRT with early salvage radiotherapy (eSRT). In these three different randomized trials with event-free survival as the primary outcome and a planned meta-analysis, eSRT appeared as non-inferior to aRT, answering, for some, this never-ending question. For many, however, the debate persists; these results raised several questions among urologists and radiation oncologists. BCR is thought to be a surrogate for clinically meaningful endpoints such as overall survival and cancer-specific survival but may be poorly efficient in comparison with metastasis-free survival. Imaging of rising prostate-specific antigen (PSA), post-operative persistent PSA and BCR was revolutionized by the broader use of MRI and nuclear imaging such as PET-PSMA; these imaging modalities were not analyzed in the previous randomized trials. A sub-group of very high-risk patients could possibly benefit from an adjuvant radiotherapy; but their usual risk factors such as high Gleason score or invaded surgical margins mean they are unable to be selected. More precise biomarkers of early BCR or even metastatic-relapse were developed in this setting and could be useful for the patients' stratification. In this review, we insist on the need for multidisciplinary discussions to fully comprehend the individual characteristics of each patient and propose the best treatment strategy for every patient.


Measuring sustainability within the Veterans Administration Mental Health System Redesign initiative.
To examine how attributes affecting sustainability differ across Veterans Health Administration organizational components and by staff characteristics. Surveys of 870 change team members and 50 staff interviews within the Veterans Affairs' Mental Health System Redesign initiative. A 1-way ANOVA with a Tukey post hoc test examined differences in sustainability by Veteran Integrated Service Networks, job classification, and tenure from staff survey data of the Sustainability Index. Qualitative interviews used an iterative process to identify "a priori" and "in vivo" themes. A simple stepwise linear regression explored predictors of sustainability. Sustainability differed across Veteran Integrated Service Networks and staff tenure. Job classification differences existed for the following: (1) benefits and credibility of the change and (2) staff involvement and attitudes toward change. Sustainability barriers were staff and institutional resistance and nonsupportive leadership. Facilitators were commitment to veterans, strong leadership, and use of quality improvement tools. Sustainability predictors were outcomes tracking, regular reporting, and use of Plan, Do, Study, Adjust cycles. Creating homogeneous implementation and sustainability processes across a national health system is difficult. Despite the Veterans Affairs' best evidence-based implementation efforts, there was significant variance. Locally tailored interventions might better support sustainability than "one-size-fits-all" approaches. Further research is needed to understand how participation in a quality improvement collaborative affects sustainability.


CycLing and EducATion (CLEAT): protocol for a single centre randomised controlled trial of a cycling and education intervention versus standard physiotherapy care for the treatment of hip osteoarthritis.
Osteoarthritis (OA) is a chronic degenerative joint disorder for which there is no known cure. Non-surgical management for people with mild-to-moderate hip OA focuses mainly on alleviating pain and maximising function via the National Institute for Health and Care Excellence (NICE) recommended combination of education and advice, exercise, and, where appropriate, weight loss. The CHAIN (Cycling against Hip pAIN) intervention is a group cycling and education intervention conceived as a way of implementing the NICE guidance. CycLing and EducATion (CLEAT) is a pragmatic, two parallel arm, randomised controlled trial comparing CHAIN with standard physiotherapy care for the treatment of mild-to-moderate hip OA. We will recruit 256 participants referred to the local NHS physiotherapy department over a 24-month recruitment period. Participants diagnosed with hip OA according to NICE guidance and meeting the criteria for GP exercise referral will be eligible to participate. Primary outcome is the difference in Hip Disability and Osteoarthritis Outcome Score (HOOS) function, daily living subscale between those receiving CHAIN and standard physiotherapy care. Secondary outcomes include performance-based functional measures (40 m walking, 30s chair stand and stair climb tests), ability for patient to self-care (patient activation measure) and self-reported health-related resource use including primary and secondary care contacts. The primary economic endpoint is the number of quality adjusted life years (QALYs) at 24 weeks follow-up. The study is funded by the National Institute for Health Research, Research for Patient Benefit PB-PG-0816-20033. The literature identifies a lack of high-quality trials which inform on the content and design of education and exercise in the treatment of patients with hip OA and explore cost-effectiveness. CLEAT is a pragmatic trial which seeks to build further evidence of the clinical benefits of the CHAIN intervention compared to standard physiotherapy care within a randomised, controlled trial setting, and examine its cost-effectiveness. ISRCTN19778222. Protocol v4.1, 24th October 2022.


The potential of HEART score to detect the severity of coronary artery disease according to SYNTAX score.
Clinical scoring systems such as the HEART score can predict major adverse cardiovascular events, but they cannot be used to demonstrate the degree and severity of coronary artery disease. We investigated the potential of HEART Score in detecting the existence and severity of coronary artery disease based on SYNTAX score. This multi-centric cross-sectional study investigated patients referred to the cardiac emergency departments of three hospitals between January 2018 and January 2020. Data including age, gender, risk factors, comorbidities, 12-lead ECG, blood pressure and echocardiogram were recorded for all the participants. Serum troponin I level was measured on admission and 6 h later. Coronary angiography was done via the femoral or radial route. HEART and SYNTAX scores were calculated for all patients and their association was assessed. 300 patients (65% female) with mean age of 58.42 ± 12.42 years were included. mean HEART Score was 5.76 ± 1.56 (min = 3, max = 9), and mean SYNTAX score was 14.82 ± 11.42 (min = 0, max = 44.5). Pearson correlation coefficient was 0.493 between HEART Score and SYNTAX score which was statistically significant (P < 0.001). We found that HEART Score of more than 6 is 52% sensitive and 74.7% specific to detect extensive coronary artery involvement (SNTAX score ≥ 23). The present study showed that the HEART score has a moderate and positive correlation with the SYNTAX score and HEART score with a cut-off value of 6 is a predictor for SYNTAX score of ≥ 23.


Comparison of proliferation, apoptosis and expression of syndecan-1 and α-SMA in edentulous ridge oral mucosa of successful and early failed submerged dental implants--An immunohistochemical study.
Pathogenic mechanisms involved in early submerged implant failure are poorly understood. In this study we immunohistochemically analyse differences in proliferation, apoptosis and inflammation in edentulous ridge oral mucosa (ERM) of successful and early failed submerged implants. 30 samples of ERM covering successful and early failed submerged implants were obtained at the end of osseointegration period along with control samples of healthy ERM. Sections were stained with Ki-67 (proliferation), caspase-3 (apoptosis) and syndecan-1 (epithelial marker). Percentage of positive cells was analysed by Kruskal-Wallis test and Dunn's post hoc test. Co-localization of Ki-67 and caspase-3 with α-SMA, CD68 and TGF-β was done by double immunofluorescence. There was no significant difference in number of Ki-67 positive cells within surface epithelium (SE) in all groups. Proliferation was significantly higher in underlying connective tissue (UCT) of ERM of early failed submerged implants (26%) compared to ERM of successful submerged implants (3%) and controls (4%). More apoptotic cells appeared in UCT of early failed submerged implants (8%) compared to UCT of successful submerged implants (4%) and UCT of control ERM (3%). Co-localization of Ki-67 and α-SMA in ERM of early failed submerged implants disclosed proliferating fibroblasts and pericytes of blood vessels. Macrophages and cells expressing TGF-β appeared in UCT of failed implants. Expression of syndecan-1 was significantly weaker in SE of early failed submerged implants. Imbalance between proliferation and apoptosis, changes in syndecan-1 expression and inflammation are histopathological features of ERM of early failed submerged implants.


Some species of the genus Myxobolus (Myxozoa: Myxosporea) infecting freshwater fish of the River Nile, Egypt, and the impact on their hosts.
Six Myxobolus species are described from Nile fish, five of which are new and one is redescribed: M. naffari Abdel Ghaffar et al., 1998 was recovered from the gills of Labeo niloticus and the mouth of Barbus bynni; M. caudatus sp. n. was observed in the tail fin of B. bynni; M. fahmii sp. n. occurred in the gills of B. bynni; M. imami sp. n. was found in the kidney of L. niloticus; M. intestinalis sp. n. was recorded from the intestine of B. bynni; and M. perforata sp. n. was found in the internal surface of the operculum of Hydrocynus forskalii. The histological effects of some of the Myxobolus infections present are described.


Signal Denoising Method Using AIC-SVD and Its Application to Micro-Vibration in Reaction Wheels.
To suppress noise in signals, a denoising method called AIC-SVD is proposed on the basis of the singular value decomposition (SVD) and the Akaike information criterion (AIC). First, the Hankel matrix is chosen as the trajectory matrix of the signals, and its optimal number of rows and columns is selected according to the maximum energy of the singular values. On the basis of the improved AIC, the valid order of the optimal matrix is determined for the vibration signals mixed with Gaussian white noise and colored noise. Subsequently, the denoised signals are reconstructed by inverse operation of SVD and the averaging method. To verify the effectiveness of AIC-SVD, it is compared with wavelet threshold denoising (WTD) and empirical mode decomposition with Savitzky-Golay filter (EMD-SG). Furthermore, a comprehensive indicator of denoising (CID) is introduced to describe the denoising performance. The results show that the denoising effect of AIC-SVD is significantly better than those of WTD and EMD-SG. On applying AIC-SVD to the micro-vibration signals of reaction wheels, the weak harmonic parameters can be successfully extracted during pre-processing. The proposed method is self-adaptable and robust while avoiding the occurrence of over-denoising.


Antimicrobial constituents from the tubers of Bletilla ochracea.
A new 2-(2-methylpropyl)butanedioic acid derivative, bletillin A ( 1), and a new bibenzyl, bletillin B ( 2), together with seventeen known compounds ( 3- 19), were isolated from the tubers of Bletilla ochracea Schltr. Their structures were established by detailed spectroscopic analyses. Phenanthrenes ( 12- 14) exhibited antibacterial activities against gram-positive bacteria Staphylococcus aureus, S. epidermidis, and Bacillus subtilis, with MIC values of 12.5-25 µg/mL.


Cross-talk between AMPK and EGFR dependent Signaling in Non-Small Cell Lung Cancer.
Lung cancers globally account for 12% of new cancer cases, 85% of these being Non Small Cell Lung Cancer (NSCLC). Therapies like erlotinib target the key player EGFR, which is mutated in about 10% of lung adenocarcinoma. However, drug insensitivity and resistance caused by second mutations in the EGFR or aberrant bypass signaling have evolved as a major challenge in controlling these tumors. Recently, AMPK activation was proposed to sensitize NSCLC cells against erlotinib treatment. However, the underlying mechanism is largely unknown. In this work we aim to unravel the interplay between 20 proteins that were previously associated with EGFR signaling and erlotinib drug sensitivity. The inferred network shows a high level of agreement with protein-protein interactions reported in STRING and HIPPIE databases. It is further experimentally validated with protein measurements. Moreover, predictions derived from our network model fairly agree with somatic mutations and gene expression data from primary lung adenocarcinoma. Altogether our results support the role of AMPK in EGFR signaling and drug sensitivity.


Profiles of toxin production by thermophilic Campylobacter of animal origin.
Seventy-five strains of Campylobacter jejuni and C. coli, which were isolated from a variety of animal species, primarily poultry, were examined for production of toxin. Polymyxin extracts were tested in in vitro assays using CHO-KI, FCL (foetal calf lung), Vero, HeLa and CEF (chicken embryo fibroblast) cells. The toxic effects observed were cell rounding and death. Extracts from almost all C. jejuni and C. coli strains were toxic to both CHO-KI and FCL cells and 69.0% of C. jejuni isolates and 75% of C. coli isolates were also toxic to CEF cells. 50.7% of C. jejuni extracts were toxic to Vero cells and 46.5% toxic to HeLa cells. None of the C. coli isolates were toxic to either of these cell lines. None of the strains tested produced cytotonic enterotoxin. No differences in toxigenicity patterns were evident between Campylobacter isolated from different sources.


Incidence, Mortality, and Imaging Outcomes of Atrial Arrhythmias in COVID-19.
Atrial arrhythmias (AAs) are common in hospitalized patients with COVID-19; however, it remains uncertain if AAs are a poor prognostic factor in SARS-CoV-2 infection. In this retrospective cohort study from 2014 to 2021, we report in-hospital mortality in patients with new-onset AA and history of AA. The incidence of new-onset congestive heart failure (CHF), hospital length of stay and readmission rate, intensive care unit admission, arterial and venous thromboembolism, and imaging outcomes were also analyzed. We further compared the clinical outcomes with a propensity-matched influenza cohort. Generalized linear regression was performed to identify the association of AA with mortality and other outcomes, relative to those without an AA diagnosis. Predictors of new-onset AA were also modeled. A total of 6,927 patients with COVID-19 were included (626 with new-onset AA, 779 with history of AA). We found that history of AA (adjusted relative risk [aRR] 1.38, confidence interval [CI], 1.11 to 1.71, p = 0.003) and new-onset AA (aRR 2.02, 95% CI 1.68 to 2.43, p <0.001) were independent predictors of in-hospital mortality. The incidence of new-onset CHF was 6.3% in history of AA (odds ratio 1.91, 95% CI 1.30 to 2.79, p <0.001) and 11.3% in new-onset AA (odds ratio 4.01, 95% CI 3.00 to 5.35, p <0.001). New-onset AA was shown to be associated with worse clinical outcomes within the propensity-matched COVID-19 and influenza cohorts. The risk of new-onset AA was higher in patients with COVID-19 than influenza (aRR 2.02, 95% CI 1.76 to 2.32, p <0.0001), but mortality associated with new-onset AA was higher in influenza (aRR 12.58, 95% CI 4.27 to 37.06, p <0.0001) than COVID-19 (aRR 1.86, 95% CI 1.55 to 2.22, p <0.0001). In a subset of the patients with COVID-19 for which echocardiographic data were captured, abnormalities were common, including valvular abnormalities (40.9%), right ventricular dilation (29.6%), and elevated pulmonary artery systolic pressure (16.5%); although there was no evidence of a difference in incidence among the 3 groups. In conclusion, new-onset AAs are associated with poor clinical outcomes in patients with COVID-19.


An ER-Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non-Small-Cell Lung Cancer.
Immunogenic cell death (ICD) is a vital component of therapeutically induced anti-tumor immunity. An iridium(III) complex (Ir1), containing an N,N-bis(2-chloroethyl)-azane derivate, as an endoplasmic reticulum-localized ICD inducer for non-small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage-associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1-treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long-acting anti-tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir-based complex that is capable of developing an immunomodulatory response by immunogenic cell death.


The effects of recombinant human bone morphogenetic protein-2, recombinant human bone morphogenetic protein-12, and adenoviral bone morphogenetic protein-12 on matrix synthesis in human annulus fibrosis and nucleus pulposus cells.
Bone morphogenetic proteins (BMPs) are potential therapeutic factors for degenerative discs, and BMP-12 does not have the osteogenic potential of BMP-2, making it better suited for intradiscal injection. However, no reports have compared the actions of BMP-2 and -12 on human annulus fibrosus (AF) and nucleus pulposus (NP) cells nor evaluated adenoviral-mediated gene therapy in human AF cells. To evaluate and compare the effects of recombinant human (rh) BMP-2, rhBMP-12, and adenoviral BMP-12 (Ad-BMP-12) on nucleus pulposus and annulus fibrosis cell matrix protein synthesis. In vitro study using rhBMP-2 and -12 and adenoviral BMP-12 with human intervertebral disc (IVD) cells. Human NP and AF IVD cells were isolated, maintained in monolayer, and incubated with BMP-2 or -12 for 2 days. AF and NP cells were transduced with Ad-BMP-12, pellets formed, and incubated for 6 days. Growth factor-treated cells were labelled with either 35-S or 3H-proline to assay matrix protein synthesis. rhBMP-2 increased NP proteoglycan, collagen, and noncollagen protein synthesis to 355%, 388%, and 234% of control. RhBMP-12 increased the same NP matrix proteins' synthesis to 140%, 143%, and 160% of control. Effects on AF matrix protein synthesis were minimal. Ad-BMP-12 significantly increased matrix protein synthesis and DNA content of AF and NP cells in pellet culture. NP synthesis of all matrix proteins and AF synthesis of proteoglycans was increased when the data were normalized to pellet DNA. AF synthesis of noncollagen protein and collagen was not modulated by Ad-BMP-12 if the data are normalized to pellet DNA content. Both rhBMP-2 and -12 increase human NP cell matrix protein synthesis while having minimal effects on AF cells. However, Ad-BMP-12 did increase matrix protein synthesis in both NP and AF cells, making it a potential therapy for enhancing matrix production in the IVD. These responses plus the proliferative action of Ad-BMP-12 seen in the current studies, and the lack of an osteogenic action noted in other studies justifies future studies to determine if gene therapy with BMP-12 could provide protective and/or reparative actions in degenerating discs.


Unsterile production of a polyhydroxyalkanoate copolymer by Halomonas cupida J9.
Microbial production of bioplastics polyhydroxyalkanoates (PHA) has opened new avenues to resolve "white pollution" caused by petroleum-based plastics. PHAs consisting of short- and medium-chain-length monomers, designated as SCL-co-MCL PHAs, exhibit much better thermal and mechanical properties than PHA homopolymers. In this study, a halophilic bacterium Halomonas cupida J9 was isolated from highly saline wastewater and proven to produce SCL-co-MCL PHA consisting of 3-hydroxybutyrate (3HB) and 3-hydroxydodecanoate (3HDD) from glucose and glycerol. Whole-genome sequencing and functional annotation suggest that H. cupida J9 may possess three putative PHA biosynthesis pathways and a class I PHA synthase (PhaCJ9). Interestingly, the purified His6-tagged PhaCJ9 from E. coli BL21 (DE3) showed polymerizing activity towards 3HDD-CoA and a phaCJ9-deficient mutant was unable to produce PHA, which indicated that a low-substrate-specificity PhaCJ9 was exclusively responsible for PHA polymerization in H. cupida J9. Docking simulation demonstrated higher binding affinity between 3HB-CoA and PhaCJ9 and identified the key residues involved in hydrogen bonds formation between 3-hydroxyacyl-CoA and PhaCJ9. Furthermore, His489 was identified by site-specific mutagenesis as the key residue for the interaction of 3HDD-CoA with PhaCJ9. Finally, PHA was produced by H. cupida J9 from glucose and glycerol in shake flasks and a 5-L fermentor under unsterile conditions. The open fermentation mode makes this strain a promising candidate for low-cost production of SCL-co-MCL PHAs. Especially, the low-specificity PhaCJ9 has great potential to be engineered for an enlarged substrate range to synthesize tailor-made novel SCL-co-MCL PHAs.


Cytologic and biochemical examination of the subretinal fluid in diagnosis of Coats' disease.
Two babies presenting with unilateral leukocoria were found to have total retinal detachment in one eye, associated with subretinal yellowish-white deposits. As no calcification was found and subretinal fluid aspiration yielded many fat-laden macrophages without any evidence of retinoblastoma cells in addition to a high level of cholesterol, the difinitive diagnosis of Coats' disease was made. Subsequently, retinal detachment surgery and cryotherapy were performed, in an attempt to preserve the affected eye.


Are some crib deaths sudden cardiac deaths?
Research performed during the past two decades suggests that crib deaths are biphasic phenomena: the infant victims are preconditioned in subtle ways before birth so that some of their most critical physiologic functions are subtly deficient. Then, at 2 to 4 months of age, when confronted by some challenge, such as a head cold, they are unable to overcome or adapt to the stress and die, seemingly without cause. It is likely that these deaths represent a heterogeneous group of pathogenetic phenomena rather than a single entity. Spontaneous idiopathic pathologic apnea, for example, may be responsible for 5 to 7% of crib deaths. Infant botulism may account for another 5%. A recent report on a prospective study of more than 5,000 babies showed that all 3 infants who ultimately succumbed to crib death had had abnormally prolonged corrected QT intervals on day 4 of life; the report contends that that irregularity leads to ventricular fibrillation, which is then the immediate cause of death. Although this work has not been confirmed and some take issue with the method, it now seems the most valid available body of data on the subject and suggests that some crib deaths, probably less than 10%, may be sudden cardiac deaths.


Maternal exposure to bacterial endotoxin during pregnancy enhances amphetamine-induced locomotion and startle responses in adult rat offspring.
An increased incidence of schizophrenia has been associated with several perinatal insults, most notably maternal infection during pregnancy and perinatal hypoxia. This study used a rat model to directly test if maternal exposure to bacterial endotoxin (lipopolysaccharide, LPS) during pregnancy alters behaviors relevant to schizophrenia, in offspring at adulthood. The study also tested if postnatal anoxia interacted with gestational LPS exposure to affect behavior. At adulthood, offspring from dams administered LPS on days 18 and 19 of pregnancy showed significantly increased amphetamine-induced locomotion, compared to offspring from saline-treated dams. A period of anoxia on postnatal day 7 had no effect on amphetamine-induced locomotion and there was no interaction between effects of gestational LPS and postnatal anoxia on this behavior. Offspring from LPS-treated dams also showed enhanced acoustic startle responses as adults, compared to offspring from saline-treated dams. In offspring tested for pre-pulse inhibition (PPI) of acoustic startle and for apomorphine modulation of PPI, no effects of either gestational LPS or of postnatal anoxia and no interactions between LPS and anoxia were observed. It is concluded that maternal LPS exposure during pregnancy in the rat may be a useful model to study mechanisms responsible for effects of maternal infection on behaviors relevant to schizophrenia, in offspring.


Effect of dietary inclusions of different types of Acacia mearnsii on milk performance and nutrient intake of dairy cows.
This study investigated the effects of including different types of Acacia mearnsii (tannin extract and forage) on nutrient intake and milk performance in dairy cattle. Holstein-Friesian x Jersey dairy cows (n per Experiment = 24) that had 200 days in milk were selected for this study in a completely randomized study design. This study was conducted under on-farm conditions at Springfontein dairy farm, a farm that lacked a functional bodyweight scale to measure the cow bodyweight and a computer system to register cow parity. Cows were assigned Acacia mearnsii tannin extract (ATE) pellets which were added with 0 (0ATE), 0.75 (0.75ATE), 1.5 (1.5ATE) or 3 (3ATE) % ATE in pellets while 0ATE was a commercial protein concentrate (Experiment 1). Cows were assigned Acacia mearnsii forage (AMF) at a rate of 0 (0AMF), 5 (5AMF), 15 (15AMF) or 25 (25AMF) % AMF inclusion in corn silage-based diet (Experiment 2). For both Experiments, treatments had six cows each, in which they were adapted (14 d) to diets before data collection (21 d). All AMF inclusions decreased (P<0.0001) dry matter intake (DMI), crude protein intake (CPI), neutral detergent fibre intake (NDFI), acid detergent fibre intake (ADFI) and organic matter intake (OMI) at 25AMF. Linear (P<0.0001) and quadratic (P<0.001) effects were observed on DMI, CPI, NDFI, ADFI and OMI. Inclusions of AMF in corn silage diets affected milk yield, protein yield, lactose yield and milk protein percentage (P<0.001). Linear effect was present in milk yield per DMI (P<0.0001). In conclusion, the dairy cow diet supplemented with ATE pellets did not have a beneficial effect on the nutrient intakes and milk yield. However, the AMF supplemented in corn silage of the dairy cow diet, increased milk production due to positive effects on nutrient intake, which was favourably influenced from a nutritional point of view.


Protein phosphorylation and regulation of carbon metabolism in gram-negative versus gram-positive bacteria.
Bacteria impose regulatory mechanisms on metabolic processes to ensure that the needs of the cell are met but not exceeded. Here, we discuss the basic features of a mechanism by which carbohydrate catabolism in Gram-positive bacteria is regulated. Although the physiological consequences of this regulation are the same as in Gram-negative bacteria, the mechanism is entirely different. These regulatory processes evidently evolved late, after the divergence of Gram-negative bacteria, even though the targets of regulation are universal.


Morphology of the optic nerve head in glaucomatous eyes with visual field defects in superior or inferior hemifield.
To evaluate the morphology of optic nerve head (ONH) and border tissue (BT) of Elschnig in glaucomatous eyes with visual field defects in superior or inferior hemifield. In a case-control study, we included 25 patients with superior arcuate scotoma, 25 patients with inferior arcuate scotoma, and 25 healthy controls. They received visual field testing, measurement of peripapillary retinal nerve fiber layer (RNFL) thickness, and ONH examination in a radial pattern with spectral-domain optical coherence tomography. In each ONH scan, the length of Bruch membrane opening (BMO) and BT were measured. Pattern deviation of 6 areas of the visual field and RNFL thickness in corresponding sectors was calculated. Mean BMO length did not differ between groups. Compared with controls, glaucomatous eyes with superior scotoma had a greater BT length in inferior sectors (p<0.001), and eyes with inferior scotoma had a greater BT length in superotemporal sectors (p = 0.006). In both groups, a significant correlation was found between BT length and pattern deviation and RNFL thickness of corresponding sectors of superior and inferior hemifields. In patients with arcuate scotoma in one hemifield, the length of the BT correlates with glaucomatous anatomical and functional damage.


Integrating network pharmacology and experimental verification to explore the mechanisms of salidroside against myocardial fibrosis.
Myocardial fibrosis (MF) is the manifestation of a variety of cardiovascular diseases. Salidroside (SAL) has been proved to have a certain effect on anti-fibrosis in various organs. However, the mechanism of SAL in the treatment of MF remains unclear. Network pharmacology showed that there were 1228 SAL-related target genes and 2793 MF-related target genes. The intersection of these genes resulted in 271 drug-disease interactions, and 15 core active targets were filtered from protein-protein interaction mapping. The top 20 Gene ontology biological processes analysis showed that the involved processes were close to the pathogenesis of MF. Among the top 20 enriched KEGG pathways, Wnt/β-catenin and TGF-β1/Smad3 signaling pathways were identified. In vivo, MI rats exhibited thinning of the myocardial region and the formation of fibrous scars, the expression of smad3 and β-catenin were increased. After SAL treatment, there was a significant reduction in collagen area and a decrease in the ratio of collagen type I to type III. The expression of smad3 and β-catenin was suppressed and positively correlated with the dosage of SAL. SAL may contribute to the progression of MF through the TGF-β1/Smad3 and Wnt/β-catenin signaling pathways.


The effects of manual treatment on rounded-shoulder posture, and associated muscle strength.
A relationship between pectoralis minor muscle tightness and rounded shoulder posture (RSP) has been suggested, but evidence demonstrating that treatment aimed at the pectoralis minor affects posture or muscle function such as lower trapezius strength (LTS) remains lacking. In this randomized, blinded, controlled study of the 56 shoulders of 28 healthy participants, the experimental treatment consisting of pectoralis minor soft tissue mobilization (STM) and self-stretching significantly reduced RSP compared to the pre-treatment baseline (Friedman test, p<.001) and the control treatment of placebo touch and pectoralis major self-stretching (Mann-Whitney U-test, p<.01). RSP remained significantly reduced 2 weeks after the single treatment. Both control and experimental treatments resulted in increased LTS (Friedman test, p<.01) with no significant difference in LTS noted between treatments (p>.05). This study demonstrated that STM and self-stretching of the pectoralis minor can significantly reduce RSP.


Microwave-assisted facile synthesis of poly(luminol-co-phenylenediamine) copolymers and their potential application in biomedical imaging.
Conjugated copolymers have attracted much attention because of their outstanding photo-physical properties. The present work reports for the first time, microwave-assisted copolymerization of o-phenylenediamine with luminol using different weight ratios of the two monomers. The composition of the copolymers was confirmed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (1H-NMR) while monomer reactivity ratios were determined using the Fineman-Ross method. Ultraviolet-visible spectroscopy revealed the variation in polaronic states upon copolymerization while X-ray diffraction (XRD) and transmission electron microscopy (TEM) analyses showed the morphology of the copolymers to be intermediate between that of the homopolymers. Confocal analysis and fluorescence studies revealed that the copolymers showed composition based blue as well as red emission which could be utilized for in vivo imaging of cancer cells.


Flooding variations affect soil bacterial communities at the spatial and inter-annual scales.
Hydrological variations have substantial effects on the diversity and composition of soil bacterial communities in wetlands. At the spatial scale, the responses of soil bacterial diversity and composition to hydrological variations in wetlands have been extensively investigated. However, at the temporal scale, especially at the inter-annual scale, the corresponding bacterial responses are rarely reported. Therefore, we explored the effects of flooding variations on the diversity and composition of soil bacterial communities at a lakeshore wetland in two hydrological contrasting years. Three flooding variables, i.e. flooding duration (FD), total duration of the growing season (TGD), and exposure duration of the growing season (EGD), were used to characterize flooding regime. Soil bacterial communities were determined using 16S rRNA gene sequencing method. We found a very high soil bacterial diversity at the lakeshore wetland. The Shannon's indexes of soil bacterial communities varied from 5.61 to 7.11 in two years. Soil bacterial α-diversity followed a unimodal curve along the elevation gradient, and was significantly lower in the flooding year than in the drought year. Principal coordinate analysis demonstrated that the compositions of soil bacterial communities were separated in order of elevation and year along the first and second axes, respectively. The apparent habitat preferences of soil bacterial families were closely connected with their respiratory traits, and this trend was stronger at the inter-annual scale than at the spatial scale. Soil bacterial compositions were predominantly determined by the direct (by changing respiratory traits) and indirect (by changing soil pH) effects of TGD at the spatial scale, while they were simultaneously regulated by the direct effects of three flooding variables at the inter-annual scale. Our results enhance the understanding of soil microbial communities in wetlands and have large implications for developing general theories to predicting soil microbial functions.


Identification of gram-negative bacilli using the Autobac IDX.
The Autobac IDX is a new system for the rapid identification of clinically significant members of the Enterobacteriaceae and Aeromonas, Acinetobacter, Alcaligenes, Flavobacterium, Moraxella, and Pseudomonas species. The use of 18 differentially inhibitory compounds such as dyes and antibiotics along with a computerized algorithm based on a multivariate analysis provides the basis for the identification of 30 different groups of gram-negative bacilli. Required preliminary tests include observations on the presence or absence of swarming on a sheep blood agar plate and noting the following: growth, lactose fermentation, and bile precipitation from a MacConkey plate. Spot indole and spot oxidase tests must be performed as well. Identification by the Autobac IDX System takes 3-6 hr after completion of the preliminary tests. From a total of 403 isolates tested, the Autobac system agreed with the MicroID AND N/F systems on 382 identifications (94.8%). Four isolates, two Acinetobacter anitratus, one Serratia marcescens and one Moraxella osloensis could not be identified by IDX. Additional testing was required on 35 (8.7%) of the isolates.


Paretic thyroid myopathy.
Reports of vertical deviation in Graves' disease in recent years have always been associated with restrictive phenomena and positive forced duction testing, usually related to a tight inferior rectus. Two cases of medically proven Graves' diseased of ten-year duration are presented with increasing vertical disparity. Forced duction testing showed no restriction. Saccadic velocity tests using electro-oculography confirmed paresis of the inferior rectus in both cases. No cases of "true" vertical extraocular muscle paresis in chronic Graves' disease have been reported in the American literature.


Postnatal colonization of porcine lung capillaries by intravascular macrophages: an ultrastructural, morphometric analysis.
Lungs of newborn and of 7- and 30-day-old pigs were fixed at total capacity by a standardized procedure. Stereologic morphometry was applied to random ultrathin sections of parenchyma. Relative volume density, absolute volume, and capillary surface coverage of intravascular macrophages as well as parameters of relative morphometric diffusion capacity of lungs were assessed. Intravascular macrophages occupied up to 25% of capillary volume in 30-day-old pigs compared with 6% in newborn pigs; this was a 14-fold increase of absolute volume. In 30-day-old pigs, 16% of capillary surface was covered with closely adherent intravascular macrophages in contrast to only 2% in newborn pigs. Determinators of morphometric diffusion capacity were similar in all pigs. Greater thickness of the arithmetic and harmonic mean air-blood tissue barrier in 30-day-old pigs (with included thickness of intravascular macrophages) compared with air-blood tissue barriers (without intravascular macrophages) was not statistically significant. The relative difference of arithmetic mean was larger than the difference of harmonic mean, and reflected preferential adherence of intravascular macrophages to the thick portion of the air-blood tissue barrier. Our findings confirm morphologic observations of perinatal colonization of the porcine lung by monocytes that replicate and differentiate into large, highly phagocytic, resident, intravascular macrophages. Preferential adherence to sites where basal laminae of capillary endothelium and alveolar epithelium were separated by interstitium may explain the minimal morphometric impact of intravascular macrophages on the air-blood tissue barrier thickness. This location would be expected to have less effect on gas diffusion than location of intravascular macrophages on the thin side of the air-blood barrier.


The Context of Values in Pain Control: Understanding the Price Effect in Placebo Analgesia.
The experience of pain relief arises from physiological and psychological factors, and attributes such as the commercial features of analgesic treatments have been shown to influence placebo analgesia by affecting treatment expectations. Therefore, treatment valuation from price information should influence the placebo analgesic effect. This hypothesis was tested in a functional magnetic resonance imaging study in which healthy subjects were enrolled in a 2-day experiment. On day 1, the participants (n = 19) had treatment experiences with 2 different placebo creams during a conditioning session without receiving information on treatment price. On day 2, placebo analgesia was tested after providing price information (high vs low) while functional magnetic resonance imaging was performed. The results showed that the higher priced placebo treatment leads to enhanced pain relief. Placebo analgesia in response to the higher priced treatment was associated with activity in the ventral striatum, ventromedial prefrontal cortex, and ventral tegmental area. The behavioral results indicate that the experience of pain was influenced by treatment valuation from price. Our findings reveal that the context of values in pain control is associated with activity in expectation- and reward-related circuitry. PERSPECTIVE: Treatment with higher price was associated with enhanced placebo analgesia, and this effect was influenced by activities in expectation and reward processing brain areas. The context of value such as medical cost influences cognitive evaluation processes to modulate pain. Our study may help evaluate a patient's preference toward high-priced drugs.


Pharmacology in the Era of Targeted Therapies: The Case of PI3K Inhibitors.
The PI3K pathway is often aberrantly activated in estrogen receptor positive (ER(+)) breast cancer and therapies combining PI3K inhibitors and antiestrogens are under clinical development. Given that many PI3K inhibitors have substantial toxicities with continuous dosing and that alternate dosing schedules are equally active, further clinical exploration is warranted. Clin Cancer Res; 22(9); 2099-101. ©2016 AACRSee related article by Yang et al., p. 2250.


Anticariogenic and phytochemical evaluation of Eucalyptus globules Labill.
In the present study, in vitro anticariogenic potential of ethyl acetate, hexane and methanol and aqueous extracts of plant leaves of Eucalyptus globules Labill. were evaluated by using four cariogenic bacteria, Lactobacillus acidophilus, Lactobacillus casei, Staphylococcus aureus and Streptococcus mutans. Agar well diffusion method and minimum inhibitory concentration (MIC) were used for this purpose. The ethyl acetate extracted fraction of plant leaves showed good inhibitory effects against all selected bacteria. In Eucalyptus globules, hexane and ethyl acetate extracts found highly effective against, Lactobacillus acidophilus with MIC value of 0.031 and 0.062 mg/mL, respectively. Qualitative phytochemical investigation of above extracts showed the presence of alkaloids, phenolic compounds, steroids, cardiac glycosides and terpenes. Based on the MIC value and bioautography, ethyl acetate of plant leaf was selected for further study. Further investigation on the structure elucidation of the bioactive compound using IR, GC-MS and NMR techniques revealed the presence of alpha-farnesene, a sesquiterpene. Eucalyptus globules plant leaf extracts have great potential as anticariogenic agents that may be useful in the treatment of oral disease.


Benefit-risk assessment of brensocatib for treatment of non-cystic fibrosis bronchiectasis.
Brensocatib is a novel anti-inflammatory therapy in development for bronchiectasis treatment. Phase 2 WILLOW trial data demonstrate a low number needed to treat and negative number needed to harm, suggesting a favourable benefit-risk profile. https://bit.ly/3SbisW3.


Effects of mycophenolic acid-glucosamine conjugates on the base of kidney targeted drug delivery.
Mycophenolic acid has played an important role in treating immunosuppression and autoimmune diseases. Nevertheless, the agent needs a high dosage in treatment, following some side effects. To tackle this problem, in this study, mycophenolic acid-glucosamine conjugate (MGC), modified by 2-glucosamine, was synthesized to achieve kidney targeting and improved drug efficacy with a lower dosage. (1)H NMR, (13)C NMR and HRMS spectroscopy were used to verify the conjugate whose stability was good in vitro. The transport of MGC by human proximal renal tubular epithelial HK-2 cells was temperature-, time-, concentration-dependent and saturable, suggesting the involvement of carrier-mediated uptake. In addition, the cellular uptake of MGC dropped substantially with the inhibition of megalin receptor. The specific tissue distribution indicated the commendable renal-targeting capability of MGC. The concentration of MGC was improved in the kidney except for other tissues, about 6.76 times higher than that of MPA. Further, the bioavailability of MGC in plasma decreased as compared with mycophenolic acid. Moreover, therapeutic effect of MGC was enhanced significantly compared with MPA in the acute kidney injury model. All the findings suggested the potential of mycophenolic acid-glucosamine conjugate in kidney targeted drug delivery.


Fetal macrosomia greater than or equal to 4000 grams. Comparing maternal and neonatal outcomes in diabetic and nondiabetic women.
To compare maternal and neonatal outcomes of fetal macrosomia in diabetic and nondiabetic women. A retrospective case-control study was conducted at Riyadh Military Hospital, Riyadh, Kingdom of Saudi Arabia from January 2004 to December 2006. A total of 766 macrosomic newborns met the inclusion criteria. We compared maternal and neonatal characteristics and outcomes between diabetic (group 1, n=207) and nondiabetic (group 2, n=559) women. There were significantly more macrosomic newborns in nondiabetic women; 73% versus 27% in diabetic women, p=0.0001. Cesarean deliveries were significantly higher in diabetic women compared to nondiabetic women (30.4% versus 19.5%, p=0.002). There were no significant differences between either group in total maternal morbidity (12.6% versus 14.1%, p=0.7). There were significantly more severe cases of shoulder dystocia occurring in newborns of diabetic women compared to nondiabetic women (1.9% versus 0.2%, p=0.03). Elective cesarean delivery for estimated fetal weight > or =4500g for nondiabetic women and > or =4250 g for diabetic women may avoid severe shoulder dystocia without increasing maternal morbidity rates.