Age-related changes in the calcium homeostasis of adherent neutrophils.
The elderly are susceptible to infections and show a decline in neutrophil (PMN) functions that are regulated by cytosolic calcium [Ca2+]i. This study measures [Ca2+]i in suspended and adherent PMN of young and elderly individuals by using flow cytometry, confocal microscopy, the bacterial peptide fMLP, and the fluorescent Ca2+ indicator fluor-3/acettoxymethyl ester. PMN from both age groups show a steep and transient fMLP-induced Ca2+ increase. This increase is independent of external divalent cations and is desensitized by a subsequent exposure to the same agonist. Adherent PMN of the elderly express elevated [Ca2+]i before (basal) and after fMLP activation but show reduced ability to mobilize Ca2+ into and from the cytosol. PMN of the elderly take longer (13.7 +/- 3 s) to attain the maximal response compared to those of young adults (5.7 +/- 0.8 s). PMN from both age groups show heterogeneity in the time and magnitude of this response. However, PMN of the elderly show a decrease in the proportion of cells with prompt and effective reaction and an increase in the representation of a cell subpopulation manifesting delayed response. We conclude that age-related delayed and reduced PMN response to a bacterial peptide could hamper functional activities that are essential in host protection against infections.


Use of psychotropic drugs in elderly nursing home residents with and without dementia in Helsinki, Finland.
Use of psychotropic medication is very common in nursing home residents. Our objective was to describe the use of psychotropic drugs in all long-term nursing home residents > or =65 years of age with and without dementia in Helsinki, Finland. The study was a cross-sectional assessment of the nursing home population. The residents' health status was assessed and data on their demographic factors, health and medication use were collected from medical charts in February 2003. Of all nursing home residents in Helsinki, 82% (n = 1987) participated in the study. The nursing home residents' mean age was 83.7 (SD 7.7) years, 80.7% were female, and 69.5% were diagnosed with dementia. The mean number of drugs [corrected] given regularly was 7.9 (SD 3.6) per day per resident[corrected] Of the participants, 79.7% were regularly taking psychotropic medication. Conventional antipsychotics were administered to 18.9% of residents and atypical antipsychotics to 27.0%. Of the residents, 26.7% were on selective serotonin reuptake inhibitors (SSRIs), 3.1% on tricyclic antidepressants and 17.6% on other antidepressants. Altogether, 44.6% of residents were taking one or more antidepressant. More than a quarter (26.3%) were taking at least one anxiolytic drug. Hypnotics were used by 27.5%. However, only moderate dosages of psychotropic drugs were being taken. Only 10.4% of individuals with dementia were regularly taking cholinesterase inhibitors and four residents were taking memantine. Use of psychotropic drugs is very common in nursing homes in Helsinki, Finland, with four of five nursing home residents regularly receiving psychotropic drugs. Only one in ten residents were receiving cholinesterase inhibitors. Physicians caring for nursing home residents require further education on the benefits and adverse effects of psychotropic drugs in frail elderly people.


Vaginal administration of PGE2 for induction of labor stimulates endogenous PGF2 alpha production.
Prostaglandin E2 is effective for induction of labor but many preparations exist using a variety of vehicles from which the active ingredient may not be equally available. Plasma concentrations of bicyclic PGE2 metabolite (PGEM) and 13, 14-dihydro, 15-keto PGF2 alpha (PGFM) were measured following administration of a 3mg PGE2 vaginal tablet or 1mg PGE2 vaginal gel to twenty-four parous women with favorable induction features, randomly allocated to receive one or other preparation. PGEM increased rapidly following both administration of the 3mg PGE2 vaginal tablet and the 1mg PGE2 vaginal gel, reaching a peak within 40 minutes of PGE2 administration. The maximal rise in PGEM in the gel group correlated directly with the change in cervical score and inversely with the need for augmentation with oxytocin and the induction-delivery interval. A secondary rise in PGFM was noted in both groups 3-4 hours following PGE2 administration. The magnitude of the increase in PGE2 may be important in the clinical response to PGE2 administration, while PGE2 absorption may switch-on endogenous PGF2 alpha production, similar to what is seen in spontaneous labor.


Design, synthesis, and biological evaluation of cyclopropyl analogues of stilbene with raloxifene side chain as subtype-selective ligands for estrogen receptor.
We have designed the cyclopropane analog of stilbene as subtype-selective ligands for estrogen receptor based on the bioisosterism that cyclopropane could act as alkene bioisoster. Three cyclopropane analogs were prepared efficiently starting from 4-benzyloxybenzaldehyde, and evaluated for their binding to estrogen receptors ERα and ERβ. These cyclopropane analogs were also found to be full agonists in estrogen receptor-mediated gene transcription assay. Compared to the stilbene analogs such as tamoxifen and raloxifene, the three cyclopropane analogs showed lower binding affinity for estrogen receptor, but higher subtype selectivity for ERα. The structure-activity relationship revealed from this study might provide clues for improving subtype selectivity for ERα.


Examining Perceptions of Spanish Language Health Information Among Hispanics Living in the United States: A Qualitative Study Assessing Videos, Brochures, and Websites.
Nationally, Hispanics experience health disparities manifested as a higher prevalence of chronic diseases in comparison to non-Hispanic Whites. Factors that influence health disparities in this population include inadequate dissemination of culturally and linguistically appropriate health information. Our qualitative analysis is based on data obtained from three focus groups with Spanish-speaking Hispanic adults conducted at a clinic in Nebraska. Participants were asked about their perceptions of health information in the form of videos, brochures, and websites. We followed the consolidated criteria for reporting qualitative research and used the theoretical framework of content analysis. For videos, attributes associated with higher levels of trust included a friendly health professional, the logo or name of a health care institute, and a reference specifying "se habla Español." For brochures, attributes associated with trust included use of visual aids, use of numerous colors and big font sizes, the year of printing, and a health care agency logo. For websites, characteristics associated with trust were inclusion of plain language, use of pictures and videos, and date of last update. In all focus groups, participants perceived the use of mixed English/Spanish language in health information from pamphlets and websites as unprofessional. The use of unknown governmental logos in health promotional videos and websites was perceived as untrustworthy information. Spanish-speaking Hispanics prefer health information supported by a health care agency or delivered by a health care professional. Health communication strategies should avoid the use of mixed English/Spanish language in sensitive information especially when combined with governmental logos.


Changing PACES: developments to the examination in 2009.
As a consequence of change in medical, educational and regulatory practice, MRCP(UK) successfully modified the international PACES examination in 2009. This brief paper explains the rationale for change and summarises the development and implementation process.


Contrast examination of cerebrospinal fluid shunt malfunction in infancy and childhood.
The technique of contrast examination of the common types of cerebrospinal fluid (CSF) shunts is described. The findings in 250 shuntograms are analysed and the results discussed. The most common cause of shunt malfunction was shunt blockage. Errors of interpretation occurred in 16 shuntograms and were more frequent in Pudenz systems than in Spitz-Holter. The technique is simple, safe, accurate and does not require special apparatus. There was only one serious complication in 250 shuntograms. It is particularly useful when the anterior fontanelle has closed.


Neurohistochemical biomarkers of the marine neurotoxicant, domoic acid.
Domoic acid and its potent excitotoxic analogues glutamic acid and kainic acid, are synthesized by marine algae such as seaweed and phytoplankton. During an algal bloom, domoic acid may enter the food web through its consumption by a variety of marine organisms held in high regard as seafoods by both animals and humans. These seafoods include clams, mussels, oysters, anchovies, sardines, crabs, and scallops, among others. Animals, such as pelicans, cormorants, loons, grebes, sea otters, dolphins, and sea lions, which consume seafood contaminated with domoic acid, suffer disorientation and often death. Humans consuming contaminated seafood may suffer seizures, amnesia and also sometimes death. In addition to analytical measurement of domoic acid exposure levels in algae and/or seafood, it is useful to be able to identify the mode of toxicity through post-mortem evaluation of the intoxicated animal. In the present study, using the rat as an animal model of domoic acid intoxication, we compared histochemical staining of the limbic system and especially the hippocampus with degeneration-selective techniques (Fluoro-Jade and silver), a conventional Nissl stain for cytoplasm (Cresyl violet), a myelin-selective stain (Black-Gold), an astrocyte-specific stain (glial fibrillary acidic protein), early/immediate gene responses (c-Fos and c-Jun), as well as for heat shock protein (HSP-72) and blood-brain barrier integrity (rat IgG). The results demonstrate that the degeneration-selective stains are the biomarkers of domoic acid neurotoxicity that are the most useful and easy to discern when screening brain sections at low magnification. We also observed that an impairment of blood-brain barrier integrity within the piriform cortex accompanied the onset of domoic acid neurotoxicity.


Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis.
Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selectively inhibiting TNFR1 in mice with experimental autoimmune encephalomyelitis, we used chimeric human/mouse TNFR1 knock-in mice allowing the evaluation of antagonistic anti-human TNFR1 antibody efficacy. Treatment of mice after onset of disease with ATROSAB resulted in a robust amelioration of disease severity, correlating with reduced central nervous system immune cell infiltration. Long-term efficacy of treatment was achieved by treatment with the parental mouse anti-human TNFR1 antibody, H398, and extended by subsequent re-treatment of mice following relapse. Our data support the hypothesis that anti-TNFR1 therapy restricts immune cell infiltration across the blood-brain barrier through the down-regulation of TNF-induced adhesion molecules, rather than altering immune cell composition or activity. Collectively, we demonstrate the potential for anti-human TNFR1 therapies to effectively modulate immune responses in autoimmune disease.


Angiotensin converting enzyme (ACE) gene expression in the human left ventricle: effect of ACE gene insertion/deletion polymorphism and left ventricular function.
We investigated the effect of the angiotensin converting enzyme (ACE) I/D polymorphism and left ventricular (LV) function on ACE gene expression in tru-cut LV myocardial biopsies from 50 consecutive patients (II: 18, ID: 18, DD: 14; 40 males) with ischaemic heart disease undergoing coronary artery bypass grafting (CABG). The polymerase chain reaction was used for ACE genotyping. LV function [normal (n=22) or impaired] was determined by left ventriculography at cardiac catheterisation prior to bypass surgery. ACE expression was determined (n=46) by a competitive quantitative reverse transcription PCR assay using 5x10(5), 12. 5x10(5) and 20x10(5) copies of a mutant DNA internal standard (IS). PCR products were analysed by negative film photography and laser densitometry to determine the number of ACE transcripts present. Mean age was similar (II: 59.1+/-10.4, ID: 57.0+/-10.6, DD: 61.4+/-6.2; P=NS) with no differences between groups in sex (P=0. 25); hypertension, P=0.31; previous myocardial infarction, P=0.44; LV function, P=0.23; and ACE inhibitor therapy, P=0.06. ACE expression per 100 ng of total RNA varied with genotype [<5x10(5) copies in II: 6, 5-12.5x10(5) copies in II: 6, ID: 16, DD: 4; and >12.5x10(5) (II: 4, ID: 2, DD: 8), Kendall's tau-b coefficient (tau(b))=0.43, P=0.003]. Impaired LV function also correlated with higher levels of ACE expression, Kendall's tau(b)=0.40, P=0.001. ACE gene expression in the left ventricle varied with ACE genotype and LV function in IHD patients undergoing CABG.


The reliability of selected motion- and pain provocation tests for the sacroiliac joint.
The objective of the study was to assess inter-rater reliability of one palpation and six pain provocation tests for pain of sacroiliac origin. The sacroiliac joint (SIJ) is a potential source of low back and pelvic girdle pain. Diagnosis is made primarily by physical examination using palpation and pain provocation tests. Previous studies on the reliability of such tests have reported inconclusive and conflicting results. Fifty-six women and five men aged 18-50 years old were included in the study. Fifteen patients had ankylosing spondylitis; 30 women had post partum pelvic girdle pain for more than 6 weeks; and 16 people had no low back or pelvic girdle pain. All participants were examined twice on the same day by experienced manual therapists. Percentage agreement and kappa statistic were used to evaluate the tests reliability. Results showed percentage agreement and kappa values ranged from 67% to 97% and 0.43 to 0.84 for the pain provocation tests. For the palpation test the percent agreement was 48% and the kappa value was -0.06. Clusters of pain provocation tests were found to have good percentage agreement, and kappa values ranged from 0.51 to 0.75. In conclusion this study has shown the reliability of the pain provocation tests employed were moderate to good, and for the palpation test, reliability was poor. Clusters out of three and five pain provocation tests were found to be reliable. The cluster of tests should now be validated for assessment of diagnostic power.


Anthracyclines in the treatment of malignancy in pregnancy.
This article reports two cases and reviews the literature regarding chemotherapy using anthracyclines during pregnancy. Twenty-six additional cases using this class of agents to treat malignancy during pregnancy are summarized from 18 reports for a total of 28 pregnancies. Final outcome of pregnancy is analyzed with regard to the following factors: diagnosis, gestational age at start of therapy, total dose of anthracycline, number and type of agents used, neonatal pathologic findings and months of follow-up of infants. Final outcome of 28 pregnancies resulted in 24 normal infants including a set of twins in the current report. Limited pharmacokinetic information is inconclusive with regard to the appearance of anthracyclines and their known metabolites in placental or fetal tissue.


Macronutrient composition of sea otter diet with respect to recolonization, life history, and season in southern Southeast Alaska.
The sea otter (Enhydra lutris) population of Southeast Alaska has been growing at a higher rate than other regions along the Pacific coast. While good for the recovery of this endangered species, rapid population growth of this apex predator can create a human-wildlife conflict, negatively impacting commercial and subsistence fishing. Previous foraging studies throughout the sea otter range have shown they will reduce invertebrate prey biomass when recolonizing an area. The goal of this study was to examine and quantify the energy content of sea otter diets through direct foraging observations and prey collection. Our study area, Prince of Wales Island in southern Southeast Alaska, exhibits a gradient of sea otter recolonization, thus providing a natural experiment to test diet change in regions with different recolonization histories. Sea otter prey items were collected in three seasons (spring, summer, and winter) to measure caloric value and lipid and protein content. We observed 3523 sea otter dives during the spring and summer. A majority of the sea otter diet consisted of clams. Sea otters in newly recolonized areas had lower diet diversity, higher energetic intake rates (EIR, kcal/min), and prey had higher energy content (kcal/g). Females with pups had the highest diet diversity and the lowest EIR. Sea otter EIR were higher in the fall and winter vs. spring and summer. Sea cucumber energy and lipid content appeared to correspond with times when sea otters consumed the highest proportion of sea cucumbers. These caloric variations are an important component of understanding ecosystem-level effects sea otters have in the nearshore environment.


Truncal ataxia and the vestibulo spinal reflex. A historical review.
The vestibulospinal pathway was described many years ago. Along with it, the vestibulospinal signs that are used for the diagnosis of vestibular disorders were described. In this work we summarize the history of the vestibulospinal pathway, the classic signs and the new signs that can be used in the diagnosis of vestibular disorders, paying special attention to truncal ataxia as a useful element to differentiate central from peripheral pathology.


Mechanistic contribution of electroconductive hydroxyapatite-titanium disilicide composite on the alignment and proliferation of cells.
We elucidate here the mechanistic contribution of a novel electroconductive hydroxyapatite-20 wt.% titanium disilicide (HA-TiSi2) composite system in favorably modulating osteoblast functions in relation to the monolithic HA. The higher electrical conductivity of HA-TiSi2(σDC ∼ 67.117 ± 3.57 S/m) in comparison to glass sample effectively guided the electroactive myoblast, leading to their significant alignment and proliferation. This favorable behavior is attributed to the formation of small electrochemical cells between HA and TiSi2phase, which produce a small electric field, directing the electroactive myoblast to migrate and grow in a particular direction. In contrast, no impact of TiSi2on osteoblast function was observed because of their inability to respond to small electric field. However, thein vitrobioactivity in simulated body fluid indicated the nucleation and growth of apatite crystals. Moreover, in the context of load-bearing capability, the presence of 20 wt.% TiSi2in HA led to increase in the fracture toughness by ∼100%. This study underscores the effectiveness of HA-TiSi2in favorably modulating the cellular activity, myoblast in particular.


Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia.
Advances in multiagent chemotherapy have led to recent improvements in survival for patients with acute lymphoblastic leukemia (ALL); however, a significant fraction do not respond to frontline chemotherapy or later relapse with recurrent disease, after which long-term survival rates remain low. To develop new, effective treatment options for these patients, we conducted a series of high-throughput combination drug screens to identify chemotherapies that synergize in a lineage-specific manner with MRX-2843, a small molecule dual MERTK and FLT3 kinase inhibitor currently in clinical testing for treatment of relapsed/refractory leukemias and solid tumors. Using experimental and computational approaches, we found that MRX-2843 synergized strongly-and in a ratio-dependent manner-with vincristine to inhibit both B-ALL and T-ALL cell line expansion. Based on these findings, we developed multiagent lipid nanoparticle formulations of these drugs that not only delivered defined drug ratios intracellularly in T-ALL, but also improved anti-leukemia activity following drug encapsulation. Synergistic and additive interactions were recapitulated in primary T-ALL patient samples treated with MRX-2843 and vincristine nanoparticle formulations, suggesting their clinical relevance. Moreover, the nanoparticle formulations reduced disease burden and prolonged survival in an orthotopic murine xenograft model of early thymic precursor T-ALL (ETP-ALL), with both agents contributing to therapeutic activity in a dose-dependent manner. In contrast, nanoparticles containing MRX-2843 alone were ineffective in this model. Thus, MRX-2843 increased the sensitivity of ETP-ALL cells to vincristine in vivo. In this context, the additive particles, containing a higher dose of MRX-2843, provided more effective disease control than the synergistic particles. In contrast, particles containing an even higher, antagonistic ratio of MRX-2843 and vincristine were less effective. Thus, both the drug dose and the ratio-dependent interaction between MRX-2843 and vincristine significantly impacted therapeutic activity in vivo. Together, these findings present a systematic approach to high-throughput combination drug screening and multiagent drug delivery that maximizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL and describe a novel translational agent that could be used to enhance therapeutic responses to vincristine in patients with T-ALL. This broadly generalizable approach could also be applied to develop other constitutively synergistic combination products for the treatment of cancer and other diseases.


Molecular characterization of an anthocyanin-related glutathione S-transferase gene in cyclamen.
Anthocyanins are a subclass of flavonoids and are a major contributor to flower colors ranging from red to blue and purple. Previous studies in model and ornamental plants indicate a member of the glutathione S-transferase (GST) gene family is involved in vacuolar accumulation of anthocyanins. In order to identify the anthocyanin-related GST in cyclamen, degenerate PCR was performed using total RNA from immature young petals. Four candidates of GSTs (CkmGST1 to CkmGST4) were isolated. Phylogenetic analysis indicated that CkmGST3 was closely related to PhAN9, an anthocyanin-related GST of petunia, and this clade was clustered with other known anthocyanin-related GSTs. Expression analysis at different developmental stages of petals revealed that CkmGST3 was strongly expressed in paler pigmented petals than in fully pigmented petals, in contrast to the constitutive expression of the other three candidates during petal development. This expression pattern of CkmGST3 was correlated with those of other anthocyanin biosynthetic genes such as CkmF3'5'H and CkmDFR2. Molecular complementation of Arabidopsis tt19, a knockout mutant of an anthocyanin-related GST gene, demonstrated that CkmGST3 could complement the anthocyanin-less phenotype of tt19. Transgenic plants that expressed the other three CkmGSTs did not show anthocyanin accumulation. These results indicate CkmGST3 functions in anthocyanin accumulation in cyclamen.


Strain-specific differences in lung tissue viscoelasticity of mechanically ventilated infant Sprague-Dawley and Wistar rats.
Rats are often used in ventilator-induced lung injury (VILI) models. However, strain-specific susceptibility for VILI has not been elucidated yet. The aim of this study was to demonstrate strain-specific differences in VILI in infant Sprague-Dawley and Wistar rats. VILI was compared in 2-wk-old pups after 8 h of protective or injurious ventilation. Pups were ventilated with tidal volumes (VT) of ∼7 mL/kg and positive end-expiratory pressures (PEEP) of 6 cmH2O (VT7 PEEP6) or with VT of ∼21 mL/kg and PEEP 2 cmH2O (VT21 PEEP2). Interleukin-6, macrophage inflammatory protein-2 (MIP-2), inflammatory cells, and albumin in bronchoalveolar lavage fluid (BALF); histology; and low-frequency forced oscillation technique (LFOT) and pressure-volume (PV) maneuvers were assessed. Alveolar macrophages, neutrophils, and MIP-2 derived from BALF revealed more pronounced VILI after VT21 PEEP2 in both strains. LFOT and PV analyses demonstrated rat strain-specific differences both at baseline and particularly in response to VT21 PEEP2 ventilation. Sprague-Dawley rats showed higher airway and tissue resistance and elastance values with no difference in hysteresivity between ventilation strategies. Wister rats challenged by VT21 PEEP2 experienced significantly more energy dissipation when compared with VT7 PEEP6 ventilation. In conclusion, both rat strains are useful for VILI models. The degree of VILI severity depends on ventilation strategy and selected strain. However, fundamental and time-dependent differences in respiratory system mechanics exist and reflect different lung tissue viscoelasticity. Hence, strain-specific characteristics of the respiratory system need to be considered when planning and interpreting VILI studies with infant rats.


Understanding DNA Damage Response and DNA Repair in Multiple Myeloma.
Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.


Treatment of failed aortic bioprostheses: An evaluation of conventional redo surgery and transfemoral transcatheter aortic valve-in-valve implantation.
The use of bioprostheses for surgical aortic valve replacement increased substantially within the last years. In case of prosthesis failure, re-SAVR is standard of care, whereas valve-in-valve deployment of a transfemoral transcatheter aortic valve prosthesis (VinV-TFAVI) has recently emerged as an alternative. We sought to evaluate early safety, clinical efficacy, and all-cause 1-year-mortality of VinV-TFAVI and redo surgery for failing aortic bioprostheses (re-SAVR). Patients receiving either VinV-TFAVI (n = 147) or re-SAVR (n = 111) for a degenerated aortic bioprosthesis between 01/2006 and 05/2017 were included in this analysis. All-cause 1-year mortality was the primary outcome measure. Early safety and clinical efficacy according to VARC-2 endpoint definitions were evaluated at 30 days. Baseline characteristics differed significantly between both groups including age, STS-PROM, and incidence of relevant comorbidities. Re-stenosis was the predominant mode of failure in 45.9% of re-SAVR and 63.1% of VinV-TFAVI patients. The rate of "early safety" endpoints was lower with VinV-TFAVI (17.7% vs. 64.9%, p < 0.01), the rate of "clinical efficacy" endpoints was lower, e.g. better with re-SAVR (53.1% vs. 32.4%, p < 0.01). All-cause 1-year-mortality (VinV-TFAVI 8.8% vs re-SAVR 9.9%, p = 0.84) was not different. Treatment strategy was not associated with 1-year-mortality in a Cox regression analysis. The incidence of prosthesis-patient-mismatch was higher in VinV-TFAVI compared to re-SAVR. VinV-TFAVI represents a viable alternative for treatment of degenerated aortic bioprostheses in patients at increased surgical risk. However, in patients at low risk for reoperation, a better clinical efficacy and acceptable safety may favour re-SAVR.


Long-term safety and tolerability of epoetin zeta, administered intravenously, for maintenance treatment of renal anemia.
The aim of this trial was to gather data on the long-term safety of a new erythropoietin preparation (epoetin zeta), focusing on the formation of anti-erythropoietin antibodies, when administered intravenously for maintenance of target hemoglobin concentration in anemic patients with end-stage renal failure receiving chronic hemodialysis. In addition, we aimed to provide information on the efficacy of epoetin zeta under open, noncontrolled conditions. Patients received epoetin zeta intravenously, 1-3 times/week for 56 weeks (overall patient group, n=745) or 108 weeks (Bulgarian subgroup, n=164). The aim of treatment was to maintain hemoglobin values between 10.5 and 12.5 g/dL with constant epoetin dosage. Primary (safety) endpoints were the occurrence of anti-erythropoietin antibodies and the evaluation of adverse events (AEs). Secondary (efficacy) endpoints included the mean weekly dose of epoetin per kg of body weight and mean hemoglobin concentrations. No patients developed neutralizing anti-erythropoietin antibodies. The most commonly reported AEs were infections and infestations (34.1%); followed by injury, poisoning, and procedural complications (25.8%); and gastrointestinal disorders (21.9%); 37.3% of patients reported serious AEs. The hemoglobin values remained stable, with mean values after 56 weeks of 11.3-11.6 g/dL for the overall group and 11.1-11.6 g/dL for the Bulgarian subgroup. The dosage of epoetin zeta was stable throughout the course of the trial. No cases of lack of (or loss of ) efficacy were observed in the course of the trial. The evaluation of the primary endpoints provided data supporting the intravenous administration of epoetin zeta in patients with chronic renal failure. Neutralizing antibodies against erythropoietin were not detected, and there were no reports of patients with increasing erythropoietin resistance. Our results suggest that intravenous administration of epoetin zeta is effective regarding its ability to maintain stabilized hemoglobin levels within the target range of 10.5-12.5 g/dL.


New chemical constituents from the fruits of Tetradium ruticarpum.
Two new γ-lactone derivatives, evodinoids A (1) and B (2), along with a new essential oil (3) were isolated from the nearly ripe fruits of Tetradium ruticarpum. The structures of these isolations were determined by 1D and 2D NMR, HR-ESI-MS and ECD data analysis. In addition, the cytotoxic effect of compounds 1-3 was evaluated against human cancer cells A498, A549, HepG-2, MCF-7 and SHSY-5Y, which displayed no significant cytotoxicity (IC50 > 100 μM).


Effects of operating parameters on in situ NH3 emission control during kitchen waste composting and correlation analysis of the related microbial communities.
Ammonia emission during composting results in anthropogenic odor nuisance and reduces the agronomic value of the compost due to the loss of nitrogen. Adjusting the operating parameters during composting is an emerging in situ odor control technique that is cheap and highly efficient. The effects of in situ NH3 emission control were investigated in this study by simultaneously adjusting key operating parameters (such as C/N ratio, aeration rate, and moisture content) during the composting processes (C1-C9). Results showed that the average NH3 emission concentrations for different treatments were in the order of C1 > C4 > C2 > C5 > C3 > C6 > C7 > C8 > C9. The total content of NH3 emission (21.02 g/kg) in C9 (C/N ratio = 35, aeration rate = 15 L/min, and moisture content = 60%) was much lower than that (65.95 g/kg) in C1 (C/N ratio = 15, aeration rate = 5 L/min, and moisture content = 60%). The nitrogen loss ratio was 27.36% for C1, while 16.15% for C9. The microbial diversity and abundance in C9 and C1 were compared using high-throughput sequencing. The relationship between NH3 emission, operating parameters, and the related functional microbial communities was also investigated. Results revealed that Nitrosospira, Nitrosomonas, Nitrobacter, Pseudomonas, Methanosaeta, Rhodobacter, Paracoccus, and Sphingobacterium were negatively related to NH3 emission. According to the above results, the optimal values for different operating parameters for the in situ NH3 control during kitchen waste composting were, respectively, moisture content of 70%, C/N ratio of 35, and aeration rate of 15 L/min, with the order of effectiveness from high to low being aeration rate > C/N > moisture. This information could be used as a valuable reference for the in situ NH3 emission control during kitchen waste composting.


Patients' perceptions of caring behaviors at referral hospitals in Ethiopia: A cross-sectional survey.
The purpose of this study was to determine patients' perceptions of nurse caring behaviors and to identify factors associated with these perceptions. A cross-sectional study was conducted at three referral hospitals in Ethiopia. A consecutive sample of male and female patients (n = 652, response rate 98.8%) was interviewed using the Amharic version of the Caring Behaviors Inventory-16 (CBI-16, including four subscales: Assurance, Knowledge and skill, Respectful, and Connectedness) and the Patient Satisfaction Instrument (PSI). Socio-demographic and clinical factors associated with perceptions of caring behaviors were identified using multiple linear regression analysis. Patients' perceptions of nurse caring behaviors were high (total Mean = 4.86, SD = 0.72). Behaviors related to the Assurance subscale were rated the highest. The multiple linear regression analysis result showed several socio-demographic and clinical factors statistically significantly associated with patients' perceptions of caring behaviors (total mean scores). Patients who were 40-49 years (B = -0.19, P = 0.012) and single (B = -0.13, P = 0.03) scored lower on total CBI-16 scores. Whereas, patients who had a higher educational level (B = 0.35, P = 0.001), cared for at surgery units (B = 0.11, P = 0.027), and reported having spent more time with a nurse in the past 8-h shift (B = 0.16, P < 0.001) were more likely to have higher perceptions of the care they received. The CBI-16 was positively correlated with satisfaction with received care, as measured with the Patient Satisfaction Instrument (r = 0.62, P < 0.001). Hospitalized patients in Ethiopia have overall high perceptions of nurse caring behaviors, especially with regard to physical-based caring, while their expectations of emotional-focused care are lower. We identified patients who were in need of care, patients aged 40-49 years and single. The time spent with nurses plays a pivotal role in patients' perceptions of nurse caring behaviors.


Comparative study of the effects of optic design on lens epithelium in vitro.
We performed two tissue culture experiments designed to compare the effects of various posterior chamber optics on lens epithelium. In the first experiment, we recorded, by phase contrast microphotography, the migration of rabbit lens epithelium exoplants placed adjacent to the optic of various posterior chamber lenses. In the second experiment, we used phase contrast microphotographs to document the effects of various posterior chamber optics when gently placed on a confluent layer of rabbit lens epithelium. From our in vitro studies, we conclude the following: There is inhibition of lens epithelial migration and even cytotoxic effects from direct contact with polymethylmethacrylate optics; glass optics have appreciably less effect on lens epithelium; polymethylmethacrylate optics with ridges (complete annulus or incomplete) do not inhibit lens epithelial migration as well as planoconvex lenses, and they do not have a cytotoxic effect except at the points of contact between the ridge and the supporting surface.


RPIPCM: A deep network model for predicting lncRNA-protein interaction based on sequence feature encoding.
LncRNA-protein interactionplays an important regulatory role in biological processes. In this paper, the proposed RPIPCM based on a novel deep network model uses the sequence feature encoding of both RNA and protein to predict lncRNA-protein interactions (LPIs). A negative sampling of sliding window method is proposed for solving the problem of unbalanced between positive and negative samples. The proposed negative sampling method is effective and helpful to solve the problem of data imbalance in the existing LPIs research by comparative experiments. Experimental results also show that the proposed sequence feature encoding method has good performance in predicting LPIs for different datasets of different sizes and types. In the RPI488 dataset related to animal, compared with the direct original sequence encoding model, the accuracy of sequence feature encoding model increased by 1.02%, the recall increased by 4.08%, and the value of MCC increased by 1.67%. In the case of the plant dataset ATH948, the sequence feature-based encoding demonstrated a 1.58% higher accuracy, a 1.53% higher recall, a 1.62% higher specificity, a 1.62% higher precision, and a 3.16% higher value of MCC compared to the direct original sequence-based encoding. Compared with the latest prediction work in the ZEA22133 dataset, RPIPCM is shown to be more effective with the accuracy increased by 2.23%, the recall increased by 1.78%, the specificity increased by 2.67%, the precision increased by 2.52%, and the value of MCC increased by 4.43%, which also proves the effectiveness and robustness of RPIPCM. In conclusion, RPIPCM of deep network model based on sequence feature encoding can automatically mine the hidden feature information of the sequence in the lncRNA-protein interaction without relying on external features or prior biomedical knowledge, and its low cost and high efficiency can provide a reference for biomedical researchers.


Intraperitoneal interferon in the management of malignant ascites.
Ascites secondary to malignancy is a major cause of recurring morbidity in patients with ovarian cancer. In patients previously treated with cisplatin, other chemotherapeutic agents are not likely to be effective in relieving symptoms. A pilot group of ten patients was treated with intraperitoneal alpha-2B-interferon (alpha-2B-IFN) in an effort to provide symptomatic relief of their ascites. All patients had advanced epithelial ovarian cancer at the time of therapy and were receiving treatment for palliation only. Symptoms included abdominal distention (100% of patients), nausea and vomiting in the absence of mechanical intestinal obstruction (60%), and dyspepsia (40%). At a dose of 10 M units/m2 given intraperitoneally every 2 weeks for one to four treatments, the toxicity was low, but the benefits were minimal. Five (50%) patients reported symptomatic improvement of 2-7 weeks' duration. The most common side effects included fever (temperature of more than 38.5 degrees C) and abdominal pain. At the dose of 10 M units/m2 of intraperitoneal alpha-2B-IFN, this regimen did not appear to produce clinically significant palliation of the ascites in most patients.


The bioavailability of ergothioneine from mushrooms (Agaricus bisporus) and the acute effects on antioxidant capacity and biomarkers of inflammation.
Ergothioneine (ET) is a sulfur containing amino acid that functions as an antioxidant. Mushrooms are a primary source of ET containing from 0.4 to 2.0mg/g (dry-weight). The bioavailability of ET from mushrooms in humans remains unclear. We evaluated the bioavailability of ET in healthy men (n=10) in a pilot study, using a randomized, cross-over, dose-response, postprandial time-course design, conducted at the General Clinical Research Center at Pennsylvania State University in 2009. ET was administered through a mushroom test meal containing 8 g and 16 g of mushroom powder. Postprandial red blood cell concentrations of ET were measured. Plasma glucose, triglycerides, HDL, LDL and total cholesterol also were monitored. Biomarkers of inflammation and oxidative stress were evaluated using C-reactive protein and ORAC(total). ET was bioavailable after consuming mushrooms and a trend in the postprandial triglyceride response indicated that there was a blunting effect after both the 8 g and 16 g ET doses were compared with the 0 g dose. Despite ET's antioxidant properties, ORAC(total) values decreased after the 8 g and 16 g mushroom meal. Ergothioneine from A. bisporus mushrooms is bioavailable as assessed by red blood cell uptake postprandially, and consumption is associated with an attenuated postprandial TG response.


An isoflavanoid-neoflavonoid and an O-methylated isoflavone from the heartwood of Dalbergia nitidula.
An isoflavanoid (6-->2) neoflavonoid dimer and a 4',5',7-trihydroxy-2'-methoxyisoflavone, both as the acetate derivatives were isolated from the heartwood of Dalbergia nitidula. Their structures were established by spectroscopic methods.


International experience using a durable, centrifugal-flow ventricular assist device for biventricular support.
Heart transplantation is limited by the scarcity of suitable donors. Patients with advanced biventricular failure may require biventricular support to provide optimal cardiac output and end-organ perfusion. We highlight the outcomes of using the HeartWare HVAD System (HVAD) in a biventricular configuration. This retrospective study included patients implanted with HVAD as a biventricular assist device (BiVAD) between 2009 and 2017 at 12 participating centers. When used as a right ventricular assist device (VAD) (RVAD), the HVAD can be attached to the right ventricle (RV) or the right atrium (RA). Kaplan-Meier survival estimates were calculated comparing the 2 RVAD implant locations. Comparisons were also made between the timing of RVAD implantation (primary vs staged) on adverse event (AE) profiles and survival. Among the 93 patients who were implanted with a HVAD BiVAD, Kaplan-Meier survivals at 1-year and 2-year were 56% and 47%, respectively. Survival was independent of the location of the HVAD RVAD implant or whether there was an interval between left VAD and RVAD implantation. The most common AEs were bleeding (35.5%), infection (25.8%), and respiratory failure (20.4%). This study illustrated similar survival in patients receiving a primary or staged HVAD BiVAD implant at 1 year and 2 years. This study also established that the locations of the RVAD implant (RV or RA) result in similar AE profiles.


[Incidence of Toxoplasma gondii infections among children in the Kielce province].
Toxoplasma antibodies were investigated among 639 children inhabiting the province of Kielce. The percentage of seropositive children appeared high in newborns (58.4), then dropped to 1.48 in one-year-old infants and increased to 17.4 among 6-7 year old children. The percentage was significantly higher among country children.


[The impact of avian influenza on health care system].
Avian influenza is a viral transmitted disease that mainly occurs in birds. First described in 1878 in Italy the disease can be found worldwide. The causing agent belongs to the family of orthomyxoviridae. Since its enormous spread among poultry in 2003, the influenza virus H5N1 is heralded as a possible agent of a new pandemic. H5N1 is pathogen to humans with a mortality rate of over 60%. The main reason that this virus has not caused a pandemic yet is its lack to propagate freely between humans. The current review explores the impact of avian influenza on the health system.


Evaluation of the choroidal vascularity index after subthreshold yellow laser treatment in the patients with chronic central serous chorioretinopathy.
To assess the choroidal vascularity index (CVI) after subthreshold laser treatment in patients with central serous chorioretinopathy (CSC). A total of 32 eyes with CSC were included in this study. In group 1, 14 eyes with persistent CSC were treated with the PASCAL (Endpoint Management Software) at 577-nm wavelength and in group 2, 18 eyes without treatment. The luminal area (LA), stromal area (SA), total area of choroid (TA), and CVI were measured by binarization (ImageJ) of optical coherence tomography images. Changes of choroidal structure parameters were evaluated over 3 months. A significant decrease was observed in LA, TA, and CVI at the third month after the laser treatment (p = 0.018, p = 0.024, p = 0.046). The best-corrected visual acuity (BCVA) and choriocapillaris plexus (CCP) flow area values were increased after treatment in group 1 (p < 0.001, p = 0.002). The final subfoveal fluid height, and CVI were lower in group 1 (p = 0.003, p = 0.011). The visual acuity and CCP flow area were higher in group 1 at the third month (p < 0.001, p = 0.003). A positive correlation between the final BCVA and CVI was observed (r = 0.539, p = 0.01). Decreased CVI was observed in CSC eyes after subthreshold yellow laser treatment. The CVI may be a useful index to evaluate the response to treatment.


Advancing Education in Endoscopic Spinal Navigation: Novel Methods and Technical Note.
This report aims to demonstrate how to teach anatomy and understanding of spinal endoscopic vision and navigation using mnemonics. The authors present a new surgical technique for teaching endoscopic spinal navigation in a didactic manner with tips such as the "rule of the hand" and decomposition of the endoscopic navigation movement. We demonstrate how the surgery is seen and illustrate how images are projected onto the screen, then divide the navigation into spatial orientation and self-navigation. The article describes the proper puncture technique, how to introduce the working portal, and how to assimilate this new anatomical vision using the "rule of the hand." The surgeon projects their hand on the video screen to guide themselves when starting the navigation and uses the same technique to localize regions of interest during surgery. Finally, the authors break down the navigational movement into three components: forceps positioning, triangulation, and joystick motion. One of the biggest challenges when learning spinal endoscopic surgery is understanding the anatomy seen through the endoscope. By decomposing movements required for navigation, one can understand how to make proper use of the equipment as well as improve their knowledge of this "new anatomy." The learning methods taught in this article have the potential to decrease the learning curve and radiation exposure to those that are still acquainting themselves to spinal endoscopic navigation. We recommend that further studies measure and quantify the impact of these methods on surgical practice.


Susceptibility factors and DNA adducts in peripheral blood mononuclear cells of aluminium smelter workers exposed to polycyclic aromatic hydrocarbons.
Formation of DNA adducts as a result of exposure to polycyclic aromatic hydrocarbons (PAH) was studied in 98 potroom workers from an aluminium smelting plant and in 55 blue-collar workers without occupational PAH exposure. DNA from peripheral blood mononuclear cells (PBMC) was used for quantitation of individual PAH-DNA adducts by 32P-postlabelling/high performance liquid chromatography (HPLC) analysis. Four individual DNA adducts (denoted A, B, C and D) were quantified in 141 of a total of 153 subjects. Genetic polymorphisms for cytochrome P-4501A1 ( CYP1A1), microsomal epoxide hydrolase, N-acetyltransferase 2, glutathione transferases M1, P1 and T1 ( GSTM1, GSTP1 and GSTT1, respectively) and NAD(P)H: quinone oxidoreductase 1 (NQO1) were analysed. For 52 subjects, analysis of mRNA inducibility of CYP1A1 was performed. No statistically significant differences in the levels of total or individual DNA adducts A, C and D were found between potroom workers and control subjects. All potroom workers and the subgroup of potroom workers who reported to never/sometimes use personal respiratory protection ( n=72) were found to have a significantly higher likelihood of having high levels of adduct B than control subjects [odds ratio (OR) =3.4 with 95% confidence interval (CI) of 1.3-9.2, and OR=4.2 with 95% CI 1.6-11.5, respectively]. In the subgroup, levels of adducts A and B were found to be significantly higher among workers with employment time of less than 6 months ( n=5). Also, the levels of the individual DNA adducts were to some extent modified by genetic polymorphisms in CYP1A1, GSTM1, GSTP1 and NQO1 and by CYP1A1 inducibility. In conclusion, levels of adduct B, identified by 32P-postlabelling/HPLC methodology as an indicator of PAH exposure in aluminium production, were modified by the use of respiratory protection, length of employment and genetic polymorphisms.


Retinal break formation following contrecoup trauma: case report.
A previously healthy 38-year-old woman was involved in a road traffic accident resulting in severe commotio retinae. Subsequently extramacular retinal dissolution was noted (not previously described). The patient was treated by closed intraocular microsurgery with a successful anatomical and functional result.


Single vs multiple somatic nerve crushes in the rat.
Nerve lesions modify regenerative responses to subsequent lesions. Some of the modifications might be useful. To increase our understanding of these modifications, the present study determines myelinated and unmyelinated axon numbers in the distal part of rat sciatic nerve and in 2 smaller branches, the nerve to the medial gastrocnemius muscle and the sural nerve, 8 weeks and 9 months following either single or the last of 3 crushes to the rat sciatic nerve. For myelinated axons, there is a significant and proportional increase distal to the crush in the sciatic nerve and in its smaller tributaries following both single and triple crushes. These increased axons persist. We interpret these data to indicate that some of the regenerating myelinated axons branch at the site of lesion, pass without branching into the tributary nerves, and then presumably find attachments at the periphery. If true, single or multiple crushes might be useful in conditions where it would be desirable to increase numbers of processes from surviving neurons. The major differences between single and triple crushes are that myelinated axons are increased more after triple crush and increase significantly between 8 weeks and 9 months after triple crush but not after single crush. Thus not only myelinated axon numbers, but the timing of the myelination process seems to change if regeneration following single crush is compared to similar regeneration following multiple crushes. Unmyelinated axons do not regenerate in the same way as the myelinated axons.(ABSTRACT TRUNCATED AT 250 WORDS)


Acute caffeine reverses the disruptive effects of chronic fluoxetine on the sexual behavior of female and male rats.
Sexual side effects of chronic treatment with selective serotonin reuptake inhibitors (SSRIs) in humans include anorgasmia and loss of sexual desire and/or arousal which interferes with treatment compliance. There are few options at present to reduce these effects. Because orgasm and desire are mediated in part by activation of sympathetic arousal, we asked whether the sympathomimetic effects of acute caffeine treatment could reverse these effects. The present study examined whether acute treatment with caffeine (CAF; 10 or 20 mg/kg, ip) versus vehicle could ameliorate the disruption of appetitive and consummatory measures of copulatory behavior produced by chronic fluoxetine (10 mg/kg, sc) in adult, sexually active female or male rats. Sexually experienced female or male rats received daily injections of FLU over a 24-day period and were tested for sexual behaviors five times at 4-day intervals during this period in bilevel pacing chambers. Females had been ovariectomized and given hormone replacement with estradiol benzoate and progesterone prior to each test. Males were left gonadally intact. Four days after the final FLU test, rats were randomly assigned to one of the three doses of CAF and received ip injections of CAF or the saline vehicle 60 min before testing. Chronic FLU reduced solicitations and lordosis over time in females and reduced the number of ejaculations in males. Both doses of CAF restored solicitations and lordosis in females and ejaculations in males. On their own, both doses of CAF increased females' pacing behavior and the number of mounts and intromissions in the males. Stimulation of sympathetic outflow by CAF may constitute a readily accessible on-demand treatment for the sexual side-effects of SSRIs.


Effects of orexin on cultured porcine adrenal medullary and cortex cells.
New orexigenic peptides called orexins have recently been described in the neurons of the lateral hypothalamus and perifornical area. No orexins have been found in the adipose tissues or visceral organs, including the adrenal gland. However, expression of the orexin receptor (OXR) in the rat adrenal gland has been reported. With regard to the effects of orexins on peripheral organs, we previously reported that orexins suppress catecholamine synthesis and secretion in the rat pheochromocytoma cell line PC12. To further clarify the pharmacological effects of orexins on peripheral organs, we examined the effects of orexin-A on catecholamine, cortisol, and aldosterone secretion, using cultured porcine adrenal glands. We initially confirmed the expression of the orexin receptor (OXR-1) in cultured porcine adrenal medulla and cortex. Orexin-A (1000 nM) significantly increased the release of both epinephrine (E) and norepinephrine (NE) from porcine adrenal medullary cells. Similarly, orexin-A (> or = 100 nM) significantly increased the release of both cortisol and aldosterone from porcine adrenal cortex cells. Orexin-A (100 nM) significantly inhibited basal and the PACAP-induced increase in cAMP levels in adrenal medullary cells. Conversely, orexin-A (>o = 100 nM) significantly increased the cAMP level in adrenal cortex cells. These results indicate that orexin-A induces the release of catecholamine from porcine adrenal medullary cells, and aldosterone and cortisol from the cortex cells and has opposite effects on cAMP levels in adrenal medulla and cortex.


[Causes of failure after total knee arthroplasty].
To identify the causes of failure after total knee arthroplasty (TKA). Retrospective reviews were conducted for the causes of failures of 181 TKA patients between January 2007 and December 2013. Among the causes of failures after primary TKA, infection was the major cause of failure (53%, 96/181) followed by aseptic loosening (16%, 29/181), arthrofibrosis (10%, 18/181), instability (6.6%, 12/181), extensor mechanism problem (5%, 9/181), wear (4.4%, 8/181), periprosthetic fracture (2.8%, 5/181) and others (2.2%, 4/181). And 64.1% occurred in the first two years, 19.9% occurred between 2 and 5 years and 16.0% occurred after 5 years after operation. Up to 84.0% occurred in 5 years. The top three causes of failures after primary TKA at our center are infection, aseptic loosening and arthrofibrosis.


On-road Driving Performance of Patients With Bilateral Moderate and Advanced Glaucoma.
To compare on-road driving performance of patients with moderate or advanced glaucoma to controls and evaluate factors associated with unsafe driving. Case-control pilot study. A consecutive sample of 21 patients with bilateral moderate or advanced glaucoma from Washington University, St Louis, Missouri and 38 community-dwelling controls were enrolled. Participants, aged 55-90 years, underwent a comprehensive clinical evaluation by a trained occupational therapist and an on-road driving evaluation by a masked driver rehabilitation specialist. Overall driving performance of pass vs marginal/fail and number of wheel and/or brake interventions were recorded. Fifty-two percent of glaucoma participants scored a marginal/fail compared to 21% of controls (odds ratio [OR], 4.1; 95% CI, 1.30-13.14; P = .02). Glaucoma participants had a higher risk of wheel interventions than controls (OR, 4.67; 95% CI, 1.03-21.17; P = .046). There were no differences detected between glaucoma participants who scored a pass vs marginal/fail for visual field mean deviation of the better (P = .62) or worse (P = .88) eye, binocular distance (P = .15) or near (P = .23) visual acuity, contrast sensitivity (P = .28), or glare (P = .88). However, glaucoma participants with a marginal/fail score performed worse on Trail Making Tests A (P = .03) and B (P = .05), right-sided Jamar grip strength (P = .02), Rapid Pace Walk (P = .03), Braking Response Time (P = .03), and identifying traffic signs (P = .05). Patients with bilateral moderate or advanced glaucoma are at risk for unsafe driving-particularly those with impairments on psychometric and mobility tests. A comprehensive clinical assessment and on-road driving evaluation is recommended to effectively evaluate driving safety of these patients.


Hazard report. Still getting stuck--protective devices alone won't always prevent needlestick injuries.
Despite widespread use of needlestick-prevention devices (NPDs), staff injuries can occasionally occur, often because of improper technique or device failure. Although no protective device is 100% effective, hospitals can limit injuries by ensuring that their needlestick-prevention programs incorporate ongoing staff education on the use of NPDs as well as on proper handling and disposal of sharps.


Variation of lead bioaccessibility in soil reference materials: Intra- and inter-laboratory assessments.
Standard reference materials (SRMs) have been commonly used to perform quality assurance and quality control (QA/QC) in soil total metal concentration analyses or bioaccessibility assessment. In this study, 10 experimenters from 4 laboratories determined bioaccessibility of lead (Pb) in 4 widely-used SRMs (NIST 2710a, NIST 2587, BGS 102, and GBW 07405). Based on the gastric phase (GP) of the unified BARGE bioaccessibility method (UBM) and the Solubility Bioavailability Research Consortium procedure (SBRC), Pb bioaccessibility in SRMs was compared within and between laboratories to assess their intra-laboratory repeatability and inter-laboratory reproducibility. Lead bioaccessibility was 14.1 ± 2.44%-101 ± 2.48% in the 4 SRMs. The values were in vivo validated based on a mouse model in previous studies (R2 = 0.97-0.98), suggesting the reliability of Pb bioaccessibility data. Strong correlations were observed for Pb bioaccessibility among 7 experimenters (R2 = 0.94-0.99) at the Nanjing University (NJU) laboratory and similar strong correlations were also found between each two of the 4 laboratories (R2 = 0.94-0.98), illustrating consistency in intra- and inter-laboratory performance. The intra-laboratory repeatability and inter-laboratory reproducibility were generally acceptable with relative standard deviations (RSDs) of Pb bioaccessibility being ≤10% within laboratory and ≤20% between laboratories, except in a soil with low bioaccessible Pb (BSG 102). Our study suggested that measurements of Pb bioaccessibility in SRMs based on the two in vivo validated methods were repeatable and reproducible within and between laboratories, further verified their reliability being used as QA/QC samples during Pb bioaccessibility assessment.


Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway.
Vascular calcification (VC) is a complex, regulated process involved in many disease entities. So far, there are no treatments to reverse it. Exploring novel strategies to prevent VC is important and necessary for VC-related disease intervention. In this study, we evaluated whether MOTS-c, a novel mitochondria-related 16-aa peptide, can reduce vitamin D3 and nicotine-induced VC in rats. Vitamin D3 plus nicotine-treated rats were injected with MOTS-c at a dose of 5 mg/kg once a day for 4 weeks. Blood pressure, heart rate, and body weight were measured, and echocardiography was performed. The expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and the angiotensin II type 1 (AT-1) and endothelin B (ET-B) receptors was determined by Western blot analysis. Our results showed that MOTS-c treatment significantly attenuated VC. Furthermore, we found that the level of phosphorylated AMPK was increased and the expression levels of the AT-1 and ET-B receptors were decreased after MOTS-c treatment. Our findings provide evidence that MOTS-c may act as an inhibitor of VC by activating the AMPK signaling pathway and suppressing the expression of the AT-1 and ET-B receptors.


In Schizosaccharomyces pombe chs2p has no chitin synthase activity but is related to septum formation.
Chitin synthesis occurs in most fungi through the action of different chitin synthase (CS) isoenzymes. In Schizosaccharomyces pombe the chs2(+) gene codes for a protein with significant similarity to CS enzymes, but lacking most of the residues considered to be essential for activity, including the QRRRW domain. Here we show that chs2p is a functional protein that localises to the growing edge of the septum but is not a CS enzyme. Strong over-expression is lethal, while moderate expression leads to a severe defect in septum formation. These results suggest that chs2p has remained through evolution to play an alternative role in septation.


The anatomy of the circle of Willis as a predictive factor for intra-operative cerebral ischemia (shunt need) during carotid endarterectomy.
The collateral flow to the cerebral hemisphere after carotid cross clamping during carotid endarterectomy is mainly through the circle of Willis, and the circle is incomplete in the majority of cases. A correlation between the status of the circle of Willis and the necessity of shunting was evaluated in 67 carotid endarterectomies with pre-operative four-vessel cerebral angiogram. All carotid endarterectomies were performed with selective shunting, based on the change of consciousness and motor function after carotid test clamping under regional anesthesia. Of the 55 patients with either an anterior or a posterior communicating artery, only four (7.3%) required shunting. Twelve patients had neither anterior nor posterior communicating artery, and 10 (83.3%) showed signs of cerebral ischemia necessitating shunting. Mandatory shunt was significantly higher in patients with absence of collaterals (p = 0.00). The rate of intraoperative cerebral ischemia was significantly higher in patients with poor collateral circulation defined by the anatomy of the circle of Willis.


A reappraisal of boundary conditions assumed in pulmonary gas transport models.
Solutions of the classic pulmonary gas transport equation are presented in which a true 'no-flux' boundary condition is specified throughout the respiratory cycle. For the particular models studied it is demonstrated that diffusive mixing is incomplete at end expiration, and that such stratified inhomogeneities give rise to a realistic alveolar plateau for a simulated N2 washout test. The reasons for the disparity of the present findings with those obtained by contemporary workers are explained by critically examining the boundary conditions conventionally assumed at the alveolar wall.


Effect of a new macrolide antibiotic (tilmicosin) on pneumonia experimentally induced in calves by Mycoplasma bovis and Pasteurella haemolytica.
Two gnotobiotic calves were treated once with tilmicosin (20 mg kg-1) six hours before they were infected by the intratracheal route with Mycoplasma bovis and Pasteurella haemolytica serotype 1. This treatment prevented colonisation of the lungs by P haemolytica and considerably reduced colonisation by M bovis, and the clinical scores and the extent of pneumonic consolidation, compared with two untreated gnotobiotic calves, both of which had to be killed in extremis for humanitarian reasons within 24 hours of infection. In a second experiment, 10 conventionally reared calves were similarly exposed to infection and, at the onset of clinical disease, five were treated once with tilmicosin (20 mg kg-1). Colonisation by P haemolytica and M bovis, the clinical scores and extent of pneumonic consolidation were suppressed or greatly reduced in the treated compared with the untreated calves, one of which had to be killed in extremis two days after infection. It was concluded that tilmicosin had a beneficial effect.


Peripheral endothelial and microvascular damage in liver cirrhosis: A systematic review and meta-analysis.
This is the first systematic review and meta-analysis of studies using any available functional method to examine differences in peripheral endothelial function between cirrhotic and non-cirrhotic individuals. Literature search involved PubMed, Web-of-Science, and Scopus databases, as well as gray literature sources. We included studies in adult subjects evaluating endothelial function with any semi-invasive or non-invasive functional method in patients with and without liver cirrhosis. From 3378 records initially retrieved, 15 studies with a total of 570 participants were included in the final quantitative meta-analysis. In six studies examining endothelial function with flow-mediated-dilatation, no differences between patients with cirrhosis and controls were evident (WMD: 1.33, 95%CI [-2.87, 5.53], I2 = 97%, p < .00001). Among studies assessing differences in endothelial-dependent or endothelial-independent vasodilation with venous-occlusion-plethysmography, there were no significant differences between the two groups. When pooling all studies together, regardless of the technique used, no significant difference in endothelial function between cirrhotic patients and controls was observed(SMD: 0.79, 95%CI[-0.04, 1.63], I2 = 94%, p < .00001). No differences in peripheral endothelial function assessed with semi-invasive or non-invasive functional methods exist between cirrhotic and non-cirrhotic subjects. The increasing co-existence of cardiovascular risk factors leading to impaired vascular reactivity in cirrhotic patients may partly explain these findings.


Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and pro-maturation factors.
Therapeutic stimulation of angiogenesis to re-establish blood flow in ischemic tissues offers great promise as a treatment for patients suffering from cardiovascular disease or trauma. Since angiogenesis is a complex, multi-step process, different signals may need to be delivered at appropriate times in order to promote a robust and mature vasculature. The effects of temporally regulated presentation of pro-angiogenic and pro-maturation factors were investigated in vitro and in vivo in this study. Pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) cooperatively promoted endothelial sprouting and pericyte detachment in a three-dimensional in vitro EC-pericyte co-culture model. Pro-maturation factors platelet-derived growth factor B (PDGF) and angiopoietin 1 (Ang1) inhibited the early stages of VEGF- and Ang2-mediated angiogenesis if present simultaneously with VEGF and Ang2, but promoted these behaviors if added subsequently to the pro-angiogenesis factors. VEGF and Ang2 were also found to additively enhance microvessel density in a subcutaneous model of blood vessel formation, while simultaneously administered PDGF/Ang1 inhibited microvessel formation. However, a temporally controlled scaffold that released PDGF and Ang1 at a delay relative to VEGF/Ang2 promoted both vessel maturation and vascular remodeling without inhibiting sprouting angiogenesis. Our results demonstrate the importance of temporal control over signaling in promoting vascular growth, vessel maturation and vascular remodeling. Delivering multiple growth factors in combination and sequence could aid in creating tissue engineered constructs and therapies aimed at promoting healing after acute wounds and in chronic conditions such as diabetic ulcers and peripheral artery disease.


Delineating bacterial community structure of polluted soil samples collected from cancer prone belt of Punjab, India.
16S rRNA gene analysis has emerged as one of the valuable tools that are being utilized in investigating the molecular phylogenetic structure of the particular environment. Here, we embarked upon understanding and delineating the molecular phylogeny structure of microbes in polluted soil samples from cancer prone belt of the Punjab, India, which is highly contaminated with herbicide, pesticide and heavy metals. To investigate the bacterial phylogeny structure, a high-molecular weight metagenomic DNA was extracted from the soil samples, followed by PCR amplification, cloning and analysis of the 16S rRNA genes. Study employing 16S rRNA profiling of the community DNA revealed the presence of two major phylums: the Proteobacteria (26.7 %), the Bacteroidetes (11.2 %), and several minor groups, i.e., Acidobacteria (4.2 %), Actinobacteria (4.2 %), Firmicutes (2.8 %), Verrucomicrobia (2.8 %), Gemmatimonadetes (1.4 %) and Chloroflexi (1.4 %). Among the Proteobacteria, we mainly observed the α-Proteobacteria (18.3 %). Nearly, 38 % of the recovered 16S rRNA gene sequences in this study do not share similarity with known culturable bacterial sequences reported in the genebank data base and hence considered to be novel. More interestingly, 16S rRNA gene sequences of archaeal origin (7.0 %) were also recovered that primarily indicate change in their evolution pattern. A phylogenetic tree constructed based on alignment-dependent method revealed the extent of similarity these clones shared with each other, followed by alignment-independent methods that statistically confirmed the sequence variation among the clones. Despite the high level of contamination in the study area, we observed remarkable microbial diversity that mainly includes the Gram-negative bacteria. The presence of more Gram-negative bacteria indicates that they have evolved a robust mechanism to resist and cope up with these pollutants compared to Gram-positive groups. Investigation of the polluted soil samples employing culture-independent approach revealed important bacterial groups which could be engineered for future bioremediation studies.


The influence of cognitive load on static balance in chronic obstructive pulmonary disease patients.
Patients with chronic obstructive pulmonary disease (COPD) may demonstrate cognitive function and balance deterioration. These two phenomena are often realized simultaneously during daily living activities, where the risk of falling may be increased due to possible postural disturbance when focusing on a cognitive task during motion. Despite the high rate of falls in COPD, there is currently a lack of affordable clinical instruments to quantify the interaction between cognitive tasks and static balance in these patients. Therefore, this study aims to assess the balance perturbation induced by cognitive tasks using a new cost-effective protocol which can easily be implemented in clinical settings. A total of 21 COPD patients (Age: 64 ± 8 yrs, Forced Expiratory Volume in one second = 41 ± 17%, Women: 7) and 21 matched healthy controls participated in the study. They performed two cognitive tasks (counting backward by 3s and naming animals) with eyes open and with eyes closed. Each trial lasted 60 s, with balance-related parameters recorded and quantified using a Wii Balance Board. A three-way ANOVA (cognitive task, eyes action, and health status) for balance-related parameters derived from the center of pressure displacement was performed. COPD, vision, and cognitive tasks altered the balance; no interaction between conditions was observed. There was no correlation between cognitive ability, respiratory function, and the balance-related parameters. Compared to healthy controls, the COPD patients had impaired balance. Cognitive tasks altered postural control in both COPD and controls, where this alteration was more pronounced with eyes closed.


Clonal relatedness in the acquisition of intestinal carriage and transmission of multidrug resistant (MDR) Klebsiella pneumoniae and Escherichia coli and its risk factors among preterm infants admitted to the neonatal intensive care unit (NICU).
Gastrointestinal carriage of multidrug resistant (MDR) Gram-negative bacilli, especially Klebsiella pneumoniae and Escherichia coli, was highly associated with severe nosocomial infections. The main objectives of this study were to determine the clonal relatedness of intestinal carriage and transmission risk factors of MDR E. coli and K. pneumoniae amongst preterm infants admitted to the neonatal intensive care unit (NICU). A prospective cohort study of preterm infants with gestational age < 37 weeks was conducted in the NICU of the University of Malaya Medical Centre (UMMC). Infants' stool specimens were collected on day 1 (meconium), week 1, week 2, week 8 and week 10 during their admission (from 1st June to 31st August 2017) until discharge. The presence and antibiotic resistance pattern of MDR E. coli and K. pneumoniae were determined. Strain clonality and relatedness were explored via pulsed-field gel electrophoresis (PFGE) fingerprints. The risk factors for MDR strains acquisition were evaluated using the Cox proportional-hazards model and Firth logistic regression. A total of 139 stool specimens were obtained from 50 subjects. Twenty-six (52%) infants were colonized with MDR K. pneumoniae and/or E. coli. High clonal dissemination between two clusters of ESBL-producing K. pneumoniae strains was seen from PFGE profile. We detected a persistent, dominant, aminoglycosides-resistant strains cluster (cluster B), which harbored blaTEM, blaSHV, blaOXA-1, blaCTX-M-1, ompK35 and ompK36 genes. Infants born to women who were anemic in pregnancy [OR = 0.01 (CI = 0.00-0.39), P-value = 0.042] and infants exposed to penicillin/β-lactams group antibiotics during the first week of life [OR = 0.02 (CI = 0.02-0.32), P-value = 0.013] were found to have a lower risk of MDR K. pneumoniae and E. coli colonization. The prevalence of dominant aminoglycosides-resistant strains cluster in the NICU is alarming. Awareness of and vigilance for the dominant cluster found will enable the reduction of cross-transmission amongst high-risk infants.


Update on the imaging diagnosis of otosclerosis.
Otosclerosis is a primary osteodystrophy of the temporal bone that causes progressive conductive hearing loss. The diagnosis is generally clinical, but multidetector CT (MDCT), the imaging technique of choice, is sometimes necessary. The objective of this article is to systematically review the usefulness of imaging techniques for the diagnosis and postsurgical assessment of otosclerosis, fundamentally the role of MDCT, to decrease the surgical risk.


The Acquisition of Directionals in Two Mayan Languages.
We use the comparative method of language acquisition research in this article to investigate children's expression of directional clitics in two Eastern Mayan languages - K'iche' and Mam (Pye and Pfeiler, 2014; Pye, 2017). The comparative method in historical linguistics reconstructs the grammatical antecedents of modern languages and traces the evolution of each linguistic feature (Paul, 1889; Campbell, 1998). This history informs research on language acquisition by demonstrating how phonological and morphological features interact in the evolution of new uses for common inherited traits. Children acquiring modern languages must learn the arbitrary constraints imposed on their language by its history.


En-bloc transurethral resection vs. conventional transurethral resection for primary non-muscle invasive bladder cancer: A meta-analysis.
We performed a meta-analysis to evaluate the effect of en-bloc transurethral resection vs. conventional transurethral resection for primary non-muscle invasive bladder cancer. A systematic literature search up to January 2022 was done and 28 studies included 3714 primary non-muscle invasive bladder cancer subjects at the start of the study; 1870 of them were en-bloc transurethral resection, and 1844 were conventional transurethral resection for primary non-muscle invasive bladder cancer. We calculated the odds-ratio (OR) and mean-difference (MD) with 95% confidence-intervals (CIs) to evaluate the effect of en-bloc transurethral resection compared with conventional transurethral resection for primary non-muscle invasive bladder cancer by the dichotomous or continuous methods with random or fixed-effects models. En-bloc transurethral resection had significantly lower twenty-four-month recurrence (OR: 0.63; 95%CI: 0.50-0.78; p < 0.001), catheterization-time (MD: -0.66; 95%CI: -1.02-[-0.29]; p < 0.001), length of hospital stay (MD: -0.95; 95%CI: -1.55-[-0.34]; p = 0.002), postoperative bladder irrigation duration (MD: -6.06; 95%CI: -9.45-[-2.67]; p < 0.001), obturator nerve reflex (OR: 0.08; 95%CI: 0.02-0.34; p = 0.03), and bladder perforation (OR: 0.14; 95%CI: 0.06-0.36: p < 0.001) and no significant difference in the 12-month-recurrence (OR: 0.79; 95%CI: 0.61-1.04; p = 0.09), the operation time (MD: 0.67; 95%CI: -1.92 to 3.25; p = 0.61), and urethral stricture (OR: 0.46; 95%CI: 0.14-1.47; p = 0.0.19) compared with conventional transurethral resection for primary non-muscle invasive bladder cancer subjects. En-bloc transurethral resection had a significantly lower twenty-four-month recurrence, catheterization time, length of hospital stay, postoperative bladder irrigation duration, obturator nerve reflex, bladder perforation, and no significant difference in the twelve-month recurrence, operation time, and urethral stricture compared with conventional transurethral resection for primary non-muscle invasive bladder cancer subjects. Further studies are required.


Porous cobalt spheres for high temperature gradient magnetically assisted fluidized beds.
Porous metallic cobalt spheres have been prepared as high temperature capable media for employment in gradient magnetically assisted fluidization and filtration technologies. Cobalt impregnated alginate beads are first formed by extrusion of an aqueous suspension of Co3O4 into a Co(II) chloride solution. The organic polymer is thermally decomposed yielding cobalt oxide spheres, followed by reduction to the metallic state, and densification. Cobalt beads have been produced with porosities ranging between 10 and 50%, depending upon sintering conditions. The product media have been characterized by scanning electron microscopy (SEM), nitrogen adsorption porosimetry, and vibrating sample magnetometry.


Hypertrophic cardiomyopathy is a component of subacute necrotizing encephalomyelopathy.
Twelve patients, ranging from the neonatal period through adolescence, with subacute necrotizing encephalomyelopathy (Leigh disease) were studied. Autopsies of these patients demonstrated an associated hypertrophic cardiomyopathy in seven; of these, four had asymmetric septal hypertrophy. In two patients, the cardiac lesion was observed by premortem echocardiograms. The common occurrence of a cardiac lesion emphasizes the probable systemic nature of SNEM and may serve to segregate these patients into two groups. Because of the involvement of the two systems, we suggest that SNEM may have some relation to a variety of other cardioneurologic syndromes.


Functional differentiation and cooperative interaction between two eukaryote-like archaeal Orc1/Cdc6 proteins on the replication origin.
The DNA replication apparatus of archaea represents a core version of that in eukaryotes. Archaeal Orc1/Cdc6s can be an integral component in the replication machineries cooperatively regulating DNA replication. We investigated the DNA-binding activities of two eukaryote-like Orc1/Cdc6 proteins (SsoCdc6-1 and -2) and interactions between them on the different structural duplex DNA substrates derived from oriC1 of Sulfolobus solfataricus. The results showed that two Orc1/Cdc6 proteins stimulated mutual DNA-binding activities at lower concentrations and formed bigger SsoCdc6-1/SsoCdc6-2/DNA complex at higher concentrations. Furthermore, SsoCdc6-2 stimulated the DNA-binding activity of SsoMCM and demonstrated a high affinity to the 5-forked DNA. In contrast, SsoCdc6-1 inhibited the binding of SsoMCM and demonstrated better affinity to the sequence-specific blunt DNA substrate. Finally, we found that the two proteins physically interacted with each other and with SsoMCM. Thus, the two Orc1/Cdc6 proteins were functionally different, but they may keep the coordinated interaction on the replication origin.


Characteristics of the inhibitory effect of chronic treatment with an LHRH agonist on testicular steroidogenesis in the dog.
Daily subcutaneous administration for 3 months of the potent LHRH agonist (D-Ser(TBU)6, des-Gly-NH2(10] LHRH ethylamide (25 micrograms) to adult dogs having spontaneous benign prostate hyperplasia (BPH) causes a marked inhibition of testicular androstenedione and testosterone secretion. This inhibition of delta 4-androgen secretion is accompanied by a decrease of testicular progestin precursors and 5 alpha-androgen metabolites, thus suggesting that, in dog, the loss of testicular steroidogenic activity, induced by the administration of an LHRH agonist, is due to a total inhibition of testicular steroidogenesis. In plasma, the concentration of both testosterone and dihydrotestosterone is also markedly depressed while androstane-3 alpha, 17 beta-diol levels remain unchanged. Measurement of prostatic steroid content has shown that administration of the LHRH agonist as well as castration is associated with a marked decrease in androstenedione, testosterone, and dihydrotestosterone levels in prostate while there is a small inhibition of androst-5-ene-3 beta, 17 beta-diol, androstane-3 beta, 17 beta-diol, dehydroepiandrosterone, and estrone concentrations in this tissue. The present data show that treatment with an LHRH agonist in the dog causes a marked inhibition of testicular steroid secretion similar to the one observed in adult men, and suggest that steroids from adrenal origin may also be involved in prostatic function.


Comparing optimization algorithms for conventional and freeform optical design: erratum.
We want to acknowledge prior research with a very similar focus to our own which we failed to discover before the publication of our paper.


Excess free fructose, apple juice, high fructose corn syrup and childhood asthma risk - the National Children's Study.
Recent research provides consistent evidence that the unexplained doubling of childhood asthma prevalence (1980-1995), its continued climb and 2013 plateau, may be associated with the proliferation of high-fructose-corn-syrup (HFCS) in the US food supply. The HFCS used in soft drinks has been shown to contain a higher fructose-to-glucose ratio than previously thought. This coincides with a preference shift from orange to apple juice among young children. Apple juice naturally contains a high (≥2:1) fructose-to-glucose ratio. Thus, children have received high excess-free-fructose doses, the fructose type associated with fructose malabsorption. Unabsorbed excess-free-fructose in the gut may react with dietary proteins to form immunogens that bind asthma mediating receptors, and/or alter the microbiota towards a profile linked to lung disorders. Studies with longitudinal childhood data are lacking. Therefore, we tested the hypothesis that excess-free-fructose intake is associated with childhood asthma risk. Cox regression models were used to analyze prospective early childhood data (12-30 months of age) from the National Children's Study. Intake frequencies for soda/sports/fruit drinks, and 100% juices were used for analyses. Greater consumption of 100% juice, soda/sports/fruit drinks, and any combination, was associated with ~two (P = 0.001), ~ 2.5 (P = 0.001), and ~ 3.5 times (P < 0.0001) higher asthma incidence. Given these results, prior research and case-study evidence, it is reasonable to suggest that the two-fold higher asthma risk associated with 100% juice consumption is due to apple juice's high fructose-to-glucose ratio, and that the ~ 2.5/~ 3.5 times higher risk associated with soda/sports/fruit drinks intake is with the excess-free-fructose in HFCS.


UF, a WOX gene, regulates a novel phenotype of un-fused flower in tomato.
Flower formation is a basic condition for fruit set in all flowering plants. The normal stamen of tomato flower fused together to form a yellow cylinder surrounding the carpels. In this study, we identified an un-fused flower (uf) tomato mutant that is defective in petal, carpal and stamen fusion and lateral outgrowth. After RNA-seq-based BSA (BSR), the candidate region location was identified in the long arm of chromosome 3. Using map-based cloning with InDel and CAPS markers, the UF candidate gene was mapped in a 104 kb region. In this region, a WOX (WUSCHEL-related homeobox) transcription factor SlWOX1 was considered as a candidate of UF as there is a 72bp deletion in its second exon in uf mutant. The mutations of SlWOX1 generated by CRISPR/CAS9 approach under wild-type background reproduced the phenotypes of uf mutant, indicating that the SlWOX1 gene is indeed UF. Interestingly, expression analysis of organ lateral polarity determinant genes showed that abaxial genes (SlYABBY5 and SlARF4) and adaxial genes (AS and HD-ZIPIII) were significantly down-regulated in the uf mutant, which is different to that in Arabidopsis and petunia. In conclusion, this work revealed a novel function of SlWOX1 in the regulation of flower development in tomato.


Microglia-induced autophagic death of neurons via IL-6/STAT3/miR-30d signaling following hypoxia/ischemia.
There is a relationship between autophagy and the occurrence, maintenance, and progression of several neurodegenerative diseases. The activation of microglia after ischemia contributes to neuronal injury via proinflammatory cytokines and neurotoxic elements. The purpose of this study was to evaluate the function of autophagy in the microglia-mediated death of neuronal cells. Microglial activation by oxygen/glucose deprivation induced both apoptosis and autophagy in neuron-like PC12 cells. Microglia-derived interleukin (IL)-6 induced PC12 cell apoptosis in vitro; however, this effect was inhibited by the autophagy inhibitor chloroquine. Further analysis demonstrated that miR-30d in PC12 cells suppressed microglia-induced PC12 apoptosis and autophagy by directly targeting autophagy protein 5. Moreover, microglia-derived IL-6 activated signal transducer and activator of transcription 3 (STAT3), which can then directly repress miR-30d genes via a conserved STAT3-binding site in its promoter, thereby promoting PC12 cell autophagy and apoptosis. Our study identified IL-6-dependent autophagy-related signaling between microglia and neurons, which contributed to neuronal apoptosis. Importantly, we also provided potential therapeutic targets for ischemic treatment via the interruption of proinflammatory signaling.


Novel homozygous variants in the TMC1 and CDH23 genes cause autosomal recessive nonsyndromic hearing loss.
Hereditary hearing loss (HL) is a heterogeneous and most common sensory neural disorder. At least, 76 genes have been reported in association with autosomal recessive nonsyndromic HL (ARNSHL). Herein, we subjected two patients with bilateral sensorineural HL in two distinct consanguineous Iranian families to figure out the underlying genetic factors. Physical and sensorineural examinations were performed on the patients. Imaging also was applied to unveil any abnormalities in anatomical structures of the middle and inner ear. In order to decipher the possible genetic causes of the verified GJB2-negative samples, the probands were subjected to whole-exome sequencing and, subsequently, Sanger sequencing was applied for variant confirmation. Clinical examinations showed ARNSHL in the patients. After doing whole exome sequencing, two novel variants were identified that were co-segregating with HL that were absent in 100 ethnically matched controls. In the first family, a novel homozygous variant, NM_138691.2: c.530T>C; p.(lle177Thr), in TMC1 gene co-segregated with prelingual ARNSHL. In the second family, NM_022124.6: c.2334G>A; p.(Trp778*) was reported as a nonsense variant causing prelingual ARNSHL. These findings can, in turn, endorse how TMC1 and CDH23 screening is critical to detecting HL in Iranian patients. Identifying TMC1 and CDH23 pathogenic variants doubtlessly help in the detailed genotypic characterization of HL.


Abundance, characteristics, fate, and removal of microplastics during municipal wastewater treatment plant in the west of Iran: the case of Kermanshah city.
The threat of microplastics (MPs) in aquatic systems is almost a new challenge in environmental management. The municipal wastewater treatment plants (WWTPs) act both as collectors of MPs from anthropic use and as a source to natural environments. This study is aimed to determine the abundance, characteristics, and removal of MPs in a municipal WWTP with conventional activated sludge process. Particle size/type, influent loads, and removal rate of MPs in bar screen, grit chamber, primary sedimentation, returned activated sludge, and secondary clarification units of this WWTP were studied by collecting composite samples from wastewater and sludge over a 3-month sampling campaign. Suspected MP particles were counted by light microscopy and characterized using SEM, EDS, FTIR, and TGA-DSC techniques. The mean total MPs, fibers, and fragment concentration after the grit chamber were 6608, 3594, and 3014 which were reduced to 1855, 802, and 1053 particles/L in the effluent, respectively. The sludge retention of total MPs, fibers, and fragments were 8001, 3277, and 4719 particles/L, respectively. The overall efficiency of WWTP with an activated sludge process to remove MPs was 64% and it removed 66.6% and 60% of fibers and fragments, respectively. Fibers were the dominant shape for the collected samples after the grit chamber and fragments were prevalent in the effluent. Polyethylene polymer was detected in most wastewater samples. Existing treatment processes are effective in the removal of MP particles but still act as a potential source to the aquatic ecosystem.


Rapid detection of 1B, 1BL/1RS heterozygotes in the development of homozygous 1BL/1RS translocation stocks of Triticum turgidum (2n = 4x = 28).
A biochemical marker was utilized to facilitate detection of chromosome 1B, 1BL/1RS translocation heterozygote plants in segregating backcross progenies during the development of 1BL/1RS homozygous lines in several Triticum turgidum L. cultivars (2n = 4x = 28; AABB). Isoelectric focussing of glucose phosphate isomerase (GPI) on either pH 3.5-9.5 or 5.5-8.5 polyacrylamide gels facilitated the detection of 1B, 1BL/1RS translocation heterozygotes from the homozygous 1B or 1BL/1RS derivatives during each backcross of the heterozygote to the respective recurrent parent. The biochemical diagnostic procedure complements the more time consuming and cumbersome chromosome banding technique. This GPI diagnostic in durum 1BL/1RS development is also swifter than a similar stocks development in T. aestivum where both GPI and acid PAGE are essential.


A selective and highly sensitive high performance liquid chromatography with fluorescence derivatization approach based on Sonogashira coupling reaction for determination of ethinyl estradiol in river water samples.
A selective and highly sensitive high performance liquid chromatography (HPLC) with fluorescence derivatization method was developed for determination of ethinyl estradiol (EE); one of endocrine-disrupting compounds (EDCs). The fluorescence derivatization procedure was based on Sonogashira coupling reaction using 4-(4, 5-diphenyl-1H-imidazole-2-yl) iodobenzene (DIB-I), a fluorescence labeling reagent, to derivatize EE in presence of copper and palladium ions. The formed fluorescent product was separated on Cosmosil 5C18 MS-II by an isocratic elution with a mobile phase composed of acetonitrile: 5.0 mM Tris-HNO3 buffer, pH 7.4 (60:40, v/v %). The detection wavelengths were set at 310 and 400 nm as excitation and emission wavelengths, respectively. Various parameters affecting derivatization reaction were optimized. Further, the proposed method was validated and a good linearity with low detection limit (S/N=3) 7.4 ng L-1 was obtained in water sample after a simple solid-phase disk extraction (C18 SPE disk) method. The proposed method was successfully applied for detection of EE in river water samples in order to monitor EE concentration and to distinguish its effect on the ecosystem and human health.


Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis.
There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.


An Unexpected Transannular [4+2] Cycloaddition during the Total Synthesis of (+)-Norcembrene 5.
We report a concise and versatile total synthesis of the diterpenoid (+)-norcembrene 5 from simple building blocks. Ring-closing metathesis and an auxiliary-directed 1,4-addition are the key steps of our synthetic route. During the synthesis, an unprecedented, highly oxidized pentacyclic structural motif was established from a furanocembranoid through transannular [4+2] cycloaddition.


Complete genome sequences of three Propionibacterium acnes isolates from the type IA(2) cluster.
Propionibacterium acnes is an anaerobic Gram-positive bacterium that has been linked to a wide range of opportunistic human infections and conditions, most notably acne vulgaris (I. Kurokawa et al., Exp. Dermatol. 18:821-832, 2009). We now present the whole-genome sequences of three P. acnes strains from the type IA(2) cluster which were recovered from ophthalmic infections (A. McDowell et al., Microbiology 157:1990-2003, 2011).


Oxidatively modified proteins in aging and disease.
There is a large body of evidence implicating oxidative damage in the pathogenesis of both normal aging and neurodegenerative diseases. Oxidative damage to proteins has been well established. Although there are a large number of potential oxidative modifications only a few have been systematically studied. The most frequently studied marker of oxidative damage to proteins is protein carbonyl groups. 3-Nitrotyrosine is thought to be a relatively specific marker of oxidative damage mediated by peroxynitrite. Increased concentrations of both protein carbonyls and 3-nitrotyrosine have been documented in both normal aging as well as in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These findings help to provide a rationale for trials of antioxidants in neurodegenerative diseases.


Biocompatibility of poly(lactic acid) with incorporated graphene-based materials.
The incorporation of graphene-based materials has been shown to improve mechanical properties of poly(lactic acid) (PLA). In this work, PLA films and composite PLA films incorporating two graphene-based materials - graphene oxide (GO) and graphene nanoplatelets (GNP) - were prepared and characterized regarding not only biocompatibility, but also surface topography, chemistry and wettability. The presence of both fillers changed the films surface topography, increasing the roughness, and modified the wettability - the polar component of surface free energy increased 59% with GO and decreased 56% with GNP. Mouse embryo fibroblasts incubated with both fillers exceeded the IC(50) in both cases with a concentration of 10 μg mL(-1). No variations in cell proliferation at the surface of the composite films were observed, except for those containing GO after 24 h incubation, which presented higher cell proliferation than pristine PLA films. Platelet adhesion to PLA and PLA/GNP films was lower in the presence of plasma proteins than when no proteins were present. Furthermore, incorporation of GNP into PLA reduced platelet activation in the presence of plasma proteins. The results indicated that low concentrations of GO and GNP may be incorporated safely in PLA to improve aspects relevant for biomedical applications, such as mechanical properties.